Bone Basics and Bone Anatomy

Have you ever seen fossil remains of dinosaur and ancient human bones in textbooks, television, or in person at a museum? It's easy to look at these and think of bones as dry, dead sticks in your body, but this couldn't be further from the truth. Bones are made of active, living cells that are busy growing, repairing themselves, and communicating with other parts of the body. Lets take a closer look at what your bones do and how they do it.

The skeleton of an adult human is made up of 206 bones of many different shapes and sizes. Added together, your bonesmake up about 15% of your body weight. Newborn babies are actually born with many more bonesthan this (around 300),but many bones grow together, orfuse, as babiesbecome older. Some bones are long and thick, like your thigh bones. Others are thin, flat, and wide, like your shoulder blades.

Support: Like a house is built around a supportive frame,a strong skeleton is required to support the rest of the human body. Without bones, it would be difficult for your body to keep its shape andto stand upright.

Protection: Bones form astrong layer around some of the organs in your body, helping tokeep them safe when you fall down or get hurt. Your rib cage, for example, acts like a shield around your chest to protect important organs inside such as your lungs and heart. Your brain is another organ that needs a lot of protection. The thick bone layer of your skull protects your brain. For this purpose, being "thick-headed" is a very good thing.

Movement: Many of your bones fit togetherlike the pieces of a puzzle. Eachbone has a very specific shape which often matches up with neighboring bones. The place where two bones meet to allow your body to bend is called a joint.

How many different ways can you move your joints? Some bones, like your elbow, fit together like a hingethat lets you bend your arm in one specific direction. Other bones fit together like a ball and socket, such as the joint between your shoulder and arm. This type of jointlets you rotate your shoulder in many directions, or swing it all the way around in a circle like softball pitchersdo.

The movement of our bodies is possible because of both joints and muscles. Muscles often attach to two different bones, so that when the muscle flexes and shortens, thebones move. This allows youto bend your elbows and knees, or pick up objects. A skeleton has plenty of joints, but without muscles, there is nothing to pull the bones in different directions. More than half of the bones in your body are actually located in your hands and feet. These bones are attached to many little muscles that give you very exact control over how you move your fingers and feet.

Blood Cell Formation: Did you know that most of the red and white blood cells in your body were created inside of your bones? This is done by a special group of cells called stem cells that are found mostly in the bone marrow, which is the innermost layerof your bones.

Storage: Bones are like a warehousethat storesfat and many important minerals so they are available when your body needs them. These minerals are continuously being recycled through your bones--deposited and then taken out and moved through the bloodstream to get to other parts of your body where they are needed.

Now that you know what bones do, let's take a look at what they're made of and their anatomy.

Each bone in your body is made up of three main types of bone material: compact bone, spongy bone, and bone marrow.

Compact Bone

Compact bone is the heaviest, hardest type of bone. It needs to be very strong as it supports your body and muscles as you walk, run, and move throughout the day. About 80% of the bone in your body is compact. It makes up the outer layer of the bone and also helps protect the more fragile layers inside.

If you were to look at a piece of compact bone without the help of a microscope, it would seem to be completely solid all the way through. If you looked at it through a microscope, however, you would see that it's actually filled with many very tiny passages,or canals,for nerves and blood vessels. Compact bone is made of special cells called osteocytes. These cells arelined up inrings around the canals. Together, a canal and the osteocytes that surround it are called osteons. Osteons are like thick tubes all going the same direction inside the bone, similar to a bundle of straws with blood vessels, veins, and nerves in the center.

Spongy Bone

Spongy bone is found mostly at the ends of bones and joints. About 20% of the bone in your body is spongy. Unlike compact bone that is mostly solid, spongy bone is full of open sections called pores. If you were to look at it in under a microscope, it would look a lot like your kitchen sponge. Pores are filled with marrow, nerves, and blood vessels that carry cells and nutrients in and out of the bone.Though spongy bone may remind you of a kitchen sponge,this bone is quite solid and hard, and is not squishy at all.

