Sharing is caring!

Cardiac muscle cells or cardiomyocytes (also known as cardiac myocytes) are the muscle cells (myocytes) that make up the heart muscle. Cardiomyocytes go through a contraction-relaxation cycle that enables cardiac muscles to pump blood throughout the body.

[In this image] Immunostaining of human cardiomyocytes with antibodies for actin (red), myomesin (green), and nuclei (blue).Photo source: https://www.fujifilmcdi.com/products/cardiac-cells/icell-cardiomyocytes

Cardiomyocytes are highly specialized cell types in terms of their structures and functions. Each cardiomyocyte contains myofibrils, unique organelles consisting of long chains of sarcomeres, the fundamental contractile units of muscle cells.

[In this image] Cardiomyocyte geometry and cellular architecture are controlled by micropatterned ECM substrate. Scientists used this technique to study how cells sense and respond to mechanical forces.Photo source: https://diseasebiophysics.seas.harvard.edu/research/mechanotransduction/

The heart is a muscular organ that pumps blood through the blood vessels of the circulatory system. It is composed of individual heart muscle cells (cardiomyocytes) and several other cell types.

[In this figure] The anatomy of the human heart showing 4 heart chambers (left atrium, left ventricle, right atrium, right ventricle) and the blood flow. The myocardium is referred to the cardiac muscle layers building the wall of each chamber.

[In this figure] The thickness of the heart wall (or myocardium) consists of cardiac muscle cells.Photo source: biologydictionary

[In this video] Structure of the human heart.

Cardiovascular disease is a leading cause of death worldwide. Nearly 2,400 Americans die of cardiac causes each day, one death every 37 seconds.

As the chief cell type of the heart, cardiac muscle cells primarily dedicate to the contractile function of the heart and enable the pumping of blood around the body. If anything goes wrong in the heart, it can lead to a catastrophic outcome. A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow ceases to a part of the heart, causing massive cardiomyocyte death in that area. Severe cases can, ultimately, lead to heart failure and death.

[In this figure] The progress of myocardial infarction or heart attack. At time post-infarction:

0-12 hours: Beginning of necrotic coagulation due to the blockage of coronary arteries Cardiomyocytes suffer the lack of oxygen (hypoxia)

12-72 hours: Culmination of necrotic coagulation Neutrophils infiltrate by an inflammatory response.

1-3 weeks: Disintegration of death myocytes and formation of granulation tissue (collagenous fibers, macrophages, and fibroblasts)

> 1 month: Formation of fibrous scar (fewer cells with an abundance of collagenous fibers)

A human heart contains an estimated 23 billion cardiomyocytes. There are several non-myocyte populations in the heart, including endothelial cells, smooth muscle cells, myofibroblasts, epicardial cells, endocardial cells, valve interstitial cells, resident macrophages, and other immune system-related cells, and potentially, adult stem cells (mesenchymal stem cells and cardiac stem cells). These distinct cell pools are not isolated from one another within the heart but interact physically to maintain the function of the whole organ. Overall, cardiomyocytes only account for less than a third of the total cell number in the heart.

[In this image] Immunostaining showing highly vascularized heart muscle.Cardiomyocytes are labeled by the striated pattern of sarcomeric -actinin (green). Capillaries are red and nuclei are blue.Photo source: biocompare.

The three main types of muscle include: Cardiac muscle, Skeletal muscle, and Smooth muscle.

[In this figure] Morphology and comparison of cardiac, skeleton, and smooth muscles.

Note: Involuntary muscles are the muscles that cannot be controlled by will or conscious.

There are two types of cells within the heart: the cardiomyocytes and the cardiac pacemaker cells.

The heart is composed of cardiac muscle cells that have specialized features that relate to their function:

These structural features contribute to the unique functional properties of the cardiac tissue:

Like other animal cells, cardiomyocytes contain all the cell organelles that are essential for normal cell physiology. Moreover, cardiomyocytes have several unique cellular structures that allow them to perform their function effectively. Here are five main characteristics of mature cardiomyocytes: (1) striated; (2) uninucleated; (3) branched; (4) connected by intercalated discs; (5) high mitochondrial content.

[In this figure] Main characteristics of cardiac myocytes.Modified from lumen Anatomy and Physiology I.

Lets get closer to look inside a cardiomyocyte and learn its unique ultrastructure.

All cardiomyocytes and pacemaker cells are linked by cellular bridges. Intercalated discs, which form porous junctions, bring the membranes of adjacent cardiomyocytes very close together. These pores (gap junctions) permit ions, such as sodium, potassium, and calcium, to easily diffuse from cell to cell, establishing a cell-cell communication. This joining is called electric coupling, and it allows the quick transmission of action potentials and the coordinated contraction of the entire heart.

Intercalated discs also function as mechanical anchor points that enable the transmission of contractile force from one cardiomyocyte to another (by desmosomes and adherens junctions). This allows for the heart to work as a single coordinated unit.

[In this figure] Cardiac muscle cells are connected together to coordinate the cardiac contraction. This joining is called electric coupling and is achieved by the presence of irregularly-spaced dark bands between cardiomyocytes. These bands are known as intercalated discs.Photo source: bioninja.

[In this figure] Cardiac myocytes are branched and interconnected from end to end by structures called intercalated disks, visible as dark lines in the light microscope.Photo source: https://doctorlib.info/physiology/medical/49.html

There are 3 main types of junctional complexes within the intercalated discs. They work in different ways to maintain cardiac tissue integrity and cardiomyocyte synchrony.

The term desmosome came from Greek words of bonding (desmo) and body (soma). Desmosomes serve as the anchor points to bring the cardiac muscle fibers together. Desmosomes can withstand mechanical stress, which allows them to hold cells together. Without desmosomes, the cells of the cardiac muscles will fall apart during contraction.

The ability of desmosome to resist mechanical stress comes from its unique 3-D structure. Desmosome is an asymmetrical protein complex bridging between two adjacent cardiomyocytes, with each end residing in the cytoplasm. The intracellular part anchors intermediate filaments in the cytoskeleton to the cell surface. The middle part bridges the intercellular space between two cytoplasmic membranes.

[In this figure] Desmosomes connect intermediate filaments from two adjust cardiomyocytes. This job is accomplished by the formation of a dense protein complex or plaque in the intercalated discs. Major protein players include transmembrane cadherins: desmogleins (Dsgs) and desmocollins (Dscs), cytoplasmic anchors: plakophilins (PKPs) and plakoglobin (PG), and cytoskeleton adaptor: desmoplakin (DP). Cadherins link cells together, and other proteins form a dense complex called plaque.

In addition to desmosomes, adherens junctions (Ajs) are another type of mechanical intercellular junctions in cardiomyocytes. The difference is that adherens junctions link the intercalated disc to the actin cytoskeleton and desmosomes attach to intermediate filaments.

Adherens junctions keep the cardiac muscle cells tightly together as the heart pump. Adherens junctions are also the anchor point where myofibrils are attached, enabling transmission of contractile force from one cell to another.

[In this figure] Adherens junctions link actin cytoskeleton from two adjust cardiomyocytes together.Adherens junctions are constructed from cadherins and catenins. Cadherins (in cardiomyocytes N-Cadherin is the main cadherin) are transmembrane proteins that zip together adjacent cells in a homophilic manner. The transmembrane cadherins form complexes with cytosolic catenins, thereby establishing the connection to the actin cytoskeleton. At the adherens junctions, the opposing membranes become separated by 20nm.

Gap junctions are essential for the chemical and electrical coupling of neighboring cells. Gap junctions work like intercellular channels connecting the cytoplasm of neighboring cells, enabling passive diffusion of various compounds, like metabolites, water, and ions, up to a molecular mass of 1000 Da. Thereby they establish direct communication between adjacent cells.

[In this figure] Neonatal rat cardiac myocytes in cell culture.Cells were immunostained for actinin (green), gap junctions (red), and counterstained with DAPI (blue).Photo source: bioscience

Gap junctions are present in nearly all tissues and cells throughout the entire body. In cardiac muscle, gap junctions ensure proper propagation of the electrical impulse (from pacemaker cells to neighboring cardiomyocytes). This electrical wave triggers sequential and coordinated contraction of the cardiomyocytes as a whole.

[In this figure] A gap junction channel consists of twelve connexin proteins, six of which are contributed by each cell. The six connexin subunits form a hemi-channel in the plasma membrane, which is called a connexon. A connexon docks to another connexon in the intercellular space to create a complete gap junction channel. The intercellular space between adjacent cells at the site of a gap junction is 2-4 nm.

A second feature of cardiomyocytes is the sarcomeres, which are also present in skeletal muscles. The sarcomeres give cardiac muscle their striated appearance and are the repeating sections that make up myofibrils.

[In this image] Freshly isolated heart muscle cells showing intercalated discs (green), sarcomeres (red), and nuclei (blue).Photo source: https://christianz.artstation.com/

Cardiac muscle cells are equipped with bundles of myofibrils that contain myofilaments. These fiber-like structures can occupy 45-60% of the volume of cardiomyocytes. The myofibrils are formed of distinct, repeating units, termed sarcomeres. The sarcomeres, which are composed of thick and thin myofilaments, represent the basic contractile units of a muscle cell and are defined as the region of myofilament structures between two Z-lines (see image below). The distance between Z-lines in human hearts ranges from around 1.6 to 2.2 m.

[In this figure] Labeled diagram of myofibril showing the unit of a sarcomere. A sarcomere is defined as a segment between two neighboring Z-discs.

[In this image] Immunofluorescence image of adult mouse cardiomyocytes showing the Z-lines of the sarcomeres. 3D color projection of alpha-actinin 2 acquired with a confocal microscope.Photo source: Dylan Burnette.

The thick filaments are composed of myosin II. Each myosin contains two ATPase sites on its head. ATPase hydrolyzes ATP and this process is required for actin and myosin cross-bridge formation. These heads bind to actin on the thin filaments. There are about 300 molecules of myosin per thick filament.

The thin filaments are composed of single units of actin known as globular actin (G-actin). Two strands of actin filaments form a helix, which is stabilized by rod-shaped proteins termed tropomyosin. Troponin proteins, which function as regulators, bind to the tropomyosin at regular intervals. Whereas troponin lies in the grooves between the actin filaments, tropomyosin covers the sites on which actin binds to myosin. Their respective actions, therefore, control the binding of myosin to actin and consequently in the contraction and relaxation of cardiac muscles.

To generate muscular contraction, the myosin heads bind to actin filaments, allowing myosin to function as a motor that drives filament sliding. The actin filaments slide past the myosin filaments toward the middle of the sarcomere. This results in the shortening of the sarcomere without any change in filament length.

[In this figure] Sliding-filament model of muscle contraction.

Sarcolemma (also called myolemma) is a specialized cell membrane of cardiomyocytes and skeletal muscle cells. It consists of a lipid bilayer and a thin outer coat of polysaccharide material (glycocalyx) that contacts the basement membrane. The sarcolemma is also part of the intercalated disks as well as the T-tubules of the cardiac muscle.

Basement membrane is an extracellular matrix (ECM) coat that cover individual cardiomyocytes. Its composed of glycoproteins laminin and fibronectin, type IV collagen as well as proteoglycans that contribute to its overall width of about 50nm. Basement membrane provides a scaffold to which the muscle fiber can adhere.

[In this figure] A cross-section of a mouse heart showing the basement membrane (green) wrapping around an individual myocyte.

In cardiomyocytes and skeletal muscle cells, the sarcolemma (i.e. the plasma membrane) forms deep invaginations known as T-tubules (or transverse tubules). These invaginations increase the total surface area and allow depolarization of the membrane to penetrate quickly to the interior of the cell.

Without t-tubules, the wave of calcium ions (Ca2+) takes time to propagate from the periphery of the cell into the center. This time lag will first activate the peripheral sarcomeres and then the deeper sarcomeres, resulting in sub-maximal force production.

The t-tubules make it possible that current is simultaneously relayed to the core of the cell, and trigger near to all sarcomeres simultaneously, resulting in a maximal force output. T-tubules also stay close to sarcoplasmic reticulum (SR) networks, which is the modified endoplasmic reticulum (ER) of calcium storage in myocytes.

[In this figure] T-tubules (transverse tubules) are extensions of the cell membrane that penetrate into the center of skeletal and cardiac muscle cells. T-tubules permit the rapid transmission of the action potential into the cell and also play an important role in regulating cellular calcium concentration.

Mitochondria are the powerhouse of the cell because they generate most of the cells energy supply of adenosine triphosphate (ATP). It is no doubt that the normal functions of cardiomyocytes require a lot of energy. Effective heart pumping is primarily dependent on oxidative energy production by mitochondria. Cardiomyocytes have a densely packed mitochondrial network, which allows them to produce ATP quickly, making them highly resistant to fatigue.

Different types of mitochondria can be distinguished within cardiomyocytes, and their morphological features are usually defined according to their location: intermyofibrillar mitochondria, subsarcolemmal mitochondria, and perinuclear mitochondria.

[In this figure] Mitochondrial morphology in cardiomyocytes.(Top) The anatomy of a mitochondrion. (Bottom left) Schematic diagram of the location of subsarcolemmal mitochondria (SSM), interfibrillar mitochondria (IFM), and perinuclear mitochondria (PNM). (Bottom right) TEM images of mitochondria in cardiomyocytes.Photo source: researchgate, wiki

Intermyofibrilar Mitochondria are found deeper within the cells and strictly ordered between rows of contractile proteins, apparently isolated from each other by repeated arrays. They play a huge role in producing enough energy for muscle contractions.

[In this figure] Immunofluorescent confocal imaging showing the densely packed mitochondria in cardiomyocytes. (A): Z-line (actinin); (B): Mitochondria; (C): Merge image.Photo source: MDPI

Subsarcolemmal Mitochondria reside beneath the sarcolemma. They collect oxygen from the circulating blood in the arteries and are responsible for providing the energy needed for conserving the integrity of the sarcolemma.

Perinuclear mitochondria are organized in clusters around the nucleus to provide energy for transcription and translation processes.

The cardiac function requires high energy demands; therefore, the adult cardiomyocytes contain numerous mitochondria, which can occupy at least 30% of cell volume. They meet >90% of the energy requirements by oxidative phosphorylation (OXPHOS) in the mitochondria, which requires a huge demand for oxygen consumption.

In humans, at a heart rate of 6070 beats per minute, the oxygen consumption of the myocardium is 20-fold higher than that of skeletal muscle at rest (compared by a normalization per gram of cell mass). In order to meet this high oxygen demand, the capillary density in the heart is 2-8 times higher than that in skeletal muscle (3,0004,000/mm2 compared to 5002,000 capillaries/mm2, respectively). Also, cardiomyocytes maintain a very high level of oxygen extraction (from blood) of 7080% compared with 3040% in skeletal muscle.

[In this image] Myofibrils in cultured cardiomyocytes.Photo source: https://christianz.artstation.com/

Cardiomyocytes go through a contraction-relaxation cycle that enables cardiac muscles to pump blood throughout the body. This is achieved through a process known as excitation-contraction coupling (ECC) that converts action potential (an electric stimulus) into muscle contraction.

[In this figure] Schematic diagram of the process of cardiac excitation-contraction coupling.Key steps in the cardiac excitation-contraction coupling:

Step 1: An action potential is induced by pacemaker cells. It travels along the sarcolemma and down into the T-tubule system to depolarize the cell membrane.

Step 2: Calcium channels in the T-tubules are activated by the action potential and permit calcium entry into the cell.

Step 3: Calcium influx triggers a subsequent release of calcium that is stored in the sarcoplasmic reticulum (SR).

Step 4: Free calcium binds troponin-C (TN-C) that is part of the regulatory complex attached to the thin filaments. Calcium binding moves the troponin complex from the actin binding site. As a result, actin is free to bind myosin. The actin and myosin filaments slide past each other thereby shortening the sarcomere length, thus initiating contraction.

Step 5: At the end of a contraction, calcium entry into the cell slows and calcium is sequestered by the SR by calcium pumps. Lowering the cytosolic calcium concentration releases myosin-actin binding and the initial sarcomere length is restored.

In human beings (and many other animals), cardiomyocytes are the first cells to terminally differentiate, thus making the heart one of the first organs to form in a developing fetus. This makes sense because the function of the circulatory system is so crucial for a growing embryo so that the heart is the top priority.

In the embryo of a mouse, for instance, precursor cells of the cardiac muscles have been shown to start developing about 6 days after fertilization. In human embryos, the heart begins to beat at about 22-23 days, with blood flow beginning in the 4th week. The heart is therefore one of the earliest differentiating and functioning organs.

The heart forms initially in the embryonic disc as a simple paired tube (heart tube formation; week 3) derived from mesoderm. Then, the heart tubes loop and begin segmenting to separate chambers primitive atrium, and primitive ventricle. During this period, the first heartbeat begins.

[In this figure] The timeline of heart development.LA means left atrium; RA means right atrium. For more details, seehttps://embryology.med.unsw.edu.au/embryology/index.php/Cardiovascular_System_-_Heart_Development

Here, cardiomyocytes grow into a spongy-like tissue (cardiac jelly), called trabeculation, to build up the thickness of myocardial muscles. Thus, the heart begins to resemble the adult heart in that it has two atria, two ventricles, and the aorta forming a connection with the left ventricle while the pulmonary trunk forms a connection with the right ventricle.

As you can see that our hearts went through a complex developmental process. Inevitably, heart developmental abnormalities could happen (affect 8-10 of every 1000 births in the United States).

Can cardiomyocytes divide? Scientists used to believe that damaged human cardiac muscles cannot regenerate themselves by cell division in adults. In other words, all cardiomyocytes are terminally differentiated. In humans, our cardiomyocytes lose the ability to divide at around 7 days after birth. However, studies have recently shown that myocytes renew at a significantly low rate throughout the life of an individual. For instance, for younger people, about 25 years of age, the annual turnover of cardiomyocytes is about 1 percent. This, however, decreases to about 0.45 percent for older individuals (75 and above). Over the lifespan of an individual, less than 50 percent of these cells are renewed. Comparing to many of the other cells, cardiomyocytes have a very long lifespan. In contrast, small intestine epithelium renews every 2-7 days and hepatocytes (liver cells) renew every 0.5-1 year.

[In this figure] Radiocarbon dating establishes the age of human cardiomyocytes.Scientists used a pretty smart way to estimate the turnover of human heart cells. Generally speaking, the half-life of 14C is too long to date a lifetime of less than a century. However, the dramatic increase in the atmospheric 14C caused by nuclear bomb tests (during the Cool War) in the 1950s and 1960s increased the sensitivity of radiocarbon dating to a temporal resolution of 1-2years.Photo source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5837331/

Low turnover of human cardiomyocytes suggests that the regenerative ability of cardiac muscles may be poor (another example is neural cells in the brain). In the event of injuries or myocardial infarction, the injured heart muscles of human beings do not regenerate sufficiently to allow the heart to heal itself. Instead, fibrotic scar tissue forms in the injured site (fibrosis), and the heart functions are compromised, leading to heart failure.

Currently, a number of methods have been studied to repair a broken heart by regenerating cardiomyocytes. These new inventions benefit from the recent advances in biotechnology, especially stem cell biology, regenerative medicine, and tissue engineering. Hopefully, this can bring new therapeutic options to patients with cardiovascular diseases in the near future.

Studies suggested that even in adults, a very small population of progenitor cells reside in the heart and are capable of producing new cardiac myocytes. These cells, known as cardiac stem cells, may not be able to regenerate fast enough to repair a large area of damaged myocardium naturally in humans. However, these cells have shown to be powerful in regenerative capability in other species, like zebrafish.

Scientists believe that once we understand these cardiac progenitors more, we may isolate and expand these cells in quantity, and transplant them to repair damaged heart tissues. For example, we already learned that these cardiac stem cells express cell surface markers like c-Kit (sca-1 in mouse) and aggregate into cardiac spheres.

[In this figure] Multiple different stem cell populations have been described in the adult heart, including c-Kit and Sca-1 cells that were shown to be cardiac progenitors.Photo source: https://dev.biologists.org/content/143/8/1242

Induced pluripotent stem cell (iPSC) technology is a huge revolution in biotechnology. Patients cells (easily obtained from skin biopsy or even urine) can be converted into powerful pluripotent stem cells that have unlimited proliferation capacity and can differentiate any cell type of our body. This eliminates the need to use human embryos for this purpose. Furthermore, these cells are autologous, meaning they wont be rejected by the immune system after transplantation.

Using iPSC technology, researchers have been able to obtain unlimited amounts of functional cardiomyocytes for cell transplantation. Basically, they control the Wnt pathway to convert iPSCs to mesodermal progenitor cells, then play with several growth factors to direct the cardiac vascular progenitors (Flk1+). Following glucose starvation, pure cardiomyocytes can be selected. You can even see these cells beating in the dish.

Therapeutic implantation of iPSC-derived cardiomyocytes progresses pretty fast. We already witnessed successful cell engraftment and cardiac repairing in non-human primates and human patients.

[In this video] Heart cells derived from iPSC stem cells beating in a cell culture dish.

Cardiac fibroblasts make up a significant portion of the total cardiac cells. In the injured heart, these fibroblasts will become active myofibroblasts and form scar tissue. Myofibroblasts survive very well and have ability to coupled with neighboring cells; therefore, myofibroblasts have been shown to be particularly ideal for direct reprogramming to convert them into cells that resemble cardiomyocytes.

Over the past decade, a number of studies have been successfully conducted, reprogramming fibroblasts into cardiomyocyte-like cells. In principle, scientists expressed transcription factors (i.e., Gata4, Mef2c, and Tbx5) that play critical roles in cardiomyocyte differentiation to force the conversion of fibroblasts. Ideally, these genes can be delivered directly to the injured heart via viruses or nanoparticles to perform in situ reprogramming.

Scientists also put their efforts into how to stimulate mature cardiomyocytes to proliferate again (Mature cardiomyocytes typically do not proliferate.) This strategy, called cell cycle re-entry, recently gained success by screening many cell-cycle regulators. Scientists found a combination of cyclin-dependent kinases (CDK) and cyclins, or regulators of the Hippo-YAP signaling pathway can do so. These findings reveal the possibility to efficiently unlock the proliferative potential in cells that had terminally exited the cell cycle.

[In this figure] Potential cardiac regenerative therapies.Photo source: https://www.nature.com/articles/s41536-017-0024-1

Cardiomyocytes can be observed by staining of histological sections of the heart. Since the heart is a 3-D organ, make sure you cut the heart at the right angle.

[In this figure] (Left) A longitudinal section through both ventricles should be made from the base to the apex of the heart. (Right) A cross-section of the heart. H&E staining.(Ao: aorta, At: atrium, Lv: left ventricle, Rv: right ventricle)

Common histological staining for heart tissues includes Hematoxylin and eosin (H&E) and Massons trichrome staining.

[In this figure] A cross section of mouse heart stained by Massons trichrome. Blue color indicates the formation of fibrous scar tissues in the infarction area.

Read more from the original source:
Cardiomyocytes (Cardiac Muscle Cells) - Structure ...

Cardiac Stem Cells Comments Off on Cardiomyocytes (Cardiac Muscle Cells) – Structure … | January 3rd, 2022

The International Space Station is the world's most extreme and expensive scientific laboratory. In its more than 20 years of operations it has housed thousands of experiments, providing fascinating insights into the effects of microgravity on the human body, cultured cells or various materials and chemical processes. Here are the most interesting findings that the space station delivered in 2021.

Stem cells are sometimes seen as the holy grail of future medicine. Capable of almost endlessly regenerating and turning themselves into all sorts of cells, stem cells are abundant in young bodies but lose their vigor as we age. There are various types of stem cells. Those found in embryos, also called the pluripotent stem cells, can give rise to all kinds of cells in the human body. But stem cells exist in adult bodies too, ensuring the ability of various organs to repair themselves.

A recent experiment flown on the International Space Station found that in the weightless environment, stem cells from the human heart improved their ability to regenerate, survive and proliferate.

The effects were observed in both adult and neonatal stem cells. The discovery, part of NASA's Cardiac Stem Cells research project, is good news for the future of regenerative medicine as it shows that it is possible to kick adult heart stem cells into better action. That is to increase their 'stemness', their ability to regenerate, proliferate and create new types of cells that a damaged organ might need. Regenerative medicine hopes to one day be able to engineer tissue to repair and replace failing organs and cells. The study was published in the International Journal of Molecular Sciences.

Related: What does space do to the human body? 29 studies investigate the effects of exploration

Microgravity is bad news for bones. The lack of mechanical loading tells the body to stop maintaining these important support structures since they don't seem to be needed. When astronauts return to Earth, they suffer from serious bone loss.

The good news is, that just like on Earth, exercising in space seems to keep the body fit, including the bones. A new study published in the British Journal of Sports Medicine revealed that crew members who increased their resistance training during their space missions were more likely to preserve their bone strength.

The study, part of NASA's Biochem Profile and the Canadian Space Agency's TBone investigations, also found that bone loss in some astronauts could be predicted by the elevation of certain biomarkers before their flight. These biomarkers, found in the astronauts' blood and urine, together with the astronauts' exercise history could help space surgeons identify astronauts at greater risk for bone loss.

Microbes can efficiently extract valuable metals from lunar and martian rocks in space, a recent experiment by the European Space Agency (ESA) revealed. The experiment, called Biorock, used microorganisms to extract the metal element vanadium from basalt, which can be commonly found on the moon and Mars.

The microbes extracted 283% more vanadium while on the space station than on Earth. Biomining is a cheaper and more environmentally friendly alternative to chemical extraction of important materials from ores, a process that usually relies on harsh chemicals and requires a lot of energy. Using biomining in space will surely come handy to future Mars and moon colonists as they will be able to get raw materials for making tools, spacecraft parts and other equipment.

A European instrument called the Atmosphere-Space Interactions Monitor (ASIM) has provided new insights into the genesis of some little understood phenomena in Earth's atmosphere. Used to study severe thunderstorms and their atmospheric effects, ASIM previously helped shed light on the generation of high-energy terrestrial gamma-ray flashes (TGFs), the most energetic natural phenomena on Earth that accompany lightings during thunderstorms.

But more recently, the instrument studied the so-called blue jets, which are essentially upward shooting bursts of lighting generated by disturbances of positively and negatively charged regions in the tops of the clouds. Blue jets, which get their characteristic blue color from nitrogen ions, can shoot up to altitudes of 30 miles (50 kilometers) in less than a second.

Scientists found that the blue jets are generated by "blue bangs," short discharges in the upper layers of storm clouds. The mechanism behind these blue jets appears to be somewhat different from that behind normal lightning that we can observe on the ground.

Astronauts on the International Space Station experimented with making cement in space and found that although it creates somewhat different microstructures than on Earth, it works. The experiment, called Microgravity Investigation of Cement Solidification (MICS), involved mixing cement powders with various additives and different amounts of water.

In the latest round of experiments, a mixture of tricalcium aluminate and gypsum showed interesting results.

In the future, these "made in space" cement blends could be used to build stations on Mars or the moon. Cement is used to make concrete, which has excellent shielding properties against cosmic radiation. It is also strong enough to protect against impacting meteorites.

And to make things easy, future Mars and moon colonists could actually 3D-print structures from concrete made from lunar and martian soils in a 3D printer similar to the Additive Manufacturing Facility that is currently on the space station.

New space station research has shown that the technology used to shield astronauts from dangerous space radiation can be made even more efficient in the future using a mineral called colemanite. This boron-rich mineral is a type of borax that forms as a deposit during evaporation of alkaline water.

An experiment by the Japan Aerospace Exploration Agency (JAXA) exposed several pieces of a polymer material to space conditions outside the International Space Station. The polymer sample treated with colemanite suffered almost no radiation damage and looked nearly indistinguishable from a sample that was not exposed to space. The researchers published their results in the Journal of Applied Polymer Science in July.

In the future, colemanite could be used to treat satellites, space station exteriors or even high altitude planes, NASA said in a statement.

Astronauts and cosmonauts in space frequently suffer from changes to the structure of their veins, especially in their legs. A study by the Russian space agency Roscosmos, however, found that these changes can be somewhat prevented by exercise and can be reversed post-flight if the space travellers have enough time off between missions.

The veins of the 11 cosmonauts that participated in this study, published in the journal Experimental and Theoretical Research, didn't show worse damage after the second flight compared to the first. The spacefarers had breaks of about 4 years between their missions.

Follow Tereza Pultarova on Twitter @TerezaPultarova. Follow us on Twitter @Spacedotcom and on Facebook.

Original post:
Here's 7 things the International Space Station taught us in 2021 - Space.com

Cardiac Stem Cells Comments Off on Here’s 7 things the International Space Station taught us in 2021 – Space.com | January 3rd, 2022

Introduction

Given the multi-lineage differentiation abilities of mesenchymal stem cells (MSCs) isolated from different tissues and organs, MSCs have been widely used in various medical fields, particularly regenerative medicine.13 The representative sources of MSCs are bone marrow, adipose, periodontal, muscle, and umbilical cord blood.410 Interestingly, slight differences have been reported in the characteristics of MSCs depending on the different sources, including their population in source tissues, immunosuppressive activities, proliferation, and resistance to cellular aging.11 Bone marrow-derived MSCs (BM-MSCs) are the most intensively studied and show clinically promising results for cartilage and bone regeneration.11 However, the isolation procedures for BM-MSCs are complicated because bone marrow contains a relatively small fraction of MSCs (0.0010.01% of the cells in bone marrow).12 Furthermore, bone marrow aspiration to harvest MSCs in human bones is a painful procedure and the slower proliferation rate of BM-MSCs is a clinical limitation.13 In comparison with BM-MSCs, adipose-derived MSCs (AD-MSCs) are relatively easy to collect and can produce up to 500 times the cell population of BM-MSCs.14 AD-MSCs showed a greater ability to regenerate damaged cartilage and bone tissues with increased immunosuppressive ability.14,15 Umbilical cord blood-derived MSCs (UC-MSCs) proliferate faster than BM-MSCs and are resistant to significant cellular aging.11

MSCs have been investigated and gained worldwide attention as potential therapeutic candidates for incurable diseases such as arthritis, spinal cord injury, and cardiac disease.3,1623 In particular, the inherent tropism of MSCs to inflammatory sites has been thoroughly studied.24 This inherent tropism, also known as homing ability, originates from the recognition of various chemokine sources in inflamed tissues, where profiled chemokines are continuously secreted and the MSCs migrate to the chemokines in a concentration-dependent manner.24 Rheumatoid arthritis (RA) is a representative inflammatory disease that primarily causes inflammation in the joints, and this long-term autoimmune disorder causes worsening pain and stiffness following rest. RA affects approximately 24.5 million people as of 2015, but only symptomatic treatments such as pain medications, steroids, and nonsteroidal anti-inflammatory drugs (NSAIDs), or slow-acting drugs that inhibit the rapid progression of RA, such as disease-modifying antirheumatic drugs (DMARDs) are currently available. However, RA drugs have adverse side effects, including hepatitis, osteoporosis, skeletal fracture, steroid-induced arthroplasty, Cushings syndrome, gastrointestinal (GI) intolerance, and bleeding.2527 Thus, MSCs are rapidly emerging as the next generation of arthritis treatment because they not only recognize and migrate toward chemokines secreted in the inflamed joints but also regulate inflammatory progress and repair damaged cells.28

However, MSCs are associated with many challenges that need to be overcome before they can be used in clinical settings.2931 One of the main challenges is the selective accumulation of systemically administered MSCs in the lungs and liver when they are administered intravenously, leading to insufficient concentrations of MSCs in the target tissues.32,33 In addition, most of the administered MSCs are typically initially captured by macrophages in the lungs, liver, and spleen.3234 Importantly, the viability and migration ability of MSCs injected in vivo differed from results previously reported as favorable therapeutic effects and migration efficiency in vitro.35

To improve the delivery of MSCs, researchers have focused on chemokines, which are responsible for MSCs ability to move.36 The chemokine receptors are the key proteins on MSCs that recognize chemokines, and genetic engineering of MSCs to overexpress the chemokine receptor can improve the homing ability, thus enhancing their therapeutic efficacy.37 Genetic engineering is a convenient tool for modifying native or non-native genes, and several technologies for genetic engineering exist, including genome editing, gene knockdown, and replacement with various vectors.38,39 However, safety issues that prevent clinical use persist, for example, genome integration, off-target effects, and induction of immune response.40 In this regard, MSC mimicking nanoencapsulations can be an alternative strategy for maintaining the homing ability of MSCs and overcoming the current safety issues.4143 Nanoencapsulation involves entrapping the core nanoparticles of solids or liquids within nanometer-sized capsules of secondary materials.44

MSC mimicking nanoencapsulation uses the MSC membrane fraction as the capsule and targeting molecules, that is chemokine receptors, with several types of nanoparticles, as the core.45,46 MSC mimicking nanoencapsulation consists of MSC membrane-coated nanoparticles, MSC-derived artificial ectosomes, and MSC membrane-fused liposomes. Nano drug delivery is an emerging field that has attracted significant interest due to its unique characteristics and paved the way for several unique applications that might solve many problems in medicine. In particular, the nanoscale size of nanoparticles (NPs) enhances cellular uptake and can optimize intracellular pathways due to their intrinsic physicochemical properties, and can therefore increase drug delivery to target tissues.47,48 However, the inherent targeting ability resulting from the physicochemical properties of NPs is not enough to target specific tissues or damaged tissues, and additional studies on additional ligands that can bind to surface receptors on target cells or tissues have been performed to improve the targeting ability of NPs.49 Likewise, nanoencapsulation with cell membranes with targeting molecules and encapsulation of the core NPs with cell membranes confer the targeting ability of the source cell to the NPs.50,51 Thus, MSC mimicking nanoencapsulation can mimic the superior targeting ability of MSCs and confer the advantages of each core NP. In addition, MSC mimicking nanoencapsulations have improved circulation time and camouflaging from phagocytes.52

This review discusses the mechanism of MSC migration to inflammatory sites, addresses the potential strategy for improving the tropism of MSCs using genetic engineering, and discusses the promising therapeutic agent, MSC mimicking nanoencapsulations.

The MSC migration mechanism can be exploited for diverse clinical applications.53 The MSC migration mechanism can be divided into five stages: rolling by selectin, activation of MSCs by chemokines, stopping cell rolling by integrin, transcellular migration, and migration to the damaged site (Figure 1).54,55 Chemokines are secreted naturally by various cells such as tumor cells, stromal cells, and inflammatory cells, maintaining high chemokine concentrations in target cells at the target tissue and inducing signal cascades.5658 Likewise, MSCs express a variety of chemokine receptors, allowing them to migrate and be used as new targeting vectors.5961 MSC migration accelerates depending on the concentration of chemokines, which are the most important factors in the stem cell homing mechanism.62,63 Chemokines consist of various cytokine subfamilies that are closely associated with the migration of immune cells. Chemokines are divided into four classes based on the locations of the two cysteine (C) residues: CC-chemokines, CXC-chemokine, C-chemokine, and CX3 Chemokine.64,65 Each chemokine binds to various MSC receptors and the binding induces a chemokine signaling cascade (Table 1).56,66

Table 1 Chemokine and Chemokine Receptors for Different Chemokine Families

Figure 1 Representation of stem cell homing mechanism.

The mechanisms underlying MSC and leukocyte migration are similar in terms of their migratory dynamics.55 P-selectin glycoprotein ligand-1 (PSGL-1) and E-selectin ligand-1 (ESL-1) are major proteins involved in leukocyte migration that interact with P-selectin and E-selectin present in vascular endothelial cells. However, these promoters are not present in MSCs (Figure 2).53,67

Figure 2 Differences in adhesion protein molecules between leukocytes and mesenchymal stem cells during rolling stages and rolling arrest stage of MSC. (A) The rolling stage of leukocytes starts with adhesion to endothelium with ESL-1 and PSGL-1 on leukocytes. (B) The rolling stage of MSC starts with the adhesion to endothelium with Galectin-1 and CD24 on MSC, and the rolling arrest stage was caused by chemokines that were encountered in the rolling stage and VLA-4 with a high affinity for VACM present in endothelial cells.

Abbreviations: ESL-1, E-selectin ligand-1; PSGL-1, P-selectin glycoprotein ligand-1 VLA-4, very late antigen-4; VCAM, vascular cell adhesion molecule-1.

The initial rolling is facilitated by selectins expressed on the surface of endothelial cells. Various glycoproteins on the surface of MSCs can bind to the selectins and continue the rolling process.68 However, the mechanism of binding of the glycoprotein on MSCs to the selectins is still unclear.69,70 P-selectins and E-selectins, major cell-cell adhesion molecules expressed by endothelial cells, adhere to migrated cells adjacent to endothelial cells and can trigger the rolling process.71 For leukocyte migration, P-selectin glycoprotein ligand-1 (PSGL-1) and E-selectin ligand-1 (ESL-1) expressed on the membranes of leukocytes interact with P-selectins and E-selectins on the endothelial cells, initiating the process.72,73 As already mentioned, MSCs express neither PSGL-1 nor ESL-1. Instead, they express galectin-1 and CD24 on their surfaces, and these bind to E-selectin or P-selectin (Figure 2).7476

In the migratory activation step, MSC receptors are activated in response to inflammatory cytokines, including CXCL12, CXCL8, CXCL4, CCL2, and CCL7.77 The corresponding activation of chemokine receptors of MSCs in response to inflammatory cytokines results in an accumulation of MSCs.58,78 For example, inflamed tissues release inflammatory cytokines,79 and specifically, fibroblasts release CXCL12, which further induces the accumulation of MSCs through ligandreceptor interaction after exposure to hypoxia and cytokine-rich environments in the rat model of inflammation.7982 Previous studies have reported that overexpressing CXCR4, which is a receptor to recognize CXCL12, in MSCs improves the homing ability of MSCs toward inflamed sites.83,84 In short, cytokines are significantly involved in the homing mechanism of MSCs.53

The rolling arrest stage is facilitated by integrin 41 (VLA-4) on MSC.85 VLA-4 is expressed by MSCs which are first activated by CXCL-12 and TNF- chemokines, and activated VLA-4 binds to VCAM-1 expressed on endothelial cells to stop the rotational movement (Figure 2).86,87

Karp et al categorized the migration of MSCs as either systemic homing or non-systemic homing. Systemic homing refers to the process of migration through blood vessels and then across the vascular endothelium near the inflamed site.67,88 The process of migration after passing through the vessels or local injection is called non-systemic homing. In non-systemic migration, stem cells migrate through a chemokine concentration gradient (Figure 3).89 MSCs secrete matrix metalloproteinases (MMPs) during migration. The mechanism underlying MSC migration is currently undefined but MSC migration can be advanced by remodeling the matrix through the secretion of various enzymes.9093 The migration of MSCs to the damaged area is induced by chemokines released from the injured site, such as IL-8, TNF-, insulin-like growth factor (IGF-1), and platelet-derived growth factors (PDGF).9496 MSCs migrate toward the damaged area following a chemokine concentration gradient.87

Figure 3 Differences between systemic and non-systemic homing mechanisms. Both systemic and non-systemic homing to the extracellular matrix and stem cells to their destination, MSCs secrete MMPs and remodel the extracellular matrix.

Abbreviation: MMP, matrix metalloproteinase.

RA is a chronic inflammatory autoimmune disease characterized by distinct painful stiff joints and movement disorders.97 RA affects approximately 1% of the worlds population.98 RA is primarily induced by macrophages, which are involved in the innate immune response and are also involved in adaptive immune responses, together with B cells and T cells.99 Inflammatory diseases are caused by high levels of inflammatory cytokines and a hypoxic low-pH environment in the joints.100,101 Fibroblast-like synoviocytes (FLSs) and accumulated macrophages and neutrophils in the synovium of inflamed joints also express various chemokines.102,103 Chemokines from inflammatory reactions can induce migration of white blood cells and stem cells, which are involved in angiogenesis around joints.101,104,105 More than 50 chemokines are present in the rheumatoid synovial membrane (Table 2). Of the chemokines in the synovium, CXCL12, MIP1-a, CXCL8, and PDGF are the main ones that attract MSCs.106 In the RA environment, CXCL12, a ligand for CXCR4 on MSCs, had 10.71 times higher levels of chemokines than in the normal synovial cell environment. MIP-1a, a chemokine that gathers inflammatory cells, is a ligand for CCR1, which is normally expressed on MSC.107,108 CXCL8 is a ligand for CXCR1 and CXCR2 on MSCs and induces the migration of neutrophils and macrophages, leading to ROS in synovial cells.59 PDGF is a regulatory peptide that is upregulated in the synovial tissue of RA patients.109 PDGF induces greater MSC migration than CXCL12.110 Importantly, stem cells not only have the homing ability to inflamed joints but also have potential as cell therapy with the anti-apoptotic, anti-catabolic, and anti-fibrotic effect of MSC.111 In preclinical trials, MSC treatment has been extensively investigated in collagen-induced arthritis (CIA), a common autoimmune animal model used to study RA. In the RA model, MSCs downregulated inflammatory cytokines such as IFN-, TNF-, IL-4, IL-12, and IL1, and antibodies against collagen, while anti-inflammatory cytokines, such as tumor necrosis factor-inducible gene 6 protein (TSG-6), prostaglandin E2 (PGE2), transforming growth factor-beta (TGF-), IL-10, and IL-6, were upregulated.112116

Table 2 Rheumatoid Arthritis (RA) Chemokines Present in the Pathological Environment and Chemokine Receptors Present in Mesenchymal Stem Cells

Genetic engineering can improve the therapeutic potential of MSCs, including long-term survival, angiogenesis, differentiation into specific lineages, anti- and pro-inflammatory activity, and migratory properties (Figure 4).117,118 Although MSCs already have an intrinsic homing ability, the targeting ability of MSCs and their derivatives, such as membrane vesicles, which are utilized to produce MSC mimicking nanoencapsulation, can be enhanced.118 The therapeutic potential of MSCs can be magnified by reprogramming MSCs via upregulation or downregulation of their native genes, resulting in controlled production of the target protein, or by introducing foreign genes that enable MSCs to express native or non-native products, for example, non-native soluble tumor necrosis factor (TNF) receptor 2 can inhibit TNF-alpha signaling in RA therapies.28

Figure 4 Genetic engineering of mesenchymal stem cells to enhance therapeutic efficacy.

Abbreviations: Sfrp2, secreted frizzled-related protein 2; IGF1, insulin-like growth factor 1; IL-2, interleukin-2; IL-12, interleukin-12; IFN-, interferon-beta; CX3CL1, C-X3-C motif chemokine ligand 1; VEGF, vascular endothelial growth factor; HGF, human growth factor; FGF, fibroblast growth factor; IL-10, interleukin-10; IL-4, interleukin-4; IL18BP, interleukin-18-binding protein; IFN-, interferon-alpha; SDF1, stromal cell-derived factor 1; CXCR4, C-X-C motif chemokine receptor 4; CCR1, C-C motif chemokine receptor 1; BMP2, bone morphogenetic protein 2; mHCN2, mouse hyperpolarization-activated cyclic nucleotide-gated.

MSCs can be genetically engineered using different techniques, including by introducing particular genes into the nucleus of MSCs or editing the genome of MSCs (Figure 5).119 Foreign genes can be transferred into MSCs using liposomes (chemical method), electroporation (physical method), or viral delivery (biological method). Cationic liposomes, also known as lipoplexes, can stably compact negatively charged nucleic acids, leading to the formation of nanomeric vesicular structure.120 Cationic liposomes are commonly produced with a combination of a cationic lipid such as DOTAP, DOTMA, DOGS, DOSPA, and neutral lipids, such as DOPE and cholesterol.121 These liposomes are stable enough to protect their bound nucleic acids from degradation and are competent to enter cells via endocytosis.120 Electroporation briefly creates holes in the cell membrane using an electric field of 1020 kV/cm, and the holes are then rapidly closed by the cells membrane repair mechanism.122 Even though the electric shock induces irreversible cell damage and non-specific transport into the cytoplasm leads to cell death, electroporation ensures successful gene delivery regardless of the target cell or organism. Viral vectors, which are derived from adenovirus, adeno-associated virus (AAV), or lentivirus (LV), have been used to introduce specific genes into MSCs. Recombinant lentiviral vectors are the most widely used systems due to their high tropism to dividing and non-dividing cells, transduction efficiency, and stable expression of transgenes in MSCs, but the random genome integration of transgenes can be an obstacle in clinical applications.123 Adenovirus and AAV systems are appropriate alternative strategies because currently available strains do not have broad genome integration and a strong immune response, unlike LV, thus increasing success and safety in clinical trials.124 As a representative, the Oxford-AstraZeneca COVID-19 vaccine, which has been authorized in 71 countries as a vaccine for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which spread globally and led to the current pandemic, transfers the spike protein gene using an adenovirus-based viral vector.125 Furthermore, there are two AAV-based gene therapies: Luxturna for rare inherited retinal dystrophy and Zolgensma for spinal muscular atrophy.126

Figure 5 Genetic engineering techniques used in the production of bioengineered mesenchymal stem cells.

Clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 were recently used for genome editing and modification because of their simpler design and higher efficiency for genome editing, however, there are safety issues such as off-target effects that induce mutations at sites other than the intended target site.127 The foreign gene is then commonly transferred into non-integrating forms such as plasmid DNA and messenger RNA (mRNA).128

The gene expression machinery can also be manipulated at the cytoplasmic level through RNA interference (RNAi) technology, inhibition of gene expression, or translation using neutralizing targeted mRNA molecules with sequence-specific small RNA molecules such as small interfering RNA (siRNA) or microRNA (miRNA).129 These small RNAs can form enzyme complexes that degrade mRNA molecules and thus decrease their activity by inhibiting translation. Moreover, the pre-transcriptional silencing mechanism of RNAi can induce DNA methylation at genomic positions complementary to siRNA or miRNA with enzyme complexes.