Bone Marrow

The inside of your bones are filled with a soft tissue called marrow. There are two types of bone marrow: red and yellow. Red bone marrow is where all new red blood cells, white blood cells, and platelets aremade. Platelets are small pieces of cells that help you stop bleeding when you get acut.Red bone marrow isfound in the center of flat bones such as your shoulder blades and ribs. Yellow marrow is made mostly of fat and is found in the hollow centers of long bones, such as the thigh bones. It does not make blood cells or platelets. Both yellow and red bone marrow have many small and large blood vessels and veins running through them to let nutrients and waste in and out of the bone.

When you were born, all of the marrow in your body was red marrow, whichmade lots and lots of blood cells and plateletsto helpyour body grow bigger. As you got older, more and more of the red marrow was replaced with yellow marrow. The bone marrow of full grown adults is about half red and half yellow.

The Inside Story

Bones are made of four main kinds of cells: osteoclasts, osteoblasts, osteocytes, and lining cells. Notice that three of these cell type names start with 'osteo.' This is the Greek word for bone. When you see 'osteo' as part of a word, it lets you know that the word has something to do with bones.

Osteoblasts are responsible for making new bone as your body grows. They also rebuild existing bones when they are broken. The second part of the word,'blast,' comes froma Greek word that means 'growth.' To make new bone, many osteoblasts come together in one spot then begin making a flexible material called osteoid. Minerals are then added to osteoid, making it strong and hard. When osteoblasts are finished making bone, they become either lining cells or osteocytes.

Osteocytes are star shaped bone cells most commonly found in compact bone. They areactually old osteoblasts that have stopped making new bone. As osteoblasts build bone, they pile it up around themselves, then get stuck in the center. At this point, they are called osteocytes.Osteocytes have long, branching arms that connect them to neighboring osteocytes. This lets them exchange minerals and communicate with other cells in the area.

Lining cells are very flat bone cells. These cover the outside surface of all bones and are also formed from osteoblasts that have finished creating bone material. These cells play an important role in controlling the movement of molecules in and out of the bone.

Osteoclasts break down and reabsorb existing bone. The second part of the word, 'clast,' comes from the Greek word for 'break,' meaning these cells break down bone material. Osteoclasts are very big and often contain more than one nucleus, which happens when two or more cells get fused together. These cells work as a team with osteoblasts to reshape bones. This might happen for a number of reasons:

It's not completely understood how bone cells in your body are able to work together and stay organized, but pressure and stress on the bone might have something to do with it.

The smallest bone in the human body is called the stirrup bone, located deep inside the ear. It's only about 3 millimeterslong in an adult.

The longest bone in the human is called the femur, or thigh bone. It's the bone in your leg that goes from your hip to your knee. In an average adult, it's about 20 inches long.

References:

Marieb. E.N. (1989) Human Anatomy and Physiology, CA: Benjamin/Cummings Publishing Company, Inc

Heller, H.C., Orians, G.H., Purves, W.K., Sadava, D. (2003) Life: The Science of Biology, 7th Edition. Sunderland, MA: Sinauer Associates, Inc. & W. H. Freeman and Company

Skeleton Image: By Lady of Hats - Mariana Ruiz Villarreal, via Wikimedia Commons.

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Bone Anatomy | Ask A Biologist

Bones make up the skeletal system of the human body. The adult human has two hundred and six bones. There are several types of bones that are grouped together due to their general features, such as shape, placement and additional properties. They are usually classified into five types of bones that include the flat, long, short, irregular, and sesamoid bones.

The human bones have a number of important functions in the body. Most importantly, they are responsible for somatic rigidity,structural outline, erect posture and movement (e.g. bipedal gait). Due to their rigidity, bones are the main 'protectors' of the internal organs and other structures found in the body.

This article will describe all theanatomical and important histological facts about the bones.

A bone is a somatic structure that is composed of calcified connective tissue. Ground substance and collagen fibers create a matrix that contains osteocytes. These cells are the most common cell found in mature bone and responsible for maintaining bone growth and density. Within the bone matrix both calcium and phosphate are abundantly stored, strengthening and densifying the structure.

Each bone is connected with one or more bones and are united via a joint (only exception: hyoid bone). With the attached tendons and musculature, the skeleton acts as a lever that drives the force of movement. The inner core of bones (medulla) contains either red bone marrow (primary site of hematopoiesis) or is filled with yellow bone marrow filled with adipose tissue.