CXC chemokine receptor 4 (CXCR4) is one of the most potent chemokine receptors that is genetically engineered to enhance the migratory properties of MSCs.130 CXCR4 is a chemokine receptor specific for stromal-derived factor-1 (SDF-1), also known as CXC motif chemokine 12 (CXCL12), which is produced by damaged tissues, such as the area of inflammatory bone destruction.131 Several studies on engineering MSCs to increase the expression of the CXCR4 gene have reported a higher density of the CXCR4 receptor on their outer cell membrane and effectively increased the migration of MSCs toward SDF-1.83,132,133 CXC chemokine receptor 7 (CXCR7) also had a high affinity for SDF-1, thus the SDF-1/CXCR7 signaling axis was used to engineer the MSCs.134 CXCR7-overexpressing MSCs in a cerebral ischemia-reperfusion rat hippocampus model promoted migration based on an SDF-1 gradient, cooperating with the SDF-1/CXCR4 signaling axis (Figure 6).37

Figure 6 Engineered mesenchymal stem cells with enhanced migratory abilities.

Abbreviations: CXCR4, C-X-C motif chemokine receptor 4; CXCR7, C-X-C motif chemokine receptor 7; SDF1, stromal cell-derived factor 1; CXCR1, C-X-C motif chemokine receptor 1; IL-8, interleukin-8; Aqp1, aquaporin 1; FAK, focal adhesion kinase.

CXC chemokine receptor 1 (CXCR1) enhances MSC migratory properties.59 CXCR1 is a receptor for IL-8, which is the primary cytokine involved in the recruitment of neutrophils to the site of damage or infection.135 In particular, the IL-8/CXCR1 axis is a key factor for the migration of MSCs toward human glioma cell lines, such as U-87 MG, LN18, U138, and U251, and CXCR1-overexpressing MSCs showed a superior capacity to migrate toward glioma cells and tumors in mice bearing intracranial human gliomas.136

The migratory properties of MSCs were also controlled via aquaporin-1 (Aqp1), which is a water channel molecule that transports water across the cell membrane and regulates endothelial cell migration.137 Aqp1-overexpressing MSCs showed enhanced migration to fracture gap of a rat fracture model with upregulated focal adhesion kinase (FAK) and -catenin, which are important regulators of cell migration.138

Nur77, also known as nerve growth factor IB or NR4A1, and nuclear receptor-related 1 (Nurr1), can play a role in improving the migratory capabilities of MSCs.139,140 The migrating MSCs expressed higher levels of Nur77 and Nurr1 than the non-migrating MSCs, and overexpression of these two nuclear receptors functioning as transcription factors enhanced the migration of MSCs toward SDF-1. The migration of cells is closely related to the cell cycle, and normally, cells in the late S or G2/M phase do not migrate.141 The overexpression of Nur77 and Nurr1 increased the proportion of MSCs in the G0/G1-phase similar to the results of migrating MSCs had more cells in the G1-phase.

MSC mimicking nanoencapsulations are nanoparticles combined with MSC membrane vesicles and these NPs have the greatest advantages as drug delivery systems due to the sustained homing ability of MSCs as well as the advantages of NPs. Particles sized 10150 nm have great advantages in drug delivery systems because they can pass more freely through the cell membrane by the interaction with biomolecules, such as clathrin and caveolin, to facilitate uptake across the cell membrane compared with micron-sized materials.142,143 Various materials have been used to formulate NPs, including silica, polymers, metals, and lipids.144,145 NPs have an inherent ability, called passive targeting, to accumulate at specific sites based on their physicochemical properties such as size, surface charge, surface hydrophilicity, and geometry.146148 However, physicochemical properties are not enough to target specific tissues or damaged tissues, and thus active targeting is a clinically approved strategy involving the addition of ligands that can bind to surface receptors on target cells or tissues.149,150 MSC mimicking nanoencapsulation uses natural or genetically engineered MSC membranes to coat synthetic NPs, producing artificial ectosomes and fusing them with liposomes to increase their targeting ability (Figure 7).151 Especially, MSCs have been studied for targeting inflammation and regenerative drugs, and the mechanism and efficacy of migration toward inflamed tissues have been actively investigated.152 MSC mimicking nanoencapsulation can mimic the well-known migration ability of MSCs and can be equally utilized without safety issues from the direct application of using MSCs. Furthermore, cell membrane encapsulations have a wide range of functions, including prolonged blood circulation time and increased active targeting efficacy from the source cells.153,154 MSC mimicking encapsulations enter recipient cells using multiple pathways.155 MSC mimicking encapsulations can fuse directly with the plasma membrane and can also be taken up through phagocytosis, micropinocytosis, and endocytosis mediated by caveolin or clathrin.156 MSC mimicking encapsulations can be internalized in a highly cell type-specific manner that depends on the recognition of membrane surface molecules by the cell or tissue.157 For example, endothelial colony-forming cell (ECFC)-derived exosomes were shown CXCR4/SDF-1 interaction and enhanced delivery toward the ischemic kidney, and Tspan8-alpha4 complex on lymph node stroma derived extracellular vesicles induced selective uptake by endothelial cells or pancreatic cells with CD54, serving as a major ligand.158,159 Therefore, different source cells may contain protein signals that serve as ligands for other cells, and these receptorligand interactions maximized targeted delivery of NPs.160 This natural mechanism inspired the application of MSC membranes to confer active targeting to NPs.

Figure 7 Mesenchymal stem cell mimicking nanoencapsulation.

Cell membrane-coated NPs (CMCNPs) are biomimetic strategies developed to mimic the properties of cell membranes derived from natural cells such as erythrocytes, white blood cells, cancer cells, stem cells, platelets, or bacterial cells with an NP core.161 Core NPs made of polymer, silica, and metal have been evaluated in attempts to overcome the limitations of conventional drug delivery systems but there are also issues of toxicity and reduced biocompatibility associated with the surface properties of NPs.162,163 Therefore, only a small number of NPs have been approved for medical application by the FDA.164 Coating with cell membrane can enhance the biocompatibility of NPs by improving immune evasion, enhancing circulation time, reducing RES clearance, preventing serum protein adsorption by mimicking cell glycocalyx, which are chemical determinants of self at the surfaces of cells.151,165 Furthermore, the migratory properties of MSCs can also be transferred to NPs by coating them with the cell membrane.45 Coating NPs with MSC membranes not only enhances biocompatibility but also maximizes the therapeutic effect of NPs by mimicking the targeting ability of MSCs.166 Cell membrane-coated NPs are prepared in three steps: extraction of cell membrane vesicles from the source cells, synthesis of the core NPs, and fusion of the membrane vesicles and core NPs to produce cell membrane-coated NPs (Figure 8).167 Cell membrane vesicles, including extracellular vesicles (EVs), can be harvested through cell lysis, mechanical disruption, and centrifugation to isolate, purify the cell membrane vesicles, and remove intracellular components.168 All the processes must be conducted under cold conditions, with protease inhibitors to minimize the denaturation of integral membrane proteins. Cell lysis, which is classically performed using mechanical lysis, including homogenization, sonication, or extrusion followed by differential velocity centrifugation, is necessary to remove intracellular components. Cytochalasin B (CB), a drug that affects cytoskeletonmembrane interactions, induces secretion of membrane vesicles from source cells and has been used to extract the cell membrane.169 The membrane functions of the source cells are preserved in CB-induced vesicles, forming biologically active surface receptors and ion pumps.170 Furthermore, CB-induced vesicles can encapsulate drugs and NPs successfully, and the vesicles can be harvested by centrifugation without a purification step to remove nuclei and cytoplasm.171 Clinically translatable membrane vesicles require scalable production of high volumes of homogeneous vesicles within a short period. Although mechanical methods (eg, shear stress, ultrasonication, or extrusion) are utilized, CB-induced vesicles have shown potential for generating membrane encapsulation for nano-vectors.168 The advantages of CB-induced vesicles versus other methods are compared in Table 3.

Table 3 Comparison of Membrane Vesicle Production Methods

Figure 8 MSC membrane-coated nanoparticles.

Abbreviations: EVs, extracellular vesicles; NPs, nanoparticles.

After extracting cell membrane vesicles, synthesized core NPs are coated with cell membranes, including surface proteins.172 Polymer NPs and inorganic NPs are adopted as materials for the core NPs of CMCNPs, and generally, polylactic-co-glycolic acid (PLGA), polylactic acid (PLA), chitosan, and gelatin are used. PLGA has been approved by FDA is the most common polymer of NPs.173 Biodegradable polymer NPs have gained considerable attention in nanomedicine due to their biocompatibility, nontoxic properties, and the ability to modify their surface as a drug carrier.174 Inorganic NPs are composed of gold, iron, copper, and silicon, which have hydrophilic, biocompatible, and highly stable properties compared with organic materials.175 Furthermore, some photosensitive inorganic NPs have the potential for use in photothermal therapy (PTT) and photodynamic therapy (PDT).176 The fusion of cell membrane vesicles and core NPs is primarily achieved via extrusion or sonication.165 Cell membrane coating of NPs using mechanical extrusion is based on a different-sized porous membrane where core NPs and vesicles are forced to generate vesicle-particle fusion.177 Ultrasonic waves are applied to induce the fusion of vesicles and NPs. However, ultrasonic frequencies need to be optimized to improve fusion efficiency and minimize drug loss and protein degradation.178

CMCNPs have extensively employed to target and treat cancer using the membranes obtained from red blood cell (RBC), platelet and cancer cell.165 In addition, membrane from MSC also utilized to target tumor and ischemia with various types of core NPs, such as MSC membrane coated PLGA NPs targeting liver tumors, MSC membrane coated gelatin nanogels targeting HeLa cell, MSC membrane coated silica NPs targeting HeLa cell, MSC membrane coated PLGA NPs targeting hindlimb ischemia, and MSC membrane coated iron oxide NPs for targeting the ischemic brain.179183 However, there are few studies on CMCNPs using stem cells for the treatment of arthritis. Increased targeting ability to arthritis was introduced using MSC-derived EVs and NPs.184,185 MSC membrane-coated NPs are proming strategy for clearing raised concerns from direct use of MSC (with or without NPs) in terms of toxicity, reduced biocompatibility, and poor targeting ability of NPs for the treatment of arthritis.

Exosomes are natural NPs that range in size from 40 nm to 120 nm and are derived from the multivesicular body (MVB), which is an endosome defined by intraluminal vesicles (ILVs) that bud inward into the endosomal lumen, fuse with the cell surface, and are then released as exosomes.186 Because of their ability to express receptors on their surfaces, MSC-derived exosomes are also considered potential candidates for targeting.187 Exosomes are commonly referred to as intracellular communication molecules that transfer various compounds through physiological mechanisms such as immune response, neural communication, and antigen presentation in diseases such as cancer, cardiovascular disease, diabetes, and inflammation.188

However, there are several limitations to the application of exosomes as targeted therapeutic carriers. First, the limited reproducibility of exosomes is a major challenge. In this field, the standardized techniques for isolation and purification of exosomes are lacking, and conventional methods containing multi-step ultracentrifugation often lead to contamination of other types of EVs. Furthermore, exosomes extracted from cell cultures can vary and display inconsistent properties even when the same type of donor cells were used.189 Second, precise characterization studies of exosomes are needed. Unknown properties of exosomes can hinder therapeutic efficiencies, for example, when using exosomes as cancer therapeutics, the use of cancer cell-derived exosomes should be avoided because cancer cell-derived exosomes may contain oncogenic factors that may contribute to cancer progression.190 Finally, cost-effective methods for the large-scale production of exosomes are needed for clinical application. The yield of exosomes is much lower than EVs. Depending on the exosome secretion capacity of donor cells, the yield of exosomes is restricted, and large-scale cell culture technology for the production of exosomes is high difficulty and costly and isolation of exosomes is the time-consuming and low-efficient method.156

Ectosome is an EV generated by outward budding from the plasma membrane followed by pinching off and release to the extracellular parts. Recently, artificially produced ectosome utilized as an alternative to exosomes in targeted therapeutics due to stable productivity regardless of cell type compared with conventional exosome. Artificial ectosomes, containing modified cargo and targeting molecules have recently been introduced for specific purposes (Figure 9).191,192 Artificial ectosomes are typically prepared by breaking bigger cells or cell membrane fractions into smaller ectosomes, similar size to natural exosomes, containing modified cargo such as RNA molecules, which control specific genes, and chemical drugs such as anticancer drugs.193 Naturally secreted exosomes in conditioned media from modified source cells can be harvested by differential ultracentrifugation, density gradients, precipitation, filtration, and size exclusion chromatography for exosome separation.194 Even though there are several commercial kits for isolating exosomes simply and easily, challenges in compliant scalable production on a large scale, including purity, homogeneity, and reproducibility, have made it difficult to use naturally secreted exosomes in clinical settings.195 Therefore, artificially produced ectosomes are appropriate for use in clinical applications, with novel production methods that can meet clinical production criteria. Production of artificially produced ectosomes begins by breaking the cell membrane fraction of cultured cells and then using them to produce cell membrane vesicles to form ectosomes. As mentioned above, cell membrane vesicles are extracted from source cells in several ways, and cell membrane vesicles are extracted through polycarbonate membrane filters to reduce the mean size to a size similar to that of natural exosomes.196 Furthermore, specific microfluidic devices mounted on microblades (fabricated in silicon nitride) enable direct slicing of living cells as they flow through the hydrophilic microchannels of the device.197 The sliced cell fraction reassembles and forms ectosomes. There are several strategies for loading exogenous therapeutic cargos such as drugs, DNA, RNA, lipids, metabolites, and proteins, into exosomes or artificial ectosomes in vitro: electroporation, incubation for passive loading of cargo or active loading with membrane permeabilizer, freeze and thaw cycles, sonication, and extrusion.198 In addition, protein or RNA molecules can be loaded by co-expressing them in source cells via bio-engineering, and proteins designed to interact with the protein inside the cell membrane can be loaded actively into exosomes or artificial ectosomes.157 Targeting molecules at the surface of exosomes or artificial ectosomes can also be engineered in a manner similar to the genetic engineering of MSCs.

Figure 9 Mesenchymal stem cell-derived exosomes and artificial ectosomes. (A) Wound healing effect of MSC-derived exosomes and artificial ectosomes,231 (B) treatment of organ injuries by MSC-derived exosomes and artificial ectosomes,42,232234 (C) anti-cancer activity of MSC-derived exosomes and artificial ectosomes.200,202,235

Most of the exosomes derived from MSCs for drug delivery have employed miRNAs or siRNAs, inhibiting translation of specific mRNA, with anticancer activity, for example, miR-146b, miR-122, and miR-379, which are used for cancer targeting by membrane surface molecules on MSC-derived exosomes.199201 Drugs such as doxorubicin, paclitaxel, and curcumin were also loaded into MSC-derived exosomes to target cancer.202204 However, artificial ectosomes derived from MSCs as arthritis therapeutics remains largely unexplored area, while EVs, mixtures of natural ectosomes and exosomes, derived from MSCs have studied in the treatment of arthritis.184 Artificial ectosomes with intrinsic tropism from MSCs plus additional targeting ability with engineering increase the chances of ectosomes reaching target tissues with ligandreceptor interactions before being taken up by macrophages.205 Eventually, this will decrease off-target binding and side effects, leading to lower therapeutic dosages while maintaining therapeutic efficacy.206,207

Liposomes are spherical vesicles that are artificially synthesized through the hydration of dry phospholipids.208 The clinically available liposome is a lipid bilayer surrounding a hollow core with a diameter of 50150 nm. Therapeutic molecules, such as anticancer drugs (doxorubicin and daunorubicin citrate) or nucleic acids, can be loaded into this hollow core for delivery.209 Due to their amphipathic nature, liposomes can load both hydrophilic (polar) molecules in an aqueous interior and hydrophobic (nonpolar) molecules in the lipid membrane. They are well-established biomedical applications and are the most common nanostructures used in advanced drug delivery.210 Furthermore, liposomes have several advantages, including versatile structure, biocompatibility, low toxicity, non-immunogenicity, biodegradability, and synergy with drugs: targeted drug delivery, reduction of the toxic effect of drugs, protection against drug degradation, and enhanced circulation half-life.211 Moreover, surfaces can be modified by either coating them with a functionalized polymer or PEG chains to improve targeted delivery and increase their circulation time in biological systems.212 Liposomes have been investigated for use in a wide variety of therapeutic applications, including cancer diagnostics and therapy, vaccines, brain-targeted drug delivery, and anti-microbial therapy. A new approach was recently proposed for providing targeting features to liposomes by fusing them with cell membrane vesicles, generating molecules called membrane-fused liposomes (Figure 10).213 Cell membrane vesicles retain the surface membrane molecules from source cells, which are responsible for efficient tissue targeting and cellular uptake by target cells.214 However, the immunogenicity of cell membrane vesicles leads to their rapid clearance by macrophages in the body and their low drug loading efficiencies present challenges for their use as drug delivery systems.156 However, membrane-fused liposomes have advantages of stability, long half-life in circulation, and low immunogenicity due to the liposome, and the targeting feature of cell membrane vesicles is completely transferred to the liposome.215 Furthermore, the encapsulation efficiencies of doxorubicin were similar when liposomes and membrane-fused liposomes were used, indicating that the relatively high drug encapsulation capacity of liposomes was maintained during the fusion process.216 Combining membrane-fused liposomes with macrophage-derived membrane vesicles showed differential targeting and cytotoxicity against normal and cancerous cells.217 Although only a few studies have been conducted, these results corroborate that membrane-fused liposomes are a potentially promising future drug delivery system with increased targeting ability. MSCs show intrinsic tropism toward arthritis, and further engineering and modification to enhance their targeting ability make them attractive candidates for the development of drug delivery systems. Fusing MSC exosomes with liposomes, taking advantage of both membrane vesicles and liposomes, is a promising technique for future drug delivery systems.

Figure 10 Mesenchymal stem cell membrane-fused liposomes.

MSCs have great potential as targeted therapies due to their greater ability to home to targeted pathophysiological sites. The intrinsic ability to home to wounds or to the tumor microenvironment secreting inflammatory mediators make MSCs and their derivatives targeting strategies for cancer and inflammatory disease.218,219 Contrary to the well-known homing mechanisms of various blood cells, it is still not clear how homing occurs in MSCs. So far, the mechanism of MSC tethering, which connects long, thin cell membrane cylinders called tethers to the adherent area for migration, has not been clarified. Recent studies have shown that galectin-1, VCAM-1, and ICAM are associated with MSC tethering,53,220 but more research is needed to accurately elucidate the tethering mechanism of MSCs. MSC chemotaxis is well defined and there is strong evidence relating it to the homing ability of MSCs.53 Chemotaxis involves recognizing chemokines through chemokine receptors on MSCs and migrating to chemokines in a gradient-dependent manner.221 RA, a representative inflammatory disease, is associated with well-profiled chemokines such as CXCR1, CXCR4, and CXCR7, which are recognized by chemokine receptors on MSCs. In addition, damaged joints in RA continuously secrete cytokines until they are treated, giving MSCs an advantage as future therapeutic agents for RA.222 However, there are several obstacles to utilizing MSCs as RA therapeutics. In clinical settings, the functional capability of MSCs is significantly affected by the health status of the donor patient.223 MSC yield is significantly reduced in patients undergoing steroid-based treatment and the quality of MSCs is dependent on the donors age and environment.35 In addition, when MSCs are used clinically, cryopreservation and defrosting are necessary, but these procedures shorten the life span of MSCs.224 Therefore, NPs mimicking MSCs are an alternative strategy for overcoming the limitations of MSCs. Additionally, further engineering and modification of MSCs can enhance the therapeutic effect by changing the targeting molecules and loaded drugs. In particular, upregulation of receptors associated with chemotaxis through genetic engineering can confer the additional ability of MSCs to home to specific sites, while the increase in engraftment maximizes the therapeutic effect of MSCs.36,225

Furthermore, there are several methods that can be used to exploit the targeting ability of MSCs as drug delivery systems. MSCs mimicking nanoencapsulation, which consists of MSC membrane-coated NPs, MSC-derived artificial ectosomes, and MSC membrane-fused liposomes, can mimic the targeting ability of MSCs while retaining the advantages of NPs. MSC-membrane-coated NPs are synthesized using inorganic or polymer NPs and membranes from MSCs to coat inner nanosized structures. Because they mimic the biological characteristics of MSC membranes, MSC-membrane-coated NPs can not only escape from immune surveillance but also effectively improve targeting ability, with combined functions of the unique properties of core NPs and MSC membranes.226 Exosomes are also an appropriate candidate for use in MSC membranes, utilizing these targeting abilities. However, natural exosomes lack reproducibility and stable productivity, thus artificial ectosomes with targeting ability produced via synthetic routes can increase the local concentration of ectosomes at the targeted site, thereby reducing toxicity and side effects and maximizing therapeutic efficacy.156 MSC membrane-fused liposomes, a novel system, can also transfer the targeting molecules on the surface of MSCs to liposomes; thus, the advantages of liposomes are retained, but with targeting ability. With advancements in nanotechnology of drug delivery systems, the research in cell-mimicking nanoencapsulation will be very useful. Efficient drug delivery systems fundamentally improve the quality of life of patients with a low dose of medication, low side effects, and subsequent treatment of diseases.227 However, research on cell-mimicking nanoencapsulation is at an early stage, and several problems need to be addressed. To predict the nanotoxicity of artificially synthesized MSC mimicking nanoencapsulations, interactions between lipids and drugs, drug release mechanisms near the targeted site, in vivo compatibility, and immunological physiological studies must be conducted before clinical application.

This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF-2019M3A9H1103690), by the Gachon University Gil Medical Center (FRD2021-03), and by the Gachon University research fund of 2020 (GGU-202008430004).

The authors report no conflicts of interest in this work.

1. Chapel A, Bertho JM, Bensidhoum M, et al. Mesenchymal stem cells home to injured tissues when co-infused with hematopoietic cells to treat a radiation-induced multi-organ failure syndrome. J Gene Med. 2003;5(12):10281038. doi:10.1002/jgm.452

2. Park JS, Suryaprakash S, Lao YH, Leong KW. Engineering mesenchymal stem cells for regenerative medicine and drug delivery. Methods. 2015;84:316. doi:10.1016/j.ymeth.2015.03.002

3. Ringe J, Burmester GR, Sittinger M. Regenerative medicine in rheumatic disease-progress in tissue engineering. Nat Rev Rheumatol. 2012;8(8):493498. doi:10.1038/nrrheum.2012.98

4. Friedenstein AJ, Petrakova KV, Kurolesova AI, Frolova GP. Heterotopic of bone marrow. Analysis of precursor cells for osteogenic and hematopoietic tissues. Transplantation. 1968;6(2):230247. doi:10.1097/00007890-196803000-00009

5. Zuk PA, Zhu M, Ashjian P, et al. Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell. 2002;13(12):42794295. doi:10.1091/mbc.e02-02-0105

6. Crisan M, Yap S, Casteilla L, et al. A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell. 2008;3(3):301313. doi:10.1016/j.stem.2008.07.003

7. Gronthos S, Mankani M, Brahim J, Robey PG, Shi S. Postnatal human dental pulp stem cells (DPSCs) in vitro and in vivo. Proc Natl Acad Sci U S A. 2000;97(25):1362513630. doi:10.1073/pnas.240309797

8. Young HE, Steele TA, Bray RA, et al. Human reserve pluripotent mesenchymal stem cells are present in the connective tissues of skeletal muscle and dermis derived from fetal, adult, and geriatric donors. Anat Rec. 2001;264(1):5162. doi:10.1002/ar.1128

9. Campagnoli C, Roberts IA, Kumar S, Bennett PR, Bellantuono I, Fisk NM. Identification of mesenchymal stem/progenitor cells in human first-trimester fetal blood, liver, and bone marrow. Blood. 2001;98(8):23962402. doi:10.1182/blood.V98.8.2396

10. Wang HS, Hung SC, Peng ST, et al. Mesenchymal stem cells in the Whartons jelly of the human umbilical cord. Stem Cells. 2004;22(7):13301337. doi:10.1634/stemcells.2004-0013

11. Heo JS, Choi Y, Kim HS, Kim HO. Comparison of molecular profiles of human mesenchymal stem cells derived from bone marrow, umbilical cord blood, placenta and adipose tissue. Int J Mol Med. 2016;37(1):115125. doi:10.3892/ijmm.2015.2413

12. Drela K, Stanaszek L, Snioch K, et al. Bone marrow-derived from the human femoral shaft as a new source of mesenchymal stem/stromal cells: an alternative cell material for banking and clinical transplantation. Stem Cell Res Ther. 2020;11(1):262. doi:10.1186/s13287-020-01697-5

13. Li J, Wong WH, Chan S, et al. Factors affecting mesenchymal stromal cells yield from bone marrow aspiration. Chin J Cancer Res. 2011;23(1):4348. doi:10.1007/s11670-011-0043-1

14. Melief SM, Zwaginga JJ, Fibbe WE, Roelofs H. Adipose tissue-derived multipotent stromal cells have a higher immunomodulatory capacity than their bone marrow-derived counterparts. Stem Cells Transl Med. 2013;2(6):455463. doi:10.5966/sctm.2012-0184

15. Trivanovic D, Jaukovic A, Popovic B, et al. Mesenchymal stem cells of different origin: comparative evaluation of proliferative capacity, telomere length and pluripotency marker expression. Life Sci. 2015;141:6173. doi:10.1016/j.lfs.2015.09.019

16. Lefevre S, Knedla A, Tennie C, et al. Synovial fibroblasts spread rheumatoid arthritis to unaffected joints. Nat Med. 2009;15(12):14141420. doi:10.1038/nm.2050

17. Cyranoski D. Japans approval of stem-cell treatment for spinal-cord injury concerns scientists. Nature. 2019;565(7741):544545. doi:10.1038/d41586-019-00178-x

18. Cofano F, Boido M, Monticelli M, et al. Mesenchymal stem cells for spinal cord injury: current options, limitations, and future of cell therapy. Int J Mol Sci. 2019;20(11):2698. doi:10.3390/ijms20112698

19. Liau LL, Looi QH, Chia WC, Subramaniam T, Ng MH, Law JX. Treatment of spinal cord injury with mesenchymal stem cells. Cell Biosci. 2020;10:112. doi:10.1186/s13578-020-00475-3

20. Williams AR, Hare JM, Dimmeler S, Losordo D. Mesenchymal stem cells: biology, pathophysiology, translational findings, and therapeutic implications for cardiac disease. Circ Res. 2011;109(8):923940. doi:10.1161/CIRCRESAHA.111.243147

21. Karantalis V, Hare JM. Use of mesenchymal stem cells for therapy of cardiac disease. Circ Res. 2015;116(8):14131430. doi:10.1161/CIRCRESAHA.116.303614

22. Bernstein HS, Srivastava D. Stem cell therapy for cardiac disease. Pediatr Res. 2012;71(4 Pt 2):491499. doi:10.1038/pr.2011.61

23. Guo Y, Yu Y, Hu S, Chen Y, Shen Z. The therapeutic potential of mesenchymal stem cells for cardiovascular diseases. Cell Death Dis. 2020;11(5):349. doi:10.1038/s41419-020-2542-9

24. Spaeth E, Klopp A, Dembinski J, Andreeff M, Marini F. Inflammation and tumor microenvironments: defining the migratory itinerary of mesenchymal stem cells. Gene Ther. 2008;15(10):730738. doi:10.1038/gt.2008.39

25. Vos T, Allen C, Arora M, et al. Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 19902015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016;388(10053):15451602.

26. Singh JA, Wells GA, Christensen R, et al. Adverse effects of biologics: a network meta-analysis and Cochrane overview. Cochrane Database Syst Rev. 2011;(2):CD008794. doi:10.1002/14651858.CD008794.pub2

27. Majithia V, Geraci SA. Rheumatoid arthritis: diagnosis and management. Am J Med. 2007;120(11):936939. doi:10.1016/j.amjmed.2007.04.005

28. Park N, Rim YA, Jung H, et al. Etanercept-synthesising mesenchymal stem cells efficiently ameliorate collagen-induced arthritis. Sci Rep. 2017;7:39593. doi:10.1038/srep39593

29. Herberts CA, Kwa MS, Hermsen HP. Risk factors in the development of stem cell therapy. J Transl Med. 2011;9:29. doi:10.1186/1479-5876-9-29

30. Rodriguez-Fuentes DE, Fernandez-Garza LE, Samia-Meza JA, Barrera-Barrera SA, Caplan AI, Barrera-Saldana HA. Mesenchymal stem cells current clinical applications: a systematic review. Arch Med Res. 2021;52(1):93101. doi:10.1016/j.arcmed.2020.08.006

31. Kabat M, Bobkov I, Kumar S, Grumet M. Trends in mesenchymal stem cell clinical trials 20042018: is efficacy optimal in a narrow dose range? Stem Cells Transl Med. 2020;9(1):1727. doi:10.1002/sctm.19-0202

32. Leibacher J, Henschler R. Biodistribution, migration and homing of systemically applied mesenchymal stem/stromal cells. Stem Cell Res Ther. 2016;7:7. doi:10.1186/s13287-015-0271-2

33. Zheng B, von See MP, Yu E, et al. Quantitative magnetic particle imaging monitors the transplantation, biodistribution, and clearance of stem cells in vivo. Theranostics. 2016;6(3):291301. doi:10.7150/thno.13728

34. Gholamrezanezhad A, Mirpour S, Bagheri M, et al. In vivo tracking of 111In-oxine labeled mesenchymal stem cells following infusion in patients with advanced cirrhosis. Nucl Med Biol. 2011;38(7):961967. doi:10.1016/j.nucmedbio.2011.03.008

35. Pittenger MF, Discher DE, Peault BM, Phinney DG, Hare JM, Caplan AI. Mesenchymal stem cell perspective: cell biology to clinical progress. NPJ Regen Med. 2019;4:22. doi:10.1038/s41536-019-0083-6

36. Marquez-Curtis LA, Janowska-Wieczorek A. Enhancing the migration ability of mesenchymal stromal cells by targeting the SDF-1/CXCR4 axis. Biomed Res Int. 2013;2013:561098. doi:10.1155/2013/561098

37. Liu L, Chen JX, Zhang XW, et al. Chemokine receptor 7 overexpression promotes mesenchymal stem cell migration and proliferation via secreting Chemokine ligand 12. Sci Rep. 2018;8(1):204. doi:10.1038/s41598-017-18509-1

38. Rittiner JE, Moncalvo M, Chiba-Falek O, Kantor B. Gene-editing technologies paired with viral vectors for translational research into neurodegenerative diseases. Front Mol Neurosci. 2020;13:148. doi:10.3389/fnmol.2020.00148

39. Srifa W, Kosaric N, Amorin A, et al. Cas9-AAV6-engineered human mesenchymal stromal cells improved cutaneous wound healing in diabetic mice. Nat Commun. 2020;11(1):2470. doi:10.1038/s41467-020-16065-3

40. van Haasteren J, Li J, Scheideler OJ, Murthy N, Schaffer DV. The delivery challenge: fulfilling the promise of therapeutic genome editing. Nat Biotechnol. 2020;38(7):845855. doi:10.1038/s41587-020-0565-5

41. Gowen A, Shahjin F, Chand S, Odegaard KE, Yelamanchili SV. Mesenchymal stem cell-derived extracellular vesicles: challenges in clinical applications. Front Cell Dev Biol. 2020;8:149. doi:10.3389/fcell.2020.00149

42. Lou G, Chen Z, Zheng M, Liu Y. Mesenchymal stem cell-derived exosomes as a new therapeutic strategy for liver diseases. Exp Mol Med. 2017;49(6):e346. doi:10.1038/emm.2017.63

43. Phinney DG, Di Giuseppe M, Njah J, et al. Mesenchymal stem cells use extracellular vesicles to outsource mitophagy and shuttle microRNAs. Nat Commun. 2015;6:8472. doi:10.1038/ncomms9472

44. Villemin E, Ong YC, Thomas CM, Gasser G. Polymer encapsulation of ruthenium complexes for biological and medicinal applications. Nat Rev Chem. 2019;3(4):261282. doi:10.1038/s41570-019-0088-0

45. Su YQ, Zhang TY, Huang T, Gao JQ. Current advances and challenges of mesenchymal stem cells-based drug delivery system and their improvements. Int J Pharma. 2021;600:120477.

46. Kwon S, Kim SH, Khang D, Lee JY. Potential therapeutic usage of nanomedicine for glaucoma treatment. Int J Nanomed. 2020;15:57455765. doi:10.2147/IJN.S254792

47. Sanna V, Sechi M. Therapeutic potential of targeted nanoparticles and perspective on nanotherapies. ACS Med Chem Lett. 2020;11(6):10691073. doi:10.1021/acsmedchemlett.0c00075

Go here to see the original:
Stem Cell Mimicking Nanoencapsulation for Targeting Arthrit | IJN - Dove Medical Press

Bone Marrow Stem Cells Comments Off on Stem Cell Mimicking Nanoencapsulation for Targeting Arthrit | IJN – Dove Medical Press | January 3rd, 2022

1Regenerative Medicine Centre, Arabian Gulf University, Manama, Bahrain; 2Department of Molecular Medicine, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Bahrain

Introduction: Stroke is a leading cause of death and disability worldwide. The disease is caused by reduced blood flow into the brain resulting in the sudden death of neurons. Limited spontaneous recovery might occur after stroke or brain injury, stem cell-based therapies have been used to promote these processes as there are no drugs currently on the market to promote brain recovery or neurogenesis. Adult stem cells (ASCs) have shown the ability of differentiation and regeneration and are well studied in literature. ASCs have also demonstrated safety in clinical application and, therefore, are currently being investigated as a promising alternative intervention for the treatment of stroke.Methods: Eleven studies have been systematically selected and reviewed to determine if autologous adult stem cells are effective in the treatment of stroke. Collectively, 368 patients were enrolled across the 11 trials, out of which 195 received stem cell transplantation and 173 served as control. Using data collected from the clinical outcomes, a broad comparison and a meta-analysis were conducted by comparing studies that followed a similar study design.Results: Improvement in patients clinical outcomes was observed. However, the overall results showed no clinical significance in patients transplanted with stem cells than the control population.Conclusion: Most of the trials were early phase studies that focused on safety rather than efficacy. Stem cells have demonstrated breakthrough results in the field of regenerative medicine. Therefore, study design could be improved in the future by enrolling a larger patient population and focusing more on localized delivery rather than intravenous transplantation. Trials should also introduce a more standardized method of analyzing and reporting clinical outcomes to achieve a better comparable outcome and possibly recognize the full potential that these cells have to offer.

Keywords: adult stem cells, autologous, neurogenesis, inflammation, clinical application, stroke, stroke recovery, systematic review, meta-analysis

Stroke is the second leading cause of death worldwide and one of the leading causes of disability.1 The blockade or the rupture of a blood vessel to the brain leads to either ischemic or hemorrhagic stroke, respectively.2,3 The extent and the location of the damaged brain tissue may be associated with irreversible cognitive impairment or decline in speech, comprehension, memory, and partial or total physical paralysis.4

Four chronological phases, namely hyperacute, acute, subacute, and chronic, describe the strokes cellular manifestations.5 The hyperacute phase is immediate and associated with glutamate-mediated excitotoxicity and a progressive neuronal death that can last a few hours.6 The glutamate, a potent excitatory neurotransmitter, is also an inducer of neurodegeneration following stroke.7 The acute phase, which could last over a week after the stroke, is associated with the delayed and progressive neuronal death and the infiltration of immune cells.5 The following subacute phase can extend up to three months after the stroke and is mainly associated with reduced inflammation and increased plasticity of neurons, astrocytes, microglia, and endothelial cells, allowing spontaneous recovery.8 In the chronic phase that follows, the plasticity of cells is reduced and only permits rehabilitation-induced recovery.5

The immediate treatments differ for ischemic and hemorrhagic strokes. Immediate intervention is required to restore the blood flow to the brain following an ischemic stroke. Thrombolytic agents, such as activase (Alteplase), a recombinant tissue plasminogen activator (tPA), are commonly given intravenously to dissolve the blood clots. Other more invasive approaches, such as a thrombectomy, use stents or catheters to remove the blood clot.9 Antiplatelet agents like Aspirin, anticoagulants, blood pressure medicines, or statins are generally given to reduce the risk of recurrence. Some ischemic strokes are caused by the narrowing of the carotid artery due to the accumulation of fatty plaques; a carotid endarterectomy is performed to correct the constriction.

The treatment of a hemorrhagic stroke requires a different approach. An emergency craniotomy is usually performed to remove the blood accumulating in the brain and repair the damaged blood vessels. Accumulation of cerebrospinal fluid in brain ventricles (hydrocephalus) is also a frequent complication following a hemorrhagic stroke, which requires surgery to drain the fluid. Medications to lower blood pressure are given before surgery and to prevent further seizures.10

These immediate treatments are critical to minimize the long-term consequence of the stroke but do not address the post-stroke symptoms caused by neurodegeneration. New therapeutic approaches adapted to the physiology of each phase of the stroke are currently developed. A promising therapy has been the use of stem cells.11 In this review, different clinical trials involving the use of various stem cells for the treatment of stroke are presented and compared using a meta-analysis of the published results.

To narrow down the relevant literature, a search strategy focused on original literature and reporting the clinical application of stem cells in stroke was established. An NCBI PubMed word search for stroke, stem cells, and adult stem cells yielded 146 clinical studies between 2010 and 2021. Finally, 11 studies, using autologous adult stem cells in the treatment of stroke, were considered. A PRISMA flow diagram detailing an overview of the study selection procedure and the inclusion and exclusion of papers is included in Appendix I. The inclusion criteria comprise the injection of autologous adult stem cells at any stroke stages (hyperacute, acute, sub-acute, chronic), and clinical trials whose results have been published in the last 11 years. The exclusion criteria include studies published more than 11 years ago, studies not published in English, all preclinical studies, other diseases related to stroke (ex. cardiovascular diseases), embryonic or induced pluripotent stem cells, allogeneic stem cells, and other cell therapies. Two independent researchers reviewed and filtered the 146 studies by reading the titles and abstracts. All three authors approved the final selected studies.

Stem cells are undifferentiated and unspecialized cells characterized by their ability to self-renew and their potential to differentiate into specialized cell types.12 Ischemic stroke causes severe damage to the brain cells by destroying the heterogeneous cell population and neuronal connections along with vascular systems. The regenerative potential of several types of stem cells like embryonic stem cells, neural stem cells, adult stem cells (mesenchymal stem cells), and induced pluripotent stem cells have been assessed for treating stroke.

Adult stem cells exhibit multipotency and the ability to self-renew and differentiate into specialized cell types. They have been widely used in clinical trials and a safe option thus far in treating various diseases.12,13,14 The plasticity of these cells allow their differentiation across tissue lineages when exposed to defined cell culture conditions.15 There are multiple easily accessible sources of adult stem cells, mainly the bone marrow, blood, and adipose tissue. In clinical settings, both autologous and HLA-matched allogeneic cells have been transplanted and are deemed to be safe.

Adult stem cells can secrete a variety of bioactive substances into the injured brain following a stroke in the form of paracrine signals.1618 The paracrine signals include growth factors, trophic factors, and extracellular vesicles, which may be associated with enhanced neurogenesis, angiogenesis, and synaptogenesis (Figure 1). Also, mesenchymal stem cells (MSCs) are thought to contribute to the resolution of the stroke by attenuating inflammation,19 reducing scar thickness, enhancing autophagy, normalizing microenvironmental and metabolic profiles and possibly replacing damaged cells.20

Figure 1 Schematic depicting the clinical application of different cells in stroke patients. The cells were delivered in one of three ways, intravenously, intra-arterially, or via stereotactic injections. Once administered, the cells play a role in providing paracrine signals and growth factors to facilitate angiogenesis and cell regeneration, immunomodulatory effects that serve to protect the neurons from further damage caused by inflammation, and finally, trans-differentiation of stem cells. Data from Dabrowska S, Andrzejewska A, Lukomska B, Janowski M.19 Created with BioRender.com.

A few routes of administration have been used to deliver the stem cells to the patients. The most common is through intravenous injection. Intra-arterial delivery is also performed; but this mode can be extremely painful to patients compared to an intravenous transfusion. The third approach is via stereotactic injections. This is an invasive surgery that involves injecting the cells directly into the site of affected in the brain.

Also known as mesenchymal stromal cells or medicinal signaling cells, MSCs can be derived from different sources including bone marrow, peripheral blood, lungs, heart, skeletal muscle, adipose tissue, dental pulp, dermis, umbilical cord, placenta, amniotic fluid membrane and many more.21 MSCs are characterized by positive cell surface markers, including Stro-1, CD19, CD44, CD90, CD105, CD106, CD146, and CD166. The cells are also CD14, CD34, and CD45 negative.22,23 The cells are thought to provide a niche to stem cells in normal tissue and releases paracrine factors that promote neurogenesis (Figure 2).19,20,24 During the acute and subacute stage of stroke, MSCs may inhibit inflammation, thus, reducing the incidence of debilitating damage and symptoms that may occur post-stroke.

Figure 2 Schematic describing the role of mesenchymal stem cells in stroke. The cells release different growth factors, signals, and cytokines that serve to facilitate various functions. Through the release of cytokines, they can modulate inflammation and block apoptosis. The growth factors aid in promoting angiogenesis and neurogenesis. Data from Maleki M, Ghanbarvand F, Behvarz MR, Ejtemaei M, Ghadirkhomi E.23 Created with BioRender.com.

Derived from the bone marrow, mononuclear cells contain several types of stem cells, including mesenchymal stem cells and hematopoietic progenitor cells that give rise to hematopoietic stem cells and various other differentiated cells. They can produce and secrete multiple growth factors and cytokines. They are also attracted to the lesion or damage site where they can accelerate angiogenesis and promote repair endogenously through the proliferation of the hosts neural stem cells. Mononuclear cells have also demonstrated the ability to decrease neurodegeneration, modulate inflammation, and prevent apoptosis in animal models.25,26

Blood stem cells are a small number of bone marrow stem cells that have been mobilized into the blood by hematopoietic growth factors, which regulate the differentiation and proliferation of cells. They are increasingly used in cell therapies, most recently for the regeneration of non-hematopoietic tissue, including neurons. Recombinant human granulocyte colony-stimulating factor (G-CSF) has been used as a stimulator of hematopoiesis, which in turn amplifies the yield of peripheral blood stem cells.27

The literature review considered 11 clinical trials that satisfied the inclusion criteria. A total of 368 patients were enrolled including 179 patients treated with various types of adult stem cells. The clinical trial number 7 contained a historical control of 59 patients included in the data analysis (Figure 3). The analysis was done on the published clinical and functional outcomes of various tests such as mRS, and mBI. The analysis compared the patients clinical outcomes post stem cell therapy to the baseline clinical results. The variance in the patient population should be noted.

Figure 3 Schematic representing an overview of the total number of patients enrolled in all 11 clinical trials and the number of patients administered with each type of adult stem cell.

Abbreviations: MSC, mesenchymal stem cells; PBSC, peripheral blood stem cells; MNC, mononuclear stem cells; ADSVF, adipose derived stromal vascular fraction; ALD401, aldehyde dehydrogenase-bright stem cells.

Meta-analyses were conducted using modified Rankin scale (mRS) and Barthel Index (BI) scores. In the clinical trials, mRS and BI scores are commonly used scales to assess functional outcome in stroke patients. The BI score was developed to measures the patients performance in 10 activities of daily life from self-care to mobility. An mRS score follows a similar outcome but measures the patients independence in daily tasks rather than performance. OpenMeta[Analyst], an open-source meta-analysis software, was used to produce random-effects meta-analyses and create the forest plots. The number of patients, mean, and standard deviation (SD) of the scores were calculated to determine the study weights and create the forest plots.

All 11 clinical trials were compared based on their clinical and functional outcomes (Table 1; Figure 4). The data shows that stem cell therapy is relatively safe and viable in the treatment of stroke, indicating an improvement in patients overall health. However, when compared to the control, the improvement is not significant as patients in the control group also exhibited an improved clinical and functional outcome. Across trials that assigned a control group, the patients either received a placebo, or alternative form of treatment including physiotherapy. Variance in functional and clinical tests used to assess patients, and the number of patients enrolled in each trial results in a discrepancy in reporting. Most of the trials failed to report whether the patients suffered from an acute, subacute or chronic stroke which also affects the results of the treatments, with acute and subacute being the optimal periods to receive treatment due to cell plasticity and inhibiting unwarranted inflammation.39 The deaths in both the treatment and control population were attributed to the progression of the disease and are likely not the result of the treatment. Albeit, it has been noted down as they had occurred during the follow-up period.

Table 1 Overview of Selected Clinical Trials

Figure 4 Overview of clinical outcomes of the 11 clinical trials (N=368). (A) The chart shows the percentages of patients who have either improved, remained stable, deteriorated, or deceased. Some clinical trials are without a control arm. (B) The plot shows the overall percentage of patients that have improved after receiving either the stem cell treatment versus the standard of care. (C) The plot shows the overall percentage of patients that have remained stable and showed no clinical or functional improvement in the follow up period. (D) The plot shows the overall percentage of the patients whose condition has deteriorated in the follow up period.