The main outcomes of bone development (e.g. skull bones development)are endochondral and membranous forms. This particular characteristic along with the general shape of the bone are used to classify the skeletal system. The bones are mainly classified into five types that include:

These bones develop via endochondral ossification, a process in which the hyaline cartilage plate is slowly replaced. A shaft, or diaphysis, connects the two ends known as the epiphyses (plural for epiphysis). The marrow cavity is enclosed by the diaphysis which is thick, compact bone. The epiphysis is mainly spongy bone and is covered by a thin layer of compact bone; the articular ends participate in the joints.

The metaphysis is situated on the border of the diaphysis and the epiphysis at the neck of the bone and is the place of growth during development.

Some examples of this type of bones include:

The short bones are usually as long as they are wide. They are usually found in the carpus of the hand and tarsus of the foot.

In the short bones, a thin external layer of compact bone covers vast spongy bone and marrow, making a shape that is more or less cuboid.

The main function of the short bones is to provide stability and some degree of movement.

Some examples of these bones are:

In flat bones, the two layers of compact bone cover both spongy bone and bone marrow space. They grow by replacing connective tissue. Fibrocartilage covers their articular surfaces. This group includes the following bones:

The prime function of flat bones is to protect internal organs such as the brain, heart, and pelvic organs. Also, due to their flat shape, these bones provide large areas for muscle attachments.

Due to their variable and irregular shape and structure, the irregular bones do not fit into any other category. In irregular bones, the thin layer of compact bone covers a mass of mostly spongy bone.

The complex shape of these bones help them to protect internal structures. For example, the irregular pelvic bones protect the contents of the pelvis.

Some examples of these types of bones include:

Sesamoid bones are embedded within tendons. These bones are usually small and oval-shaped.

The sesamoid bones are found at the end of long bones in the upper and lower limbs, where the tendons cross.

Some examples of the sesamoid bones are the patella bone in the kneeor the pisiform bone of the carpus.

The main function of the sesamoid bone is to protect the tendons from excess stress and wear byreducing friction.

Learn the basics of the skeletal system with this interactive quiz.

The bones mainly provide structural stability to the human body. Due to the development of the complex bony structures(e.g. spine) the humans are able to maintain erect posture, to walk on two feet (bipedal gait)and for all sorts of other activities not seen in animals.

Due to their rigid structure, bones are key in the protection of internal organs and other internal structures. Some bones protect other structures by reducing stress and friction (e.g. sesamoid bones) while some bones join together to form more complex structures to surround vital organs and protect them (e.g. skull, thoracic cage, pelvis).

Bones also harbor bone marrow which is crucial in production of blood cells in adults. In addition, the bone tissue can act as a storage for blood cells and minerals.

Common bone diseases often affect the bone density, e.g. in young children due to malnutrition. For example, rickets is a bone deformity seen in young children who lack vitamin D. Their legs are disfigured and they have trouble walking. The damage is irreversible though surgery may help. Osteomalacia and osteoporosis are diseases seen mainly in adulthood.

Osteomalacia is the improper mineralization of bone due to a lack of available calcium and phosphate. The bone density decreases and the bones become soft. Osteoporosis has been noted in all ages but mostly in postmenopausal and elderly women. A progressive decrease in bone density increases the risk of fracture. Patients who are on long-term steroid medication are in particular risk.

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Bones: Anatomy, function, types and clinical aspects | Kenhub

Bone Marrow: Functions, Disorders, and Treatments  Metropolis Healthcare

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Bone Marrow: Functions, Disorders, and Treatments - Metropolis Healthcare

Before we talk about bone formation, we need to discuss how cartilage turns into bone. When you're floating around in the womb, your developing body is just beginning to take its shape, and it's creating cartilage to do so. Cartilage is a tissue that isn't as hard as bone, but much more flexible and, in some ways, more functional. Cartilage is pretty good stuff to use if you're going to mold a human good enough for the finer work, especially, such as your nose or your ear.