A meta-analysis was conducted using modified Rankin scale (mRS) and Barthel Index (BI) scores. The results of the mRS scores were analyzed (Figure 5A; Table 2). In terms of study weights, CT6 is the highest (40.07%) as shown in Table 2. The combined results of the mRS functional test from CT1, CT5, CT6, and CT11 show a non-significant statistical heterogeneity in the studies (p-value 0.113). In conjunction, BI scores were analyzed and a meta-analysis was conducted using four comparable trials (Figure 5B; Table 3). In terms of study weights, CT3 is the highest (32.384%) as shown in Table 3. The combined results of BI scores from CT5, CT3, CT10, and CT11 show a statistical heterogeneity in the results of the studies (p-value 0.004) thus, precision of results is uncertain. More comparable studies are needed to have a better outcome. Therefore, standardized testing in trails should be considered in future trials.

Table 2 Clinical Outcomes of mRS Test

Table 3 Clinical Outcomes of BI Test

Figure 5 Meta-analysis conducted using three comparable trials. (A) Meta-analysis conducted using four comparable trials (CT1, CT5, CT6, CT11) for the mRS test. (B) Meta-analysis conducted using four comparable trials (CT3, CT5, CT10, and CT11) for the BI test.

Across all trials, patients injected with the MSCs, and other cell types did not trigger a degradation of the patient conditions demonstrating the safety of the procedures. However, the efficacy of the use of adult stem cells is less clear when compared to patients in the control group. This discrepancy could, however, exhibit improvement in patients receiving the treatment compared to the baseline clinical outcomes. However, when therapy results are compared to the patients in the control population that either received a placebo, physiotherapy, or prescribed medication, the efficacy of the use of adult stem cells is less clear.

Although multiple adult stem cell types have been used, mesenchymal stem cells have been widely used in many clinical trials. Albeit there is a consensus that the therapeutic and clinical outcomes of mesenchymal stem cell treatments are not yet significantly effective compared to the control treatment. Some trials have shown patient improvements, such as CT6 and CT8, where the investigators used PBSCs or BMMNSC, respectively. Although subjectively, the cells appear to be therapeutic, objectively, there are many limitations to the study designs included in this review. Not all the trials enrolled a control arm for a better comparison as some were only testing safety rather than efficacy. Therefore, we cannot conclude whether autologous adult stem cells are an effective therapeutic stroke treatment. Only autologous cells were included in this review as they are non-immunogenic.

Another factor to consider is the evident discrepancy in the number of patients enrolled in each trial. The trials included in this review are in Phase I and II trials, which primarily focus on safety rather than efficacy. Intravenous injection was the most used method of cell delivery due to its convenience and safety. However, it is commonly considered that this approach is not the most effective way of delivery, as the majority of the transplanted cells get absorbed by non-targeted organs, and the remaining cells find difficulty passing the blood-brain barrier. Due to this dilemma, the most obvious approach would be to inject the cells directly into the brain. However, a stereotactic procedure is invasive and will require general anesthesia, which may compromise patients health, especially ones suffering from acute ischemic stroke.40 Thus, an intra-arterial delivery seems feasible to accomplish the task as it is less invasive and might be more effective than an intravenous treatment such as the cases observed in CT3 and CT8. In CT11, the patients demonstrated a visible fmRI recovery as well as recovery of motor function in patients that have received a stem cell treatment. However, the analysis and test scores show no significance between the treatment group and the control group.

Only a few studies were comparable using a similar evaluation approach. Considering these factors, better study designs enrolling a higher number of patients in randomized clinical trial against the standard of care are needed. Moreover, a better grouping of the patients based on the type and stage of stroke may provide more relevant information for the safety and efficacy of adult stem cells for the recovery and prevention of recurrence of stroke patients.

ADSVF, Adipose-derived stromal vascular fraction; ASCs, Adult stem cells; ALD-401, Aldehyde dehydrogenase 401; BI, Barthel Index; BM-MNC, Bone marrow-derived mononuclear cells; FLAIR, Fluid attenuated inversion recovery; fMRI, Functional magnetic resonance imaging; G-CSF, Granulocyte colony-stimulating factor; MRI, Magnetic resonance imaging; MSCs, Mesenchymal stem cells; mRS, modified Rankin Scale; NIHSS, National Institute of Health Stroke Scale; PBSC, Peripheral blood stem cells; SD, Standard deviation; tPA, tissue plasminogen activator.

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

There is no funding to report.

We declare there is no conflict of interest.

1. Johnson W, Onuma O, Owolabi M, Sachdev S. Stroke: a global response is needed. Bull World Health Organ. 2016;94(9):634A635A. doi:10.2471/BLT.16.181636

2. Donnan G, Fisher M, Maclead M, Davis S. Stroke. Lancet. 2008;373(9674):1496. doi:10.1016/S0140-6736(09)60833-3

3. Umut Canbek YB, Imerci A, Akgn U, Yesil M, Aydin A. Characteristics of injuries caused by paragliding accidents: a cross-sectional study. World J Emerg Med. 2015;6(1):4447. doi:10.5847/wjem.j.1920

4. Roth EJ, Heinemann AW, Lovell LL, Harvey RL, McGuire JR, Diaz S. Impairment and disability: their relation during stroke rehabilitation. Arch Phys Med Rehabil. 1998;79(3):329335. doi:10.1016/S0003-9993(98)90015-6

5. Joy MT, Carmichael ST. Encouraging an excitable brain state: mechanisms of brain repair in stroke. Nat Rev Neurosci. 2021. doi:10.1038/s41583-020-00396-7

6. Lai TW, Zhang S, Wang YT. Excitotoxicity and stroke: identifying novel targets for neuroprotection. Prog Neurobiol. 2014;115:157188. doi:10.1016/j.pneurobio.2013.11.006

7. Fern R, Matute C. Glutamate receptors and white matter stroke. Neurosci Lett. 2019;694:8692. doi:10.1016/j.neulet.2018.11.031

8. Zhao L, Willing A. Progress in neurobiology enhancing endogenous capacity to repair a stroke-damaged brain: an evolving fi eld for stroke research. Prog Neurobiol. 2018;163164:526. doi:10.1016/j.pneurobio.2018.01.004

9. Hasan TF, Rabinstein AA, Middlebrooks EH, et al. Diagnosis and management of acute ischemic stroke. Mayo Clin Proc Themat Rev Neurosci. 2018;93(4):523538. doi:10.1016/j.mayocp.2018.02.013

10. Abraham MK, Chang WTW. Subarachnoid hemorrhage. Emerg Med Clin NA. 2016;34(4):901916. doi:10.1016/j.emc.2016.06.011

11. Wei L, Wei ZZ, Jiang MQ, Mohamad O, Yu SP. Stem cell transplantation therapy for multifaceted therapeutic benefits after stroke. Prog Neurobiol. 2017. doi:10.1016/j.pneurobio.2017.03.003

12. Biehl JK, Russell B. Introduction to stem cell therapy. J Cardiovasc Nurs. 2009;24(2):98103. doi:10.1097/JCN.0b013e318197a6a5

13. Larijani B, Esfahani EN, Amini P, et al. Stem cell therapy in treatment of different diseases. Acta Med Iran. 2012;50(2):7996.

14. Lo B, Parham L. Ethical issues in stem cell research. Endocr Rev. 2009;30(3):204213. doi:10.1210/er.2008-0031

15. Wagers AJ, Weissman IL. Plasticity of adult stem cells. Cell. 2004;116(5):639648. doi:10.1016/S0092-8674(04)00208-9

16. Fernndez-Susavila H, Bugallo-Casal A, Castillo J, Campos F. Adult stem cells and induced pluripotent stem cells for stroke treatment. Front Neurol. 2019;10. doi:10.3389/fneur.2019.00908

17. Bang OY. Current status of cell therapies in stroke. Int J Stem Cells. 2009;2(1):3544. doi:10.15283/ijsc.2009.2.1.35

18. Einstein O, Ben-Hur T. The changing face of neural stem cell therapy in neurologic diseases. Arch Neurol. 2008;65(4):452456. doi:10.1001/archneur.65.4.452

19. Dabrowska S, Andrzejewska A, Lukomska B, Janowski M. Neuroinflammation as a target for treatment of stroke using mesenchymal stem cells and extracellular vesicles. J Neuroinflammation. 2019;16(1):117. doi:10.1186/s12974-019-1571-8

20. Wagenaar N, Nijboer CHA, Van Bel F. Repair of neonatal brain injury: bringing stem cell-based therapy into clinical practice. Dev Med Child Neurol. 2017;59(10):9971003. doi:10.1111/dmcn.13528

21. Secunda R, Vennila R, Mohanashankar AM, Rajasundari M, Jeswanth S, Surendran R. Isolation, expansion and characterisation of mesenchymal stem cells from human bone marrow, adipose tissue, umbilical cord blood and matrix: a comparative study. Cytotechnology. 2015;67(5):793807. doi:10.1007/s10616-014-9718-z

22. Lin CS, Xin ZC, Dai J, Lue TF. Commonly used mesenchymal stem cell markers and tracking labels: limitations and challenges. Histol Histopathol. 2013;28(9):11091116. doi:10.14670/HH-28.1109

23. Maleki M, Ghanbarvand F, Behvarz MR, Ejtemaei M, Ghadirkhomi E. Comparison of mesenchymal stem cell markers in multiple human adult stem cells. Int J Stem Cells. 2014;7(2):118126. doi:10.15283/ijsc.2014.7.2.118

24. Bhartiya D. Clinical translation of stem cells for regenerative medicine: a comprehensive analysis. Circ Res. 2019;124(6):840842. doi:10.1161/CIRCRESAHA.118.313823

25. Lv W, Li WY, Xu XY, Jiang H, Bang OY. Bone marrow mesenchymal stem cells transplantation promotes the release of endogenous erythropoietin after ischemic stroke. Neural Regen Res. 2015;10(8):12651270. doi:10.4103/1673-5374.162759

26. Muir T. Peripheral blood mononuclear cells: a brief review origin of peripheral blood mononuclear cells; 2020:17.

27. Wang Z, Schuch G, Williams JK, Soker S. Peripheral blood stem cells. Handb Stem Cells. 2013;2:573586. doi:10.1016/B978-0-12-385942-6.00050-0

28. Lee JS, Hong JM, Moon GJ, et al. A long-term follow-up study of intravenous autologous mesenchymal stem cell transplantation in patients with ischemic stroke.. Stem Cells. 2010;28(6):10991106. doi:10.1002/stem.430

29. Honmou O, Houkin K, Matsunaga T, et al. Intravenous administration of auto serum-expanded autologous mesenchymal stem cells in stroke. Brain. 2011;134(6):17901807. doi:10.1093/brain/awr063

30. Banerjee S. T ISSUE -S PECIFIC P ROGENITOR AND S TEM C ELLS intra-arterial immunoselected CD34 + stem cells for acute ischemic stroke; 2014.

31. Bhasin A, Padma Srivastava MV, Mohanty S, Bhatia R, Kumaran SS, Bose S. Stem cell therapy: a clinical trial of stroke. Clin Neurol Neurosurg. 2013;115(7):10031008. doi:10.1016/j.clineuro.2012.10.015

32. Prasad K, Sharma A, Garg A, et al. Intravenous autologous bone marrow mononuclear stem cell therapy for ischemic stroke: a multicentric, randomized trial. Stroke. 2014;45(12):36183624. doi:10.1161/STROKEAHA.114.007028

33. Chen DC, Lin S-Z, Fan J-R, et al. Intracerebral implantation of autologous peripheral blood stem cells in stroke patients: a randomized Phase II study. Cell Transplantation. 2014;23(12):15991612. doi:10.3727/096368914X678562

34. Taguchi A, Sakai C, Soma T, et al. Intravenous autologous bone marrow mononuclear cell transplantation for stroke: phase1/2a clinical trial in a homogeneous group of stroke patients. Stem Cells Dev. 2015;24(19):22072218. doi:10.1089/scd.2015.0160

35. Bhatia V, Gupta V, Khurana D, Sharma RR, Khandelwal N. Randomized assessment of the safety and efficacy of intra-arterial infusion of autologous stem cells in subacute ischemic stroke. Am J Neuroradiol. 2018;39(5):899904. doi:10.3174/ajnr.A5586

36. Duma C, Kopyov O, Kopyov A, et al. Human intracerebroventricular (ICV) injection of autologous, non-engineered, adipose-derived stromal vascular fraction (ADSVF) for neurodegenerative disorders: results of a 3-year Phase 1 study of 113 injections in 31 patients. Mol Biol Rep. 2019;46(5):52575272. doi:10.1007/s11033-019-04983-5

37. Savitz SI, Yavagal D, Rappard G, et al. A phase 2 randomized, sham-controlled trial of internal carotid artery infusion of autologous bone marrow-derived ALD-401 cells in patients with recent stable ischemic stroke (RECOVER-stroke). Circulation. 2019;139(2):192205. doi:10.1161/CIRCULATIONAHA.117.030659

38. Jaillard A, Hommel M, Moisan A, et al. Autologous mesenchymal stem cells improve motor recovery in subacute ischemic stroke: a randomized clinical trial. Transl Stroke Res. 2020;11(5):910923. doi:10.1007/s12975-020-00787-z

39. Kwak K-A, Kwon H-B, Lee JW, Park Y-S. Current perspectives regarding stem cell-based therapy for ischemic stroke. Curr Pharm Des. 2018;24(28):33323340. doi:10.2174/1381612824666180604111806

40. Anastasian ZH. Anaesthetic management of the patient with acute ischaemic stroke. Br J Anaesth. 2014;113:ii9ii16. doi:10.1093/bja/aeu372

The rest is here:
Autologous Adult Stem Cells in the Treatment of Stroke | SCCAA - Dove Medical Press

Bone Marrow Stem Cells Comments Off on Autologous Adult Stem Cells in the Treatment of Stroke | SCCAA – Dove Medical Press | January 3rd, 2022

Steven Fisher is a modern-day Spartan.59, 225 pounds of pure muscle, and hes constantly exercising.

In fact, his favorite hobby is touring the country, competing in Spartan Races with his wife. If youve never heard of a Spartan Race, its essentially running miles and miles, and youre rewarded for your efforts by completing physical tasks, like doing a billion pull-ups, or crawling through mud, at each mile.

For these obstacle and endurance races, youve got to be in pretty good shape.

However, as of late Fisher has had to take a break from said races. Not because hes tired, or anything like that. The mans a machine. His hiatus has stemmed from a life-long nagging injury thats been flaring up.

He said it all started during his young and dumb days. He and his friends were tobogganing down a hill. Fisher, who was 20 at the time, said he stood up on the toboggan to attempt a little surfing. He felt like a regular Kelly Slater before falling backwards.

Learn more:Orthopedics regenerative medicine at Sanford Health

My elbow hit into the ground and just caught. I broke my humerus into three pieces. Obviously, that was a lot of trauma in my shoulder as well, Fisher said.

Because of the impact, his doctor told him he was lucky his humerus didnt shoot through his shoulder.

Normally thats what they see with that kind of fall.

He went through rehabilitation, and other than some trouble resting his hands behind his head, he said he made a full recovery.

Fast forward a few decades, and hes lifting weights, running Spartan Races, and seemed to be doing well. One day, though, he noticed a sharp pain in the same shoulder he injured as a young adult.

He said he couldnt heal it the ways he normally would. So, he went to his doctor.

He said I had arthritis. At the age of 43. He said if I was older, wed be talking about replacing my shoulder, he said.

Fisher got aPRP, or platelet rich plasma, injection. He noticed some relief for eight months, before the pain returned.

Basically at that point it was a labrum tear, and Id been re-tearing it quite a bit, Fisher said. He got another PRP shot but started to look more into stem cells and regenerative medicine. He lives in West Virgina and found a few doctors who offer stem cell therapy.

But you cant find a lot of information on how they do it, like what their method is. They dont even say if its from bone marrow or from fat. They also dont tell you how theyre extracting the stem cells, like if its mechanical or theyre doing something else. Theyre not going to tell you that stuff, he said.

He wanted to continue to explore this form of treatment, but only if it was done the right way. He talked with multiple providers on the East Coast, but it just didnt feel right.

Then, he stumbled onto Sanford.

He said he started talking with Tiffany Facile, the clinical director of regenerative medicine at Sanford Health. She explained to him that the stem cell treatment, and ENDURE clinical trial,Sanford Healthcan offer might be a great fit for Fisher.

We talked about different studies, and we talked about what Sanford is doing. Shes obviously really excited about it and there were some previous studies (Sanford has) done. I read up on the previous studies, and the results on the previous studies. For example, with a rotator cuff, they had done the same process and got great results with it, Fisher explained.

He also said he truly felt like he was heard and understood at Sanford Health. Some of the other places felt like more of a shop, so to speak, he said.

Everybody, from the top down to even the front desk, they were gracious. Everybody Ive worked with, theyre all passionate about this. I never felt like I was just getting pulled along, and I didnt have a say in my care or anything like that. I felt I was more part of the process itself and like I was walking with them, he said.

Fisher received adipose-derived stem cell treatment from Sanford. He said the way Sanford Health delivered the treatment differs from other health care providers. He explained some providers use a mechanical method to extract the stem cells, but Sanford uses a more concentrated enzyme-derived method.

There is an estimated range on the amount of stem cells that get extracted, like from an enzyme approach versus mechanical, and it can be on the order of like a thousand times more cells going to be extracted, versus the mechanical, he said.

Hes still on the sidelines for Spartan Races, but hes hoping to get back on the course soon. He has a check-up in January, but he says he feels both physically and mentally better after receiving care from Sanford.

Posted In Orthopedics, Research, Sports Medicine

Link:
Cell therapy helps Sanford patient get back to racecourse - Sanford Health News

Bone Marrow Stem Cells Comments Off on Cell therapy helps Sanford patient get back to racecourse – Sanford Health News | January 3rd, 2022

By Stephanie Banat

17-year-old Samantha Horowitz is teaching the world about the healing powers of music.

A lifelong Merrick resident, Horowitz is a senior at Calhoun High School who for the past three years has been the sole vocalist in the production of a musical documentary, Second Chance, based on her mother, Tara Notricas, long battle with mast cell disease.

Some of the songs were written from my perspective, and some were written from my moms perspective, Horowitz explained. Music has given us the freedom to express things that we couldnt put into words and I truly believe its a huge part of the reason that my mom is here with us today.

In honor of her creative, healing effort, the Herald is proud to name Horowitz its 2021 Person of the Year.

Since Notricas early 20s, she had suffered from a number of physical maladies of unknown causes, including episodes of anaphylactic shock, hair loss and other issues.

It wasnt until April 2011, after consultations with scores of specialists, that Notrica was finally diagnosed with mast cell activation syndrome, a rare disorder caused by abnormal or overly active mast cells that affects multiple organ systems, including the gastrointestinal, neurological, endocrine, cardiac and respiratory systems.

It took a huge toll on me and my family, Horowitz said. I was 5 at the time, and I didnt understand what was going on. I just knew that my mom was sick, and that she couldnt be the mom she wanted to be for my brother, Jared, and I.

In 2018, Notrica endured a stem cell transplant, which was unsuccessful. Next, that June, her doctors offered her the option of receiving a bone marrow transplant, which, they said, she had a 50-50 chance of surviving. Nonetheless, Notrica decided to go forward with the procedure.

At this time, the whole music process really started picking up, her daughter said, because there were now a lot more emotions we were experiencing to write about because there were some days that my mom woke up and really didnt think she was going to make it.

Just two weeks before the bone marrow transplant, the family began filming a documentary, directed by Rochester-based filmmakers Matthew White and Brian Gerlach. The film documents Notricas health journey, and focuses on the weeks leading up to the transplant. Its title, Second Chance, comes from one of its songs, which is about Notrica getting a second chance at life, and getting to experience everything she had missed out on because of her illness.

Since 2017, Horowitz has written and recorded 11 original songs for the film. Her music career, however, started long before the documentary.

Ive had a passion for singing since I was around 3 or 4 years old, she said. In elementary school I did musical theater, and then in middle school I began writing my own original songs.

In 2017, at age 13, she wrote her first song for the documentary, alongside her mother and her vocal coach, former American Idol contestant and Merrick native Robbie Rosen. The ballad, called Brave the Storm, was written to show Notrica that she wasnt facing her illness alone, her daughter said.

Another one of her favorite songs from the documentary, Horowitz said, is called Carry On, which she wrote from her mothers perspective. This song is basically my mom saying that if it came down to it and she didnt make it, she wants my family to carry on without her, Samantha said, because shed always be a part of us and would always be watching over us.

Now, nearly three years after the transplant, and after facing a multitude of complications from it, Notrica is still under medical care at home.

The biggest thing, Horowitz said, is throughout this whole process of my mom being sick, whats always brought her a sense of comfort is music. Not just her favorite artists on the radio, but really the fact that I could sing to her and bring her joy and show her that there are things in life that are certainly worth fighting for not just her family, but also things like music.

Aside from her music, Horowitz has earned academic accolades throughout her high school career, and is a member of Calhouns national, math, science, English, social studies and world language honor societies. She is also a peer tutor for other students.

Rosen, who has gotten to know Horowitz well over the past four years, spoke about her dedication to the film and her ability to balance her various responsibilities despite the hardships shes faced. Shes been through so much since her childhood, Rosen said, so I think that her ability to keep it together, get the grades that she does, focus on music the way she does, and persevere through everything is a testament to who she is, her strength and her talent.

Calhoun Principal Nicole Hollings also noted Horowitzs many strengths, and the reasons that she is an ideal role model for others. Aside from being an outstanding student who has taken rigorous courses throughout high school, Hollings said, Samantha has been involved in many community service opportunities, and has always given her time and help to others who need it. She is truly a role model to others, showing how to be strong, caring, and how to live life in the moment, making every moment count, no matter how difficult it might be to do that.

Horowitz said that her mothers health journey has inspired her to major in biology when she starts college next year, and that she plans to go into the medical field. Im really interested in studying the correlation between music and someone healing, she said, Although this journey has caused me a lot of suffering, its made me extremely passionate about what I want to do with my future, and honestly, it has made me into who I am today.

Aside from sharing the familys ordeal, the documentary raises awareness of rare diseases, educates about bone marrow transplants, encourages people to become bone marrow donors and promotes State Senate Bill S1377, which would require school districts to establish medical hardship waiver policies.

But Horowitz said that her overall goal in creating the documentary is to help others who may be going through similar struggles. The main purpose isnt just to share my moms story or to get our music out there, she said, but really, its for people who are going through similar situations to see that they arent alone because its not easy for everyone to talk about their condition the way my mom does, and not everyone has a family member that can make songs about their journey to comfort them but I believe this film has the power to change peoples perspectives on life and to show them that music truly is a coping mechanism.

She added that she hoped the film would teach people not to take life for granted, and to make the best of every negative situation.

See the original post:
Healing others with music - liherald

Bone Marrow Stem Cells Comments Off on Healing others with music – liherald | January 3rd, 2022

Abstract:

Over the last decade, stem cell-associated therapies are widely used because of their potential in self-renewable and multipotent differentiation ability. Stem cells have become more attractive for aesthetic uses and plastic surgery, including scar reduction, breast augmentation, facial contouring, hand rejuvenation, and anti-aging. The current preclinical and clinical studies of stem cells on aesthetic uses also showed promising outcomes. Adipose-derived stem cells are commonly used for fat grafting that demonstrated scar improvement, anti-aging, skin rejuvenation properties, etc. While stem cell-based products have yet to receive approval from the FDA for aesthetic medicine and plastic surgery. Moving forward, the review on the efficacy and potential of stem cell-based therapy for aesthetic and plastic surgery is limited. In the present review, we discuss the current status and recent advances of using stem cells for aesthetic and plastic surgery. The potential of cell-free therapy and tissue engineering in this field is also highlighted. The clinical applications, advantages, and limitations are also discussed. This review also provides further works that need to be investigated to widely apply stem cells in the clinic, especially in aesthetic and plastic contexts.

View original post here:
Exploring the potential of stem cell-based therapy for aesthetic and plastic surgery - Newswise

Skin Stem Cells Comments Off on Exploring the potential of stem cell-based therapy for aesthetic and plastic surgery – Newswise | December 23rd, 2021

Our cells are packed with unrealized potential. Almost every human cell contains the genetic information it needs to become any other kind of cell. A skin cell, for example, has the same genes as a muscle cell or a brain neuron, but in each type of cell only some of those genes are switched on, while others remain silent. Its a little like making different meals out of the same ingredients cupboard. If we understand the recipe behind each type of cell, then theoretically we can use this information to engineer every single cell type in the human body.

That is Mark Kotters goal. Kotter is the CEO and cofounder of bit.bioa Cambridge, UK, based company that wants to revolutionize clinical research and drug discovery by producing precisely engineered batches of human cells. Basic scientific research into new drugs and treatments often starts with tests in mice, or in the most widely used human cell lines: kidney cells and cervical cancer cells. This can be a problem, because the cells being experimented on may have major differences to the cells that a candidate drug is supposed to target in the human body. A drug that works in a mouse may turn out not to work when it's tested in humans. There is no mouse on this planet that has ever suffered from Alzheimers, it just doesnt exist, Kotter says. But testing a potential Alzheimers drug on a human brain cell engineered to have signs of Alzheimers disease could give a much clearer indication of whether that drug is likely to be successful.

Every cell type has its own little program, or postcodea combination of transcription factors that defines it, says Kotter. By inserting the right program into a stem cell, researchers can activate genes that code for these transcription factors and turn a stem cell into a specific type of mature cell. Unfortunately, biology has a way of fighting back. Cells often silence these genes, stopping the transcription factors from being produced. Kotters solutiondiscovered as part of his research at the University of Cambridgeis to insert this program in a region of the genome thats protected against gene silencing, something Kotter refers to as a genetic safe harbor.

Bit.bio currently sells two different reprogrammed cell lines: muscle cells and a specific kind of brain neuron, but the plan is to create bespoke cell lines for use in the pharmaceutical industry and academic research. What were doing with our partners in the industry now is to create genetic modifications that are relevant for diseases, Kotter says. He compares this approach to running software on a computer. By inserting the right bit of code into a cells genome, you can control how that cell behaves. That means that we can now run programs, and we can reprogram human cells, Kotter says. The cell reprogramming technology could also go well beyond model cell lines and help develop whole new kinds of treatment, such as cell therapy.

In some cell therapies, a patients own immune cells are grown outside of their body before being modified and inserted back into it to help fight a diseasea long and expensive process. One kind of cell therapy used to treat young people with leukemia costs more than 280,000 ($371,400) per patient. Bit.bios chief medical officer Ramy Ibrahim says that the firms technology could help drive down the cost of cell therapy and make it easier to manufacture immune cells at a large scale. Having abundant numbers of the right cell types that we can now make edits to, I think will be transformational, he says.

More Great WIRED Stories

See original here:
This Startup Is Makingand ProgrammingHuman Cells - Wired.co.uk

Skin Stem Cells Comments Off on This Startup Is Makingand ProgrammingHuman Cells – Wired.co.uk | December 23rd, 2021

"We started speaking with Kieron Jones and Andrew Strong as we were funded and started to execute our R&D plan, and the rest is history. We appreciate the variety of support services K2bio offers in addition to rental lab space," stated Kevin Slawin, CEO of Ponce Therapeutics. Ponce Therapeutics was the first client to enter into a contract with K2bio.

"We are very excited to welcome Ponce Therapeutics to the K2bio family," said Kieron Jones, Co-founder, CEO, and President of K2bio. "Our goal is to build a collaborative environment That allows companies within our facility to focus on efficiently developing their product. For companies outside of our facility, we offer a suite of contracted services to support their in-vivo and in-vitro needs as a long-term partner built on quality and timeliness."

About K2bio K2bio is a state-of-the-art facility with a unique model of providing preclinical contract research services and an incubator environment. We provide a unique and flexible co-working facility for high-potential, early-stage life science companies, with experienced biotech research managers and staff, in addition to a mouse vivarium to allow companies access to the research environment that they need to progress at an affordable cost. We've created the concierge of biolabs, offering researchers the option to add or subtract services based on their individual needs.

For more information, visit https://K2-biolabs.com.

About Ponce Therapeutics - Ponce Therapeutics is currently developing a biotechnology platform to restore young cells in the skin, targeting p16-expressing senescent cells for elimination. While initially focused on skin, Ponce plans to develop a wide-ranging portfolio of anti-aging products, which could ultimately lead to new cancer treatments. The elimination of pro-inflammatory senescent cells has been shown to suppress cancer and rejuvenate tissues by restoring stem cell niches to their healthy state. Ponce is headquartered in Miami, Florida, with research facilities located in Houston, TX.

For more information, visit https://poncetherapeutics.com.

SOURCE K2bio

See the original post:
K2bio Welcomes Ponce Therapeutics to Houston - PRNewswire

Skin Stem Cells Comments Off on K2bio Welcomes Ponce Therapeutics to Houston – PRNewswire | December 23rd, 2021

I first dismissed this as a fancy version of those old heat patches you can get in the chemist, but I couldnt have been more wrong. Embedded within the lightweight but stretchy plaster-type fabric is enough clove and safflower to help get your blood flowing, as well as borneol to reduce inflammation and pain. And they really work.

15, available at Victoriahealth.com.

Jones Road The Best Pencil in Ultra Opaque

You cant go wrong with this one-style-fits-all eye pencil from make-up maverick Bobbi Browns newest cosmetic venture, which can outline, graphic line, feline line, smoky smudge line, whatever you choose. Point it at your lids and it pretty much does the rest by itself, its the very definition of fuss-free for those who dont like to overthink their eyeliner.

20, available at Jonesroadbeauty.com.

Ffern Organic Seasonal Fragrance

This is as small batch and as sustainable as it gets. Its also highly exclusive as you have to sign up for each new-season limited-edition release. But youll be happy you did, with each perfume created by master perfumer Francois Robert and his protg Elodie Durande, and delivered in entirely sustainable packaging. My favourite this year was Spring 2021, which had top notes of ginger underpinned by neroli, jasmine sambac absolute and orange absolute.

Available at Ffern.co.

Read this article:
The 37 Best Beauty Products Of 2021 - British Vogue

Skin Stem Cells Comments Off on The 37 Best Beauty Products Of 2021 – British Vogue | December 23rd, 2021

The question really, is what should you be using retinol with. Hydrating ingredients like glycerin, peptides, ceramides, when sandwiched with your retinol, all help to support the integrity of the skin.

Ultimately, you should listen to your skin and let it be your guide. Ayodele advises keeping a diary noting any changes and taking pictures of your skin, comparing week one to week six. And remember: it is crucial to use SPF every day with retinol.

From the best formula for dark spots to products that are perfect for mature skins, heres Vogues edit of the best retinol creams and serums to try now:

The Best Retinol For Sensitive Skin: La Roche-Posay Retinol 0.3% + Vitamin B3 Serum

La Roche Posay - Retinol B3

La Roche Posay via Marionnaud.fr

La Roche-Posay knows its way around an excellent skincare product this serum is just one among many. Combining vitamin B3 with 0.3 per cent retinol, its a gentle one, and good for even the most sensitive skins.

Best Affordable Retinol: The Ordinary Granactive Retinoid 2% in Squalane

The Ordinary - mulsion de Granactive Retinoid* 2%

The Ordinary via Nocibe.fr

The Ordinary is renowned for bringing us premium ingredients at affordable prices, and this product comes in at well under 10. High potency, minimal irritation, low price whats not to love?

Retinol for Beginners: REN's Organic Retinoid Youth Serum for Sensitive Skin.

REN - Srum Jeunesse Bio Retinoid

Concerned about dryness and irritation? This REN formula is suitable for even the most sensitive skin, especially those that have previously reacted to retinol. The formula's unique delivery system allows for effective cell renewal without causing irritation.

Best Retinol Serum: Institut Esthederm Intensive Retinol Face Serum

Institut Esthederm - Intensive Retinol

6347

Institut Esthederm via Nocibe.fr

Perfect for deep-set wrinkles, this emollient-rich retinol serum effectively locks in moisture while working hard to bring plumpness back to the most sullen skin.

Best Retinol Booster: Paulas Choice 1% Retinol Booster

Paula's Choice - Boost Retinol 1%

Paula's Choice via Amazon.fr

Designed to be added to your favourite serum or moisturiser, Paulas Choice 1% Retinol Booster offers a more customisable approach to retinol use, making it perfect for beginners.

Best Retinol Overnight Mask: Allies of Skin 1A Retinal and Peptides Overnight Mask

Allies of Skin - 1A Retinal + Peptides Overnight Mask

Allies of Skin via Galerieslafayette.com

This antioxidant-rich formula delivers a jolt of nourishment to thirsty mature skin. Fortified with Ally-R, an encapsulated form of time-release retinaldehyde (a vitamin A even more powerful than retinol), this moisture barrier-maintaining formula helps promote firmness and smoothness in lacklustre skin.

Best Retinol For Acne: Lixir Night Switch Retinol 1%

Lixir Skin - Srum pour le visage Night Switch Retinol 1%

Lixir Skin via Net-a-porter.com

Lixirs Night Switch range is based on the idea that using too many active ingredients at once can confuse the skin. Instead, it advocates the frequent switching up of products. Night Switch Retinol 1% refines skin texture and boosts plumpness and firmness.

The most nourishing: Ideal Resource Youth Oil Concentrate with retinol by Darphin

Darphin - Ideal Resource Concentr huile jeunesse au retinol

9063

Darphin via Marionnaud.fr

Thanks to micro-encapsulated retinol, these mini-doses accelerate cell renewal and reinforce collagen production, helping to fight the signs of aging. Each one also contains a blend of plant oils that nourish the face and plump the eye area.

Fastest results: Este Lauder Perfectionist Pro

Este Lauder - Perfectionist Pro

12090

Este Lauder via Marionnaud.fr

Only 28 days to see visible results on the skin: that's the promise of this express treatment by Este Lauder. The result is smoother, softer, supple skin and a more radiant complexion. A must-have.

The best face cream: A-Passioni Retinol Cream by Drunk Elephant

Drunk Elephant - Crme A-Passioni Retinol

Drunk Elephant via Cultbeauty.com

Specially designed for sun-damaged skin, this cream combines 1% retinol with a cocktail of fruit extracts such as passion fruit, apricot and winter cherry to reduce the appearance of fine lines and deep wrinkles.

The Best Retinol Cream Available Over The Counter: SkinCeuticals Retinol 0.3% Cream

SkinCeuticals - Retinol 0.3 Peeling De Nuit Rides & Imperfections

SkinCeuticals via Nocibe.fr

The SkinCeuticals formula utilises encapsulation technology, to minimise irritation and allow the chamomile-derived bisabolol to counter any that does occur.

Best Retinol Night Oil: Sunday Riley Luna Sleeping Night Oil

Luna - Huile de nuit Sunday Riley

Luna via Cultbeauty.com

Sunday Rileys bestselling Luna Sleeping Night Oil combines retinoid oil with blue tansy and cold-pressed chia, grape seed and avocado oils to renew the skins surface overnight. A celebrity favourite.

Best Retinol For Wrinkles: Elizabeth Arden Retinol Ceramide Capsules Line Erasing Night Serum

Elizabeth Arden - Retinol Ceramide Capsules

5340

Elizabeth Arden via Marionnaud.fr

By combining retinol with skin-loving ceramides, Elizabeth Arden allows you to swerve any flaking. The capsule format means you wont apply too much, and also keeps the formula fresh.

Best Retinol For Dullness: Medik8 R-Retinoate Intense

Medik8 - Crme rajeunissante intense r-Retinoate

Medik8 via Net-a-porter.com

Suffering from dull skin? Look no further than Medik8s ultimate time-defying treatment. Combining retinol with clinical-strength retinoic acid, as well as nourishing peptides, ceramides, and hyaluronic acid, this miracle cream works overnight to plump and smooth the skin, firming it up and leaving it brighter and more replenished.

Best Retinol For Mature Skin: LOral Paris Pure Retinol Revitalift Laser Night Serum

L'Oral - Revitalift Laser Srum Nuit Rtinol Pur

For those in need of some extra TLC, LOrals powerhouse serum is formulated with a high concentration of pure retinol. One of the brands most potent blends, it targets fine lines and wrinkles, while added hyaluronic acid replenishes the skin with moisture.

Best Retinol Alternative: The Inkey List Bakuchiol Moisturiser

The Inkey List - Bakuchiol Moisturiser

The Inkey List via Cultbeauty.com

If youre finding retinol too harsh, there is a gentler alternative: bakuchiol, a plant-based super ingredient. Powered by bakuchiol, this moisturiser works to reduce the appearance of fine lines and wrinkles and smooths uneven skin, without causing irritation. Meanwhile added squalane, glycerin and sach inchi oil provide hydration and nourishment.

Best Retinol For Brightening: StriVectin Super-C Retinol Brighten & Correct Vitamin C Serum

Strivectin - Super-C Retinol Srum Illuminateur & Correcteur Vitamine C

Strivectin via 1001pharmacies.com

With two hardworking actives vitamin C and retinol this lightweight serum is a multi-tasking wonder. Expect it to brighten, smooth, ease fine lines and strengthen the skin barrier, too.

Best Retinol For Tackling Signs Of Ageing: Sarah Chapman Skinesis Retinol Oil

Combining plant stem cells, platinum peptide delivery and time-release retinol, Sarah Chapmans Skinesis Platinum Stem Cell Elixir is a true super serum, acting on fine lines and wrinkles, increasing collagen synthesis, and improving skin elasticity.

Available at Lookfantastic.com.

Best Retinol For Wrinkles: Murad Retinol Youth Renewal Serum

Murad Cosmetic - Resurgence Renewing Eye Cream

Murad Cosmetic via Nocibe.fr

With clever three-part retinol technology, which comprises a fast-acting retinoid, a time-released retinol and a retinol booster, expect uneven texture (and the like) to be addressed from all angles with the help of this Murad serum.

The best night cream with retinol: Lancme Corrective Night Concentrate

Lancme - Concentr nuit correcteur

Lancme via Galerieslafayette.com

A powerful treatment, rich in retinol, vitamin A and hyaluronic acid, which moisturizes and firms the skin while reducing the appearance of wrinkles. However, we recommend avoiding it if you have sensitive skin.

This article was previously published on Vogue.co.uk

Original post:
20 of the best retinol creams & serums for every skin type - VOGUE Paris

Skin Stem Cells Comments Off on 20 of the best retinol creams & serums for every skin type – VOGUE Paris | December 23rd, 2021

DUBLIN--(BUSINESS WIRE)--The "Global Regenerative Medicine Market Size, Share & Trends Analysis Report by Product (Cell-based Immunotherapies, Gene Therapies), by Therapeutic Category (Cardiovascular, Oncology), and Segment Forecasts, 2021-2027" report has been added to ResearchAndMarkets.com's offering.

The global regenerative medicine market size is expected to reach USD 57.08 billion by 2027, growing at a CAGR of 11.27% over the forecast period.

Recent advancements in biological therapies have resulted in a gradual shift in preference toward personalized medicinal strategies over the conventional treatment approach. This has resulted in rising R&D activities in the regenerative medicine arena for the development of novel regenerative therapies.

Furthermore, advancements in cell biology, genomics research, and gene-editing technology are anticipated to fuel the growth of the industry. Stem cell-based regenerative therapies are in clinical trials, which may help restore damaged specialized cells in many serious and fatal diseases, such as cancer, Alzheimer's, neurodegenerative diseases, and spinal cord injuries.

For instance, various research institutes have adopted Human Embryonic Stem Cells (hESCs) to develop a treatment for Age-related Macular Degeneration (AMD).

Constant advancements in molecular medicines have led to the development of gene-based therapy, which utilizes targeted delivery of DNA as a medicine to fight against various disorders.

Gene therapy developments are high in oncology due to the rising prevalence and genetically driven pathophysiology of cancer. The steady commercial success of gene therapies is expected to accelerate the growth of the global market over the forecast period.

Regenerative Medicine Market Report Highlights

Key Topics Covered:

Market Variables, Trends, & Scope

Competitive Analysis

Covid-19 Impact Analysis

Regenerative Medicine Market: Product Business Analysis

Regenerative Medicine Market: Therapeutic Category Business Analysis

Regenerative Medicine Market: Regional Business Analysis

Companies Mentioned

For more information about this report visit https://www.researchandmarkets.com/r/kovhgl

Here is the original post:
Global Regenerative Medicine Market is Expected to Reach USD 57.08 Billion by 2027, Growing at a CAGR of 11.27% Over the Forecast Period. -...

Spinal Cord Stem Cells Comments Off on Global Regenerative Medicine Market is Expected to Reach USD 57.08 Billion by 2027, Growing at a CAGR of 11.27% Over the Forecast Period. -… | December 23rd, 2021

Image by MasterTux from Pixabay

The brain is the most complex thing in the universe! It is made up of an intricate network of cells called neurons. Neurons are long, elongated, fibre-like cells, and billions of them form a complex network of connections called synapses. Neurons are not physically connected, but they transmit messages between them electrochemically as non-contact nerve impulses. And, there are trillions of such connections in our brain. However, in the initial stages, when the embryo is developing, the primitive neurons are rounded and lack connection to each other.

So how do these innocuous-looking rounded cells become highly connected elongated neurons? Researchers from Manipal Institute of Regenerative Medicine, Bengaluru, found the key gene that assists in making this happen. The study published in iScience journal shows that a gene called Superoxide dismutase 2 (SOD2), hitherto known to be involved in another function, is caught performing a completely different function -- promoting the generation of neurons. The authors state that although a complete understanding of the exact mechanism of how this happens remains to be unravelled, there is a possibility that one day, human nerve cells could be grown from any human tissue cells, thereby opening therapeutic avenues for patients with nerve or spinal cord injuries.

Existing literature indicates that SOD2 basically mops oxygen radicals inside the cell. During normal metabolism, cell components called mitochondria generate energy-rich molecules from carbon sources. However, the process produces an undesirable byproduct called oxygen radicals. These are oxygen molecules with an extra electron on them which makes them highly reactive with other molecules, thereby causing toxicity in the cells. The usually designated job of the SOD2 gene is to minimise this damage by mopping up these free oxygen radicals. The researchers found that the SOD2 mop had another function: to help the cells become neural precursors, which in turn become highly connected neurons. The process is termed Differentiation.

Scientists differentiate a neuron cell from an embryonic cell by its shape and by looking for specific proteins produced only in these neuronal cells. These proteins are markers for that particular cell type.

To decipher SOD2s role in the differentiation process, the researchers introduced copies of the SOD2 gene into mouse embryonic stem cells grown in the lab (cultured cells). When they increased the number of copies of the gene, the embryonic cells changed into a neuron-like appearance and exhibited markers unique to cells of neurons. However, the markers were absent when they eliminated the SOD2 gene.

In our study, using embryonic cells, we show that when SOD2 is knocked down or eliminated and subjected to differentiation, the embryonic cells could not specifically change into a neuron. However, this did not compromise the differentiation to other tissues, says Dr Anujith Kumar, corresponding author of the paper.

Owing to numerous ethical problems associated with procuring human embryonic cells, the researchers used fibroblasts or skin cells of mice and intended to convert them into stem cells that mimic embryonic cells. They achieved this by introducing another gene called OCT4 into the fibroblast cells. When the researchers transferred the SOD2 gene and OCT4, fibroblasts stopped being fibroblasts and changed into neurons, but not pluripotent stem cells. (Pluripotent stem cells are master cells that can differentiate into almost any tissue cell type).

So how does SOD2 actually do this? The researchers hypothesised that SOD2 could be having other functions that involved mitochondria. However, they had to first observe the microscopic mitochondria inside the cell to test their hypothesis. To do so, they tagged a protein found on the mitochondrial surface with a fluorescent dye. Under a fluorescent microscope, these tagged mitochondria appear fluorescent. When the SOD2 gene was introduced in the cell, they could see that the mitochondria were longer than they would be. This is because the individual mitochondria had fused to produce longer filament like mitochondria.

Mitochondria fuse because of a protein called MFN2. Researchers found that the expression of SOD2 was causing the overproduction of MFN2 protein. The fusing of mitochondria was somehow related to the embryonic cells elongating and growing into neurons. But how exactly that happens is still a mystery.

Mechanistically, it is unclear how mitochondrial fusion and fission favour commitment to neuron formation, says Dr Kumar. However, he speculates that As neurons are dynamic cells and dependent on excessive energy molecule ATP (adenosine tri-phosphate), probably mitochondrial fusion favours the energy supply and in turn facilitates neural formation.

The research done on mouse cells needs to be repeated with human cells, and hopefully, the results will one day be helpful to treat nerve injuries. At this juncture, the current findings on differentiated neurons thus produced are suitable for research purposes to study neuronal development. It could also be used to develop an experimental framework to model diseases in the cells by growing them in the lab. Such experiments could be utilised for drug screening and also where researchers test the effect of promising drugs by trying them on these cells.

This article has been run past the researchers, whose work is covered, to ensure accuracy.

More:
Scientists unravel a gene function that helps the genesis of neurons - Research Matters

Spinal Cord Stem Cells Comments Off on Scientists unravel a gene function that helps the genesis of neurons – Research Matters | December 23rd, 2021

Researchers globally produce hundreds of thousands of studies annually. It can be difficult to know if at some time in the future they will be the foundation for a disease cure or a technology such as CRISPR that revolutionizes medicine. But many are exciting for what they point to or how they spike the imagination. Heres a look at 10 of the more compelling research stories of the year.

Type 1 Diabetes Therapy Showed Promise in Early-Stage Trial

Vertex Pharmaceuticalsannouncedpositive early data from the first patient in its Phase I/II study of VX-880 in type 1 diabetes (T1D). The therapy is a stem cell-derived, fully differentiated pancreatic islet cell replacement therapy. T1D is an autoimmune disease, where the immune system attacks the islet cells in the pancreas, which is where insulin is produced. This leads to loss of insulin production and problems with blood sugar control.

In the study, the patient received a single infusion of VX-880 at half the target dose along with immunosuppressive therapy. The patient showed successful engraftment and demonstrated fast and robust improvements in several measurements, including increases in fasting and stimulated C-peptide, improvements in glycemic control, including HbA1c. It also resulted in less need for medical insulin. The therapy appeared well tolerated.

Some Alzheimers Plaques May Be Protective

Source: BioSpace

One of the hallmarks of Alzheimers disease is the buildup of beta-amyloid plaques in the brain. Yet many drugs that cleared amyloid dont seem to improve memory or cognition. Many researchers believe amyloid is only part of the issue, perhaps triggering inflammation that causes damage to the brain. New research out of theSalk Instituteadded a new twist, suggesting that some of the plaques may be protective. A type of immune cell in the brain, microglia, was long believed to inhibit the growth of plaques by eating them. Their research, however, demonstrated that microglia promote the formation of what are being dubbed dense-core plaques, which transports the wispy plaque away from neurons. They published their research in the journalNature Immunology.

We show that dense-core plaques dont form spontaneously, said Greg Lemke, a professor in Salks Molecular Neurobiology Laboratory. We believe theyre built by microglia as a defense mechanism, so they may be best left alone. There are various efforts to get the FDA to approve antibodies whose main clinical effect is reducing dense-core plaque formation, but we make the argument that breaking up the plaque may be doing more damage.

5 Genes Associated with Lewy Body Dementia, with Implications for Alzheimers and Parkinsons

Research conductedby theNIHs National Institute of Neurological Disorders and Stroke (NINDS)identified five genes that appear to play a critical role in whether a person will suffer from Lewy body dementia, a type of dementia where the brain accumulates clumps of abnormal protein deposits known as Lewy bodies. The data also supported Lewy body dementias connections to Parkinsons disease and connections to Alzheimers disease. The research was published in the journalNature Genetics.

Sonja Scholz, investigator at the NIHs NINDS and senior author of the study, said, Our results support the idea that this may be because Lewy body dementia is caused by a spectrum of problems that can be seen in both disorders. We hope that these results will act as a blueprint for understanding the disease and developing new treatments.

Why Obesity is Associated with Inflammation

Although obesity is linked with many inflammatory conditions, including cancer, diabetes, heart disease, and infection, why isnt it well understood? Researchers atUT Southwestern Medical Centeridentifieda type of cell that, at least in mice, is responsible for triggering inflammation in fat tissue. In obese individuals, white adipose tissue (WAT), stores excess calories in the form of triglycerides. In obesity, WAT is overworked, fat cells start to die, and immune cells are activated. The research team identified an adipose progenitor cell (APC), a precursor that later generates mature fat cells. These new cells are called fibro-inflammatory progenitors (FIPs) and they make signals that encourage inflammation.

Whats Behind Brain Fog in COVID-19 Patients

One of several unusual symptoms reported in COVID-19 patients is what is dubbed brain fog or COVID brain, but in medical terminology, is called encephalopathy. It appears to be loss of short-term memory, headaches and confusion. At its most severe, it is associated with psychosis and seizures. Researchers atMemorial Sloan Kettering Cancer Centerpublishedresearch in the journalCancer Cellthat explains the underlying cause of brain fog.

Jan Remsik, a research fellow in the lab, says, We found that these patients had persistent inflammation and high levels of cytokines in their cerebrospinal fluid, which explained the symptoms they were having.

New Compound Appears to Reverse Neuron Damage Caused by ALS

Researchers atNorthwestern Universityidentifieda compound that appears to reverse the ongoing degeneration of upper motor neurons associated with amyotrophic lateral sclerosis (ALS). ALS is a progressive neurodegenerative disease affecting nerve cells in the brain and spinal cord. As the motor neurons degenerate, they eventually die and the ability of the brain to initiate and control muscle movement is lost. With the disease, people may lose the ability to speak, eat, move and breathe. The compound, NU-9, was developed in the laboratory of Richard B. Silverman, the Patrick G. Ryan/Aon Professor of Chemistry at Northwestern. It can reduce protein misfolding in critical cell lines. The compound is also not toxic and can cross the blood-brain barrier. They published their research inClinical and Translational Medicine.

How Astrocytes Fix Damage in the Brain

Investigators withCharit Universittsmedizin Berlindescribed how a type of glial cell, called astrocytes, plays a role in protecting surrounding brain tissue after damage. They become part of a defense mechanism called reactive astrogliosis, which helps form scars, and contains inflammation and controls tissue damage. Astrocytes are also able to ensure the nerve cells survive that are located immediately next to the tissue injury, which preserves the function of neuronal networks. The mechanism was the protein drebrin, which controls astrogliosis. Astrocytes require drebrin to form scars and protect the surrounding tissue. Drebrin regulates the reorganization of the actin cytoskeleton, an internal scaffold that maintains astrocyte mechanical stability.

A New Spin on Jurassic Park?

In the books and filmsJurassic Park, researchers collected the blood from insects trapped in amber and cloned dinosaurs. A researcher from theUniversity of Minnesota is putting a more practical spin on amber research. Amber is the fossilized resin from a now-extinct species of pine, Sciadopityaceae. It was formed about 44 million years ago. In the Baltic regions, amber has been used for hundreds of years for traditional medicines for pain relief and its anti-inflammatory and anti-infective properties. Previous research has suggested that amber molecules might have an antibiotic effect. The team extracted even more chemicals from amber samples that appeared to show activity against gram-positive, antibiotic resistant bacteria.

They identified 20 compounds using GC-MS in the amber, most prominent being abietic acid, dehydroabietic acid and palustric acid, compounds with known biological activity. They also acquired a Japanese umbrella pine, the closest living species to theSciadopityaceae, and extracted resins and identified sclarene, a molecule present in the amber extracts that could potentially undergo chemical transformations to produce the bioactive molecules found in the Baltic amber samples.

The most important finding is that these compounds are active against gram-positive bacteria, such as certain Staphylococcus aureus strains, but not gram-negative bacteria, said Connor McDermott, a graduate student in the laboratory of Elizabeth Ambrose, who led the research. This implies the composition of the bacterial membrane is important for the activity of the compounds.

Genetics of People Who Live 105 or Older

A new study of 81 semi-supercentenarianspeople 105 years of age or olderand supercentenarians110 years or older from across Italy, werestudiedby researchers from theUniversity of Bologna, Italy andNestle Research in Lausanne, Switzerland. They compared genetic data from these extraordinary agers to 36 healthy people from the same region whose age, on average, was 68 years. Blood samples were drawn, and whole-genome sequencing was performed. They then compared their data with another previously published study that analyzed 333 Italians over 100 years of age and 358 people who were about 60 years of age. They published their research in the journal eLife.

Scientists identified five common genetic changes that were most frequent in the 105+/110+ groups, between two genes known as COA1 and STK17A. Analysis showed the same variants in the people over 100. Computational analysis predicted these variations most likely modulated the expression of three different genes: STK17A, COA1 and BLVRA.

Junk DNA and Aging

For a long time, so-called junk DNA was thought to play no role in inheritance or metabolism. Increasingly, this non-coding DNA is found to play a significant role in gene regulation. Researchers atWashington State Universityrecently identifieda DNA region called VNTR2-1 that seems to drive telomerase gene activity. In addition, it appears to prevent aging in some types of cells. Telomeres are the ends of chromosomes, and their length is associated with aging that is to say, as the older you get, the shorter they get because every time cells divide, the telomeres get a tiny bit shorter. When they get too short, cells no longer reproduce. But in some reproductive cells and cancer cells, telomerase gene activity resets telomeres to the same length when DNA was originally copied, creating a kind of immortality for those cells.

Read more here:
The 10 Most Compelling Research Stories of 2021 PharmaLive - PharmaLive

Spinal Cord Stem Cells Comments Off on The 10 Most Compelling Research Stories of 2021 PharmaLive – PharmaLive | December 23rd, 2021

As 2021 draws to a close, COVID-19 remains a pervasive influence over life at Yale and across the world. And yet, even as a new surge in cases portends a winter of uncertainty, a look back at the past year offers many reminders of just how much more we now know about this global threat, the remarkable importance of vaccines and other public health measures, and the resiliency of humankind.

After reviewing the many hundreds of stories published on Yale News this year, we identified several about Yales response to the pandemic that especially resonated with readers and that best capture how the university and our experts have helped make sense of and respond to this disruptive disease. Youll find a list below.

In a second list below, we highlight several non-COVID stories about the people and projects that inspired us and gave us hope for a healthier and more equitable 2022 and the new initiatives that will position the Yale community to be a leader in tackling the challenges of the future.

As the new year began, Yale News reviewed how the campus community pulled together to do the work of the university in the face of unprecedented challenges, and looked ahead to the spring semester.

As chair of the White Houses COVID-19 Equity Task Force, Dr. Marcella Nunez-Smith, the C.N.H Long Professor of Internal Medicine, Public Health, and Management at Yale, became a national voice on racial inequities in COVID-19 treatment and outcomes. Meanwhile, Abbe Gluck, the Alfred M. Rankin Professor of Law and professor of internal medicine at Yale School of Medicine, was named special counsel to the Biden administrations COVID-19 Response team. She also worked in the Office of White House Counsel on other health care issues, including the Affordable Care Act..

In early January, Yale launched its COVID-19 vaccination program in the Lanman Center at Payne Whitney Gymnasium, as vaccines from Moderna and Pfizer gained final approvals for use in the United States.

After spending nearly a year cataloguing and exploring the SARS-CoV-2 genomes intricate makeup, a team of Yale scientists revealed a map of it with an unprecedented level of detail, including more than 100 identifiable structures.

In February, Yale scientists developed a new class of antiviral agents that showed promise for creating COVID-19 therapeutics exhibiting particular effectiveness when used in tandem with the drug remdesivir, another antiviral medication approved for use against the virus.

For most children, COVID-19 infection results in a relatively mild illness. In a few cases, however, a severe immune reaction occurs. During the spring, Yale research found that such rare, life-threatening reactions may be triggered by high levels of alarmins, molecules that make up part of the innate immune system.

The Lanman Center, which early in the pandemic was converted into a field hospital, and later into Yales primary vaccination center, returned to being simply a gym during the summer, as the vaccination operations were shifted to the Rose Center on Ashmun Street.

In July, a Yale-led study found that the COVID-19 vaccination campaign launched in the United States in late 2020 had, at that point, saved some 279,000 lives and prevented 1.25 million hospitalizations. Researchers warned, however, that these gains could be reversed by the highly transmissible Delta variant.

In September, Yale researchers provided important insights into what were then becoming known as breakthrough COVID-19 cases in which fully vaccinated individuals are infected by SARS-CoV-2 and which populations are particularly vulnerable to serious breakthrough illness.

Since the start of the COVID-19 pandemic, scientists had been unclear about how long immunity lasts after an unvaccinated person is infected. In October, a Yale-led team of researchers found an answer: Strong protection following natural infection is short-lived, lasting as little as three months or less.

In October, a Yale-led study found that two of the commonly used COVID-19 vaccines provide protection against multiple variants of the virus that causes the disease, including the highly infectious Delta variant. Their findings also showed that those infected with the virus prior to vaccination exhibit a more robust immune response to all variants than those who were uninfected and fully vaccinated.

In November, a study by Yale political scientists and public health experts found that, when it comes to persuading people to get vaccinated against COVID-19, its more effective to appeal to community spirit than to self-interest.

Breakthrough SARS-CoV-2 infections tend to be mild, but Yale research published in December showed that more older adults have developed severe breakthrough cases during the Delta variant phase of the pandemic, particularly after a longer period of time had elapsed since their last vaccination. The findings, researchers say, reveal the importance of booster vaccinations.

White evangelical Christians have resisted getting vaccinated against COVID-19 at higher rates than other religious groups in the U.S. In November, a Yale study found that persuading these vaccine holdouts had only become more difficult.

In December, as a new COVID-19 variant, Omicron, began to spread throughout the world, public health leaders scrambled to better understand how contagious the new variant is and whether existing vaccines are effective against it. Yale doctors offered insights into the emerging threat.

In February, Yale announced the establishment of the Wu Tsai Institute, an ambitious new research enterprise that will supercharge Yales neuroscience initiative and position the university to reveal the brain in its full, dynamic complexity, thanks to a historic gift from Joseph C. Tsai 86, 90 J.D. and his wife, Clara Wu Tsai.

As a historic renovation of the Peabody Museum proceeds, conservator Mariana Di Giacomo is charged with keeping a close eye on the iconic mural The Age of Reptiles, by celebrated artist Rudolph Zallinger. The experience has allowed her to appreciate layers of detail. In February, Yale News caught up with her and shared a dazzling gallery of images.

In a promising early trial, researchers from Yale reported in February that patients with spinal cord injuries experienced substantial improvements in motor function such as the ability to walk or to use their hands after an intravenous injection of bone marrow-derived stem cells.

After 30 months of renovations, the redesigned Humanities Quadrangle formerly the Hall of Graduate Studies put a vibrant new face on Yales longstanding excellence in the humanities. The refurbished building includes dynamic spaces that promote connections among departments and programs and the cultivation of new ideas.

The late Jeremy Ayers once known as the gender-bending performance artist Silva Thin may seem like an unlikely namesake for an ant. But thanks to Yale ecologist Douglas B. Booher and rock star Michael Stipe, who shared a decades-long friendship with Ayers, a new species from the forests of Ecuador will honor his legacy and his reverence for the diversity of life.

During the summer, the university announced that present and future students at Yale Universitys drama school will no longer pay tuition, thanks to a landmark $150 million gift from entertainment executive and philanthropist David Geffen.

Psilocybin, a psychedelic drug found in some mushrooms, has long been studied as a potential treatment for depression. Yale research published in July detailed exactly what happens in the brain after a dose of psilocybin, and what makes its medicinal properties so promising.

In August, Yale scientists published a study of atmospheric patterns on Mars and Saturns moon Titan that will help lay the foundation for more accurate forecasts of weather on other worlds. Researchers say such forecasts will be vital to the safety and success of future research missions.

In 1965, Yale scholars created a sensation with the revelation of the Vinland Map, which was thought to be the earliest known European depiction of the New World. This summer, a team of Yale researchers said it proved the map to be an elaborate 20th-century forgery.

In October, a series of performances by the Yale Glee Club, Yale Bands, and the Yale Symphony Orchestra held in each of Yales residential college courtyards marked a return to live music on campus following a year of lockdowns and a response to the Black Lives Matter protests of 2020. (With video.)

In November, Yale and the City of New Haven reconfirmed their historic, three-century partnership for a new generation, announcing a six-year commitment that increases the universitys annual voluntary financial contribution to the city and creates bold opportunities for inclusive economic growth that benefit the entire community.

Tony Reno, now in his ninth season as head coach of the Yale football team, is more focused on creating a culture of responsibility, camaraderie, and integrity than on wins and losses but that hasnt kept the Bulldogs from finding success on the field.

On the long road to Yale College, Obed Gyedu-Larbi labored as a domestic aide and Greyhound baggage handler. He also founded a non-profit to feed and clothe homeless people in New York City. For me, he said, it was important to not only work hard for myself.

Excerpt from:
2021: The year in review | YaleNews - Yale News

Spinal Cord Stem Cells Comments Off on 2021: The year in review | YaleNews – Yale News | December 23rd, 2021

Find out who can be a stem cell or bone marrow donor, and how to register.

A stem cell or bone marrow transplant is an important treatment for some people with types of blood cancer such as leukaemia, lymphoma and myeloma.

A transplant allows you to have high doses of chemotherapy and other treatments. The stem cellsare collected from the bloodstream or the bone marrow.Peoplehave a transplant either:

To be a donor you need to have stem cells that match the person you are donating to. To find this out, you have a blood test to look at HLA typing or tissue typing.

Staff in the laboratory look at the surface of your blood cells. They compare them to the surface of the blood cells of the person needing a transplant.

Everyone has their own set of proteins on the surface of their blood cells. The laboratory staff look for proteins called HLA markers and histocompatibility antigens. They check for 10 HLA markers. The result of this test shows how good the HLA match is between you and the person who needs the cells.

Abrother or sisteris most likely to be a match. There is a 1 in 4 chance of your cells matching.This is called a matched related donor (MRD) transplant.Anyone else in the family is unlikely to match. This can be very frustrating for relatives who are keen to help.

Sometimes if your cells are a half (50%) match, you might still be able to donate stem cells or bone marrow to a relative. This is called a haploidentical transplant.

You can't donate stem cells or bone marrow to your relative if you're not a match.

It's sometimes possible to get a match from someoneoutside of the family. This is calleda matched unrelated donor. To find a matched unrelated donor, it'susually necessary to search large numbers of people whose tissue type has been tested. So doctorssearch national and international registers to try to find a match for your relative.

Even if you can't donate to your relative, you might be ableto become a donor for someone else. You can do this by contacting one of the UK registers.

There are different donor registersin the UK.These work with each otherand with international registersto match donors with people who need stem cells. This helps doctors find donors for their patients as quickly as possiblefrom anywhere in the world.

Each registry has specific health criteriaand listmedical conditions that mightpreventyou from donating. Check their websitefor this information. Once registered, the organisation will contactyou if you are a match for someone who needs stem cells or bone marrow.

British Bone Marrow Registry (BBMR)

To register with the BBMR, you mustbe a blood donor. BBMR would like toregister those groups they are particularly short of ontheir register.This includes men between the ages of 17 and 40. And womenaged between 17 and 40 who are from Black, Asian, and minority ethnicities and mixed ethnicity backgrounds.

You have a blood test for tissue typing. Your details are kept on file until you are 60.

Anthony Nolan

You must be aged between 16 and 30 to register with Anthony Nolan. You have a cheek swab to test fortissue typing. Your details are kept on the register until you are 60.

Welsh Bone Marrow Donor Registry

You must be aged between 17 and 30 and your details are kept on the register until you are 60. You have a blood test for tissue typing.

DKMS

To register you must be aged between 17 and 55. You havea cheek swab for tissue typing. Your details stay on the register until your61st birthday.

This page is due for review. We will update this as soon as possible.

Link:
Who can donate stem cells or bone marrow? | Stem cell and ...

Bone Marrow Stem Cells Comments Off on Who can donate stem cells or bone marrow? | Stem cell and … | December 23rd, 2021

Bone marrow is the spongy tissue inside some of the bones in the body, including the hip and thigh bones. Bone marrow contains immature cells called stem cells.

Many people with blood cancers, such as leukemia and lymphoma, sickle cell anemia, and other life threatening conditions rely on bone marrow or cord blood transplants to survive.

People need healthy bone marrow and blood cells to live. When a condition or disease affects bone marrow so that it can no longer function effectively, a marrow or cord blood transplant could be the best treatment option. For some people, it may be the only option.

This article looks at everything there is to know about bone marrow.

Bone marrow is soft, gelatinous tissue that fills the medullary cavities, or the centers of bones. The two types of bone marrow are red bone marrow, known as myeloid tissue, and yellow bone marrow, known as fatty tissue.

Both types of bone marrow are enriched with blood vessels and capillaries.

Bone marrow makes more than 220 billion new blood cells every day. Most blood cells in the body develop from cells in the bone marrow.

Bone marrow contains two types of stem cells: mesenchymal and hematopoietic.

Red bone marrow consists of a delicate, highly vascular fibrous tissue containing hematopoietic stem cells. These are blood-forming stem cells.

Yellow bone marrow contains mesenchymal stem cells, or marrow stromal cells. These produce fat, cartilage, and bone.

Stem cells are immature cells that can turn into a number of different types of cells.

Hematopoietic stem cells in the bone marrow give rise to two main types of cells: myeloid and lymphoid lineages. These include monocytes, macrophages, neutrophils, basophils, eosinophils, erythrocytes, dendritic cells, and megakaryocytes, or platelets, as well as T cells, B cells, and natural killer (NK) cells.

The different types of hematopoietic stem cells vary in their regenerative capacity and potency. They can be multipotent, oligopotent, or unipotent, depending on how many types of cells they can create.

Pluripotent hematopoietic stem cells have renewal and differentiation properties. They can reproduce another cell identical to themselves, and they can generate one or more subsets of more mature cells.

The process of developing different blood cells from these pluripotent stem cells is known as hematopoiesis. It is these stem cells that are needed in bone marrow transplants.

Stem cells constantly divide and produce new cells. Some new cells remain as stem cells, while others go through a series of maturing stages, as precursor or blast cells, before becoming formed, or mature, blood cells. Stem cells rapidly multiply to make millions of blood cells each day.

Blood cells have a limited life span. This is around 120 days for red blood cells. The body is constantly replacing them. The production of healthy stem cells is vital.

The blood vessels act as a barrier to prevent immature blood cells from leaving bone marrow.

Only mature blood cells contain the membrane proteins required to attach to and pass through the blood vessel endothelium. Hematopoietic stem cells can cross the bone marrow barrier, however. Healthcare professionals may harvest these from peripheral, or circulating, blood.

The blood-forming stem cells in red bone marrow can multiply and mature into three significant types of blood cells, each with its own job:

Once mature, these blood cells move from bone marrow into the bloodstream, where they perform important functions that keep the body alive and healthy.

Mesenchymal stem cells are present in the bone marrow cavity. They can differentiate into a number of stromal lineages, such as:

Red bone marrow produces all red blood cells and platelets and around 6070% of lymphocytes in human adults. Other lymphocytes begin life in red bone marrow and become fully formed in the lymphatic tissues, including the thymus, spleen, and lymph nodes.

Together with the liver and spleen, red bone marrow also plays a role in getting rid of old red blood cells.

Yellow bone marrow mainly acts as a store for fats. It helps provide sustenance and maintain the correct environment for the bone to function. However, under particular conditions such as with severe blood loss or during a fever yellow bone marrow may revert to red bone marrow.

Yellow bone marrow tends to be located in the central cavities of long bones and is generally surrounded by a layer of red bone marrow with long trabeculae (beam-like structures) within a sponge-like reticular framework.

Before birth but toward the end of fetal development, bone marrow first develops in the clavicle. It becomes active about 3 weeks later. Bone marrow takes over from the liver as the major hematopoietic organ at 3236 weeks gestation.

Bone marrow remains red until around the age of 7 years, as the need for new continuous blood formation is high. As the body ages, it gradually replaces the red bone marrow with yellow fat tissue. Adults have an average of about 2.6 kilograms (kg) (5.7 pounds) of bone marrow, about half of which is red.

In adults, the highest concentration of red bone marrow is in the bones of the vertebrae, hips (ilium), breastbone (sternum), ribs, and skull, as well as at the metaphyseal and epiphyseal ends of the long bones of the arm (humerus) and leg (femur and tibia).

All other cancellous, or spongy, bones and central cavities of the long bones are filled with yellow bone marrow.

Most red blood cells, platelets, and most white blood cells form in the red bone marrow. Yellow bone marrow produces fat, cartilage, and bone.

White blood cells survive from a few hours to a few days, platelets for about 10 days, and red blood cells for about 120 days. Bone marrow needs to replace these cells constantly, as each blood cell has a set life expectancy.

Certain conditions may trigger additional production of blood cells. This may happen when the oxygen content of body tissues is low, if there is loss of blood or anemia, or if the number of red blood cells decreases. If these things happen, the kidneys produce and release erythropoietin, which is a hormone that stimulates bone marrow to produce more red blood cells.

Bone marrow also produces and releases more white blood cells in response to infections and more platelets in response to bleeding. If a person experiences serious blood loss, yellow bone marrow can activate and transform into red bone marrow.

Healthy bone marrow is important for a range of systems and activities.

The circulatory system touches every organ and system in the body. It involves a number of different cells with a variety of functions. Red blood cells transport oxygen to cells and tissues, platelets travel in the blood to help clotting after injury, and white blood cells travel to sites of infection or injury.

Hemoglobin is the protein in red blood cells that gives them their color. It collects oxygen in the lungs, transports it in the red blood cells, and releases oxygen to tissues such as the heart, muscles, and brain. Hemoglobin also removes carbon dioxide (CO2), which is a waste product of respiration, and sends it back to the lungs for exhalation.

Iron is an important nutrient for human physiology. It combines with protein to make the hemoglobin in red blood cells and is essential for producing red blood cells (erythropoiesis). The body stores iron in the liver, spleen, and bone marrow. Most of the iron a person needs each day for making hemoglobin comes from the recycling of old red blood cells.

The production of red blood cells is called erythropoiesis. It takes about 7 days for a committed stem cell to mature into a fully functional red blood cell. As red blood cells age, they become less active and more fragile.

White blood cells called macrophages remove aging red cells in a process known as phagocytosis. The contents of these cells are released into the blood. The iron released in this process travels either to bone marrow for the production of new red blood cells or to the liver or other tissues for storage.

Typically, the body replaces around 1% of its total red blood cell count every day. In a healthy person, this means that the body produces around 200 billion red blood cells each day.

Bone marrow produces many types of white blood cells. These are necessary for a healthy immune system. They prevent and fight infections.

The main types of white blood cells, or leukocytes, are as follows.

Lymphocytes are produced in bone marrow. They make natural antibodies to fight infection due to viruses that enter the body through the nose, mouth, or another mucous membrane or through cuts and grazes. Specific cells recognize the presence of invaders (antigens) that enter the body and send a signal to other cells to attack them.

The number of lymphocytes increases in response to these invasions. There are two major types of lymphocytes: B and T lymphocytes.

Monocytes are produced in bone marrow. Mature monocytes have a life expectancy in the blood of only 38 hours, but when they move into the tissues, they mature into larger cells called macrophages.

Macrophages can survive in the tissues for long periods of time, where they engulf and destroy bacteria, some fungi, dead cells, and other material that is foreign to the body.

Granulocytes is the collective name given to three types of white blood cells: neutrophils, eosinophils, and basophils. The development of a granulocyte may take 2 weeks, but this time reduces when there is an increased threat, such as a bacterial infection.

Bone marrow stores a large reserve of mature granulocytes. For every granulocyte circulating in the blood, there may be 50100 cells waiting in the bone marrow to be released into the bloodstream. As a result, half the granulocytes in the bloodstream can be available to actively fight an infection in the body within 7 hours of it detecting one.

Once a granulocyte has left the blood, it does not usually return. A granulocyte may survive in the tissues for up to 45 days, depending on the conditions, but it can only survive for a few hours in circulating blood.

Neutrophils are the most common type of granulocyte. They can attack and destroy bacteria and viruses.

Eosinophils are involved in the fight against many types of parasitic infections and against the larvae of parasitic worms and other organisms. They are also involved in some allergic reactions.

Basophils are the least common of the white blood cells. They respond to various allergens that cause the release of histamines, heparin, and other substances.

Heparin is an anticoagulant. It prevents blood from clotting. Histamines are vasodilators that cause irritation and inflammation. Releasing these substances makes a pathogen more permeable and allows for white blood cells and proteins to enter the tissues to engage the pathogen.

The irritation and inflammation in tissues that allergens affect are parts of the reaction associated with hay fever, some forms of asthma, hives, and, in its most serious form, anaphylactic shock.

Bone marrow produces platelets in a process known as thrombopoiesis. Platelets are necessary for blood to coagulate and for clots to form in order to stop bleeding.

Sudden blood loss triggers platelet activity at the site of an injury or wound. Here, the platelets clump together and combine with other substances to form fibrin. Fibrin has a thread-like structure and forms an external scab or clot.

Platelet deficiency causes the body to bruise and bleed more easily. Blood may not clot well at an open wound, and there may be a higher risk of internal bleeding if the platelet count is very low.

The lymphatic system consists of lymphatic organs such as bone marrow, the tonsils, the thymus, the spleen, and lymph nodes.

All lymphocytes develop in bone marrow from immature cells called stem cells. Lymphocytes that mature in the thymus gland (behind the breastbone) are called T cells. Those that mature in bone marrow or the lymphatic organs are called B cells.

The immune system protects the body from disease. It kills unwanted microorganisms such as bacteria and viruses that may invade the body.

Small glands called lymph nodes are located throughout the body. Once lymphocytes are made in bone marrow, they travel to the lymph nodes. The lymphocytes can then travel between each node through lymphatic channels that meet at large drainage ducts that empty into a blood vessel. Lymphocytes enter the blood through these ducts.

Three major types of lymphocytes play an important part in the immune system: B lymphocytes, T lymphocytes, and NK cells.

These cells originate from hematopoietic stem cells in bone marrow in mammals.

B cells express B cell receptors on their surface. These allow the cell to attach to an antigen on the surface of an invading microbe or another antigenic agent.

For this reason, B cells are known as antigen-presenting cells, as they alert other cells of the immune system to the presence of an invading microbe.

B cells also secrete antibodies that attach to the surface of infection-causing microbes. These antibodies are Y-shaped, and each one is akin to a specialized lock into which a matching antigen key fits. Because of this, each Y-shaped antibody reacts to a different microbe, triggering a larger immune system response to fight infection.

In some circumstances, B cells erroneously identify healthy cells as being antigens that require an immune system response. This is the mechanism behind the development of autoimmune conditions such as multiple sclerosis, scleroderma, and type 1 diabetes.

These cells are so-called because they mature in the thymus, which is a small organ in the upper chest, just behind the sternum. (Some T cells mature in the tonsils.)

There are many different types of T cells, and they perform a range of functions as part of adaptive cell-mediated immunity. T cells help B cells make antibodies against invading bacteria, viruses, or other microbes.

Unlike B cells, some T cells engulf and destroy pathogens directly after binding to the antigen on the surface of the microbe.

NK T cells, not to be confused with NK cells of the innate immune system, bridge the adaptive and innate immune systems. NK T cells recognize antigens presented in a different way from many other antigens, and they can perform the functions of T helper cells and cytotoxic T cells. They can also recognize and eliminate some tumor cells.

These are a type of lymphocyte that directly attack cells that a virus has infected.

A bone marrow transplant is useful for various reasons. For example:

Stem cells mainly occur in four places:

Stem cells for transplantation are obtainable from any of these except the fetus.

Hematopoietic stem cell transplantation (HSCT) involves the intravenous (IV) infusion of stem cells collected from bone marrow, peripheral blood, or umbilical cord blood.

This is useful for reestablishing hematopoietic function in people whose bone marrow or immune system is damaged or defective.

Worldwide, more than 50,000 first HSCT procedures, 28,000 autologous transplantation procedures, and 21,000 allogeneic transplantation procedures take place every year. This is according to a 2015 report by the Worldwide Network for Blood and Marrow Transplantation.

This number continues to increase by over 7% annually. Reductions in organ damage, infection, and severe, acute graft-versus-host disease (GVHD) seem to be contributing to improved outcomes.

In a study of 854 people who survived at least 2 years after autologous HSCT for hematologic malignancy, 68.8% were still alive 10 years after transplantation.

Bone marrow transplants are the leading treatment option for conditions that threaten bone marrows ability to function, such as leukemia.

A transplant can help rebuild the bodys capacity to produce blood cells and bring their numbers to acceptable levels. Conditions that may be treatable with a bone marrow transplant include both cancerous and noncancerous diseases.

Cancerous diseases may or may not specifically involve blood cells, but cancer treatment can destroy the bodys ability to manufacture new blood cells.

A person with cancer usually undergoes chemotherapy before transplantation. This eliminates the compromised marrow.

A healthcare professional then harvests the bone marrow of a matching donor which, in many cases, is a close family member and ready it for transplant.

Types of bone marrow transplant include:

A persons tissue type is defined as the type of HLA they have on the surface of most of the cells in their body. HLA is a protein, or marker, that the body uses to help it determine whether or not the cell belongs to the body.

To check if the tissue type is compatible, doctors assess how many proteins match on the surface of the donors and recipients blood cells. There are millions of different tissue types, but some are more common than others.

Tissue type is inherited, and types pass on from each parent. This means that a relative is more likely to have a matching tissue type.

However, if it is not possible to find a suitable bone marrow donor among family members, healthcare professionals try to find someone with a compatible tissue type on the bone marrow donor register.

Healthcare professionals perform several tests before a bone marrow transplant to identify any potential problems.

These tests include:

In addition, a person needs a complete dental exam before a bone marrow transplant to reduce the risk of infection. Other precautions to lower the risk of infection are also necessary before the transplant.

Bone marrow is obtainable for examination by bone marrow biopsy and bone marrow aspiration.

Bone marrow harvesting has become a relatively routine procedure. Healthcare professionals generally aspirate it from the posterior iliac crests while the donor is under either regional or general anesthesia.

Healthcare professionals can also take it from the sternum or from the upper tibia in children, as it still contains a substantial amount of red bone marrow.

To do so, they insert a needle into the bone, usually in the hip, and withdraw some bone marrow. They then freeze and store this bone marrow.

National Marrow Donor Program (NMDP) guidelines limit the volume of removable bone marrow to 20 milliliters (ml) per kg of donor weight. A dose of 1 x 103 and 2 x 108 marrow mononuclear cells per kg is necessary to establish engraftment in autologous and allogeneic marrow transplants, respectively.

Complications related to bone marrow harvesting are rare. When they do occur, they typically involve problems related to anesthetics, infection, and bleeding.

More:
Bone marrow: Function, diseases, transplants, and donation

Bone Marrow Stem Cells Comments Off on Bone marrow: Function, diseases, transplants, and donation | December 23rd, 2021

MELVILLE, N.Y., Dec. 20, 2021 (GLOBE NEWSWIRE) -- BioRestorative Therapies, Inc. (the Company" or BioRestorative) (NASDAQ:BRTX), a life sciences company focused on adult stem cell-based therapies, today released the following year-end message.

As we reach the end of 2021, we are inspired by the many healthcare workers and biopharmaceutical companies that have worked to combat the COVID-19 pandemic. This year has been environmentally difficult, but we have seen incredible advancements in our sector which have reinforced the importance of our mission to become a clinical stage company. Since our emergence from Chapter 11 in 2020, we have sought to take positive steps at BioRestorative Therapies with the goal of making it a preeminent cell therapy company. During 2021, we achieved important transformational milestones, which created meaningful intrinsic value and advanced us toward our stated strategic goals.

In November of this year, we closed on a $23 million capital raise and concurrently listed our securities on the Nasdaq Capital Market. This is a very significant development as we are now fully funded to complete our Phase 2 trial for our lead clinical candidate, BRTX-100, for the treatment of chronic lumbar disc disease (CLDD.) During this process, we have attracted many new institutional fundamental investors as well as some retail investors. With that accomplished, I would like to briefly discuss the status of our programs and the opportunities that lie ahead of us.

BRTX-100 is our lead program for the treatment of CLDD, one of the leading causes of lower back pain. Our solution is a one-time injection of 40 million mesenchymal stem cells derived from a patients own bone marrow and expanded ex vivo before re-injection. Two things make us optimistic about this program. First, in connection with our IND filing, we referred the FDA to prior human clinical studies from different institutions that demonstrated the safety/feasibility of using mesenchymal stem cells to treat disc orders. This data not only enabled us to accelerate our clinical program and initiate a Phase 2 trial, but we believe it substantially reduces risk in offering compelling guidance on the use of cell-based interventions to treat lower back pain. Second, our manufacturing of BRTX-100 involves the use of low oxygen conditions, which ensures that the cells have enhanced survivability after introduction into the harsh avascular environment of the injured disc which has little or no blood flow. The benefits of this process are significant and are illustrated well in our recent Journal of Translational Medicine publication. Our approach is akin to transplant medicine in which specific cell types are used to replace the ones which have been lost to disease. We believe that transplanting targeted cells can offer a more attractive safety profile and potentially an improved clinical outcome. We remain optimistic that we will see significant positive clinical outcomes as we proceed with our clinical trial.

The most significant milestones we achieved in 2021 include:

Our 2022 objectives include the initiation of enrollment for our BRTX-100 clinical trial, the development of our overall product profiles via manufacturing and delivery system improvements, and the entering into of technology validation and enabling partnerships to accelerate our clinical timelines.

Some of the events and milestones that we hope to accomplish in 2022 include:

This is an exciting time to be part of the BioRestorative family. As we enter 2022 with a well-capitalized balance sheet to fully fund our Phase 2 trial, we look to accelerate our research and development pipeline. We do not take for granted that our technologies give us an opportunity to make a profound impact on the everyday lives of many people. We are grateful for the opportunity to validate such technologies; it is what we do and what we believe is the center of our core competencies.

Visit our website at http://www.biorestorative.com for more information about BioRestorative.

Thank you to the BioRestorative family for your loyalty and ongoing support.

I wish you and all those near and dear to you a wonderful Holiday Season and the very best for 2022 and beyond.

Very truly yours,

Lance AlstodtPresident, CEO and Chairman of the Board

About BioRestorative Therapies, Inc.

BioRestorative Therapies, Inc. (www.biorestorative.com) develops therapeutic products using cell and tissue protocols, primarily involving adult stem cells. Our two core programs, as described below, relate to the treatment of disc/spine disease and metabolic disorders:

Disc/Spine Program (brtxDISC): Our lead cell therapy candidate, BRTX-100, is a product formulated from autologous (or a persons own) cultured mesenchymal stem cells collected from the patients bone marrow. We intend that the product will be used for the non-surgical treatment of painful lumbosacral disc disorders or as a complementary therapeutic to a surgical procedure. The BRTX-100 production process utilizes proprietary technology and involves collecting a patients bone marrow, isolating and culturing stem cells from the bone marrow and cryopreserving the cells. In an outpatient procedure, BRTX-100 is to be injected by a physician into the patients damaged disc. The treatment is intended for patients whose pain has not been alleviated by non-invasive procedures and who potentially face the prospect of surgery. We have received authorization from the Food and Drug Administration to commence a Phase 2 clinical trial using BRTX-100 to treat chronic lower back pain arising from degenerative disc disease.

Metabolic Program (ThermoStem): We are developing a cell-based therapy candidate to target obesity and metabolic disorders using brown adipose (fat) derived stem cells to generate brown adipose tissue (BAT). BAT is intended to mimic naturally occurring brown adipose depots that regulate metabolic homeostasis in humans. Initial preclinical research indicates that increased amounts of brown fat in animals may be responsible for additional caloric burning as well as reduced glucose and lipid levels. Researchers have found that people with higher levels of brown fat may have a reduced risk for obesity and diabetes.

FORWARD-LOOKING STATEMENTS

This letter contains "forward-looking statements" within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended, and such forward-looking statements are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. You are cautioned that such statements are subject to a multitude of risks and uncertainties that could cause future circumstances, events or results to differ materially from those projected in the forward-looking statements as a result of various factors and other risks, including, without limitation, those set forth in the Company's latest Form 10-K filed with the Securities and Exchange Commission (SEC) and other filings made with the SEC. You should consider these factors in evaluating the forward-looking statements included herein, and not place undue reliance on such statements. The forward-looking statements in this letter are made as of the date hereof and the Company undertakes no obligation to update such statements.

CONTACT:

Email: ir@biorestorative.com

The rest is here:
BioRestorative Therapies, Inc. Releases Year-End Message - BioSpace

Bone Marrow Stem Cells Comments Off on BioRestorative Therapies, Inc. Releases Year-End Message – BioSpace | December 23rd, 2021

Findings from a new study could point the way to new treatments for blood diseases including cancers such as leukemia and lymphoma. [3 min read]

In this schematic, cells (black spheres) within each well are committed to a specific fate, but external stimuli, such as cell-to-cell communication, can force cells out of one state and into another. (Illustration: Courtesy of Adam MacLean.)

Scientists have found a way to prove that biochemical signals sent from cell to cell play an important role in determining how those cells develop.

The study from researchers at the USC Dornsife College of Letters, Arts and Sciences was published in the journal Development on Dec. 22.

A little background:

Whats new:

We discovered that the communication process can change the formation of blood cell types dramatically, and that cells that are closer to one another have a greater influence on each others fate, MacLean said.

A controversy resolved

Researchers trying to determine what early factors nudge a cell down one developmental path or another have wondered if random fluctuations within the cell are enough to decide which path is taken. Many models have suggested they were, but recent breakthrough studies showed that random fluctuations were not enough, that something else drives cells toward their fate.

The model MacLean and Rommelfanger have developed appears to put an end to the controversy altogether. They show that cell-to-cell communication can, in fact, be the deciding factor that sets cells along a certain path.

Why it matters:

By understanding how blood cell fate decisions are made, MacLean said, we get closer to being able to identify leukemia cells of origin, and in theory we can design strategies to control or alter cell fate decision-making and stop the development of cancer.

The research could help improve cancer therapies such as bone marrow transplant.

Better understanding stem cell fate decisions, as our study provides, could provide new insight to improve clinical outcomes for these diseases, MacLean said.

More than just blood

This new model has important implications beyond the blood system.

Our model is broadly applicable, so researchers working on other cell types can apply it to find out for those other cells how important cell-to-cell communication may be, said MacLean.

Whats next:

The role of cell-to-cell communication in determining cell fate is in its nascent stages, says MacLean, but further experiments and future technologies to integrate these new types of data with sophisticated models should help expand understanding.

In addition, the team is developing methods to study the regulation of key genes involved in cell fate decisions, which should further advance their overall theoretical model.

About the study

This work was supported by National Science Foundation grant DMS 2045327 and a USC Women in Science and Engineering Top-up Fellowship.

Read the original:
Communication between cells plays a major role in deciding their fate > News > USC Dornsife - USC Dornsife College of Letters, Arts and Sciences

Bone Marrow Stem Cells Comments Off on Communication between cells plays a major role in deciding their fate > News > USC Dornsife – USC Dornsife College of Letters, Arts and Sciences | December 23rd, 2021

Dr Pradeep Mahajan, Regenerative Medicine Researcher, StemRx Bioscience Solutions highlights the importance and other aspects of stem cell technology

Globally, we are seeing a change in the type of age-specific, chronic, debilitating diseases. Thus, the manner in which we diagnose and treat such diseases is also seeing a paradigm shift. From empirical use of drugs to target-specific treatments, we are now advancing towards molecular dysfunction-based therapies.

I have been in the field of clinical medicine and surgery for over 3 decades now and I have always been fascinated by new research. Among the substantial advances in the healthcare field, I believe regenerative medicine and cell-based therapy have been game changers. We saw hematopoietic stem cells being used to treat blood cancers and related diseases for over 3-4 decades. Now we are seeing an expansion in the applications of stem cells in treating various acute, chronic, lifestyle, and even genetic and congenital diseases. The need arose because conventional medicine is gradually losing potency in treating diseases and patients are often left at the mercy of nature to take its course.

With increasing knowledge of stem cells, the trend to utilise the endogenous repair mechanisms of the human body gained popularity. Cells, growth factors and other biological products, when present at the right site; at the right moment, stimulate the natural healing mechanisms of the body and aid in management of health conditions. Cell-based therapy thus marked the beginning of a new era in regenerative medicine.

Stem cells are present in several tissues, namely, embryo, umbilical cord, placenta, as well as adult body tissues. These are the master cells of the body that have roles in development of the body, repairing and regenerating injured tissues (at a cellular level), and maintaining homeostasis even in an healthy individual. Of course, we have all heard of ethical issues regarding the use of embryonic stem cells as well as their tumor-forming issue. Regarding umbilical cord stem cells, the trend of banking this tissue has just begun; therefore, the majority of us would not have the umbilical cord as a source of stem cells. Keeping in mind these aspects, researchers started focusing on adult stem cells that can be derived from different tissues of the human body. The common sources are bone marrow, fat tissue, peripheral blood, and teeth, among others. The chief advantage is that, the source being autologous, the therapy is safe and is not associated with side effects.

Coming to the diseases that can be treated using stem cellswe have just scratched the tip of the iceberg. There are several health conditions that plague mankindarthritis, diabetes, nerve-related conditions, traumatic injuries, etc. Conventionally, one would be prescribed medications (often for prolong periods or even for their lifetime) or be advised surgery. Nonetheless, in several cases, the quality of life of a patient is compromised. The various properties of stem cells help reduce swelling in the body, regulate the immune system, enhance the functioning of other cells, and create a healthy environment for health cells to thrive. Through this, one can target a myriad of pathologies at the molecular level, in a minimally/non-invasive manner.

Patients today are quite aware of the benefits of regenerative medicine and cell based therapy, but there is still a long distance to cover. Countries are promoting research and development in the field of regenerative medicine and cell-based therapy. Research advances pertaining to introducing products with cell and scaffold based technology through tissue engineering are underway. Bioactive scaffolds that are capable of supporting activation and differentiation of host stem cells at the required site are being developed. In the future, it will be possible to use human native sites as micro-niche/micro-environment for potentiation of the human bodys site-specific response. Another breakthrough in the field of cell-based therapy is immunotherapy that aims to utilise certain parts of a persons immune system and stimulate them to fight diseases such as cancer.

The scope of cell-based therapy is endless. All we need is more research, awareness, and implementation to permit reach of the treatment to every stratum of the society. Soon, we will talk about treating diseases with cells and not pills and knives!

See the article here:
Importance of stem cells-Past, present and future - Express Healthcare

Bone Marrow Stem Cells Comments Off on Importance of stem cells-Past, present and future – Express Healthcare | December 23rd, 2021