A large amount of that fetus cartilage begins transforming into bone, a process called ossification. When ossification occurs, the cartilage begins to calcify; that is, layers of calcium and phosphate salts begin to accumulate on the cartilage cells. These cells, surrounded by minerals, die off. This leaves small pockets of separation in the soon-to-be-bone cartilage, and tiny blood vessels grow into these cavities.

Specialized cells called osteoblasts begin traveling into the developing bone by way of these blood vessels. These cells produce a substance consisting of collagen fibers, and they also aid in the collection of calcium, which is deposited along this fibrous substance.

Eventually, the osteoblasts become part of the mix, turning into lower-functioning osteocytes. This osteocyte network helps form the spongelike lattice of cancellous bone. Cancellous bone isn't soft, but it does look spongy. Its spaces help transfer the stress of external pressures throughout the bone, and these spaces also contain marrow. Little channels called canaliculi run all throughout the calcified portions of the bone, enabling nutrients, gases and waste to make their way through.

Before turning into osteocytes, osteoblasts produce cortical bone. One way to imagine this process is to picture a bricklayer trapping himself inside a man-sized brick chamber of his own construction. After forming the hard shell (cortical bone), the bricklayer himself fills the chamber. Air makes its way through the brick and decays the bricklayer.

In bone, this part of the process is accomplished by osteoclasts, which make their way into the calcifying cartilage and take bone out of the middle of the shaft, leaving room for marrow to form. Osteoclasts do this by engulfing and digesting the bone matrix using acids and hydrolytic enzymes. So, our bricklayer (osteoblast) made the tomb (cortical bone), died inside the tomb (became an osteocyte), decayed over time (dissolved by osteoclasts) and left behind his remains that formed a network of mass and space inside the brick tomb.

Eventually, all the cartilage has turned to bone, except for the cartilage on the end of the bone (articular cartilage) and growth plates, which connect the bone shaft on each side to the bone ends. These cartilage layers help the bone expand and finally calcify by adulthood.

So, right now in your body, there are osteoclasts hard at work absorbing old bone cells and osteoblasts helping to build new bone in its place. This cycle is called remodeling. When you're young, your osteoblasts (the builders) are more numerous than the osteoclasts, resulting in bone gain. When you age, the osteoblasts can't keep up with the osteoclasts, which are still efficiently removing bone cells, and this leads to loss of bone mass (and a condition called osteoporosis, which we'll discuss shortly).

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How Bones Work | HowStuffWorks

Young Male Stem Cell Donors Could Be the Miracles Countless Patients Need Today  Good Things Guy

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Young Male Stem Cell Donors Could Be the Miracles Countless Patients Need Today - Good Things Guy

How bone marrow transplants are changing the outlook for rare blood diseases?  Healthcare Radius

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How bone marrow transplants are changing the outlook for rare blood diseases? - Healthcare Radius

Newborn with bubble boy disease now thriving, thanks to Singapores early detection programme  The Straits Times

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Newborn with bubble boy disease now thriving, thanks to Singapores early detection programme - The Straits Times

Bone marrow mesenchymal stem cells (BM-MSCs) are a vital component of regenerative medicine due to their ability to differentiate into various cell types and modulate immune responses. Their therapeutic potential has led to extensive research on their biological properties, mechanisms of action, and clinical applications.

Understanding BM-MSCs requires examining their microenvironment, distinguishing characteristics, isolation techniques, differentiation pathways, and how they compare to other stem cell types.

BM-MSCs originate from the mesodermal germ layer during embryonic development and persist into adulthood for tissue maintenance and repair. Within the bone marrow, they coexist with hematopoietic stem cells (HSCs) and other stromal components, contributing to the marrow niches structure and function. Their distribution is not uniform, with higher concentrations in trabecular-rich regions such as the iliac crest, femur, and sternum. These sites provide a supportive environment where BM-MSCs interact with the extracellular matrix, soluble factors, and neighboring cells to regulate proliferation and differentiation.

The bone marrow microenvironment is a specialized niche that governs BM-MSC behavior through biochemical and mechanical cues. It consists of an extracellular matrix composed of collagen, fibronectin, and laminin, which provides structural support and modulates adhesion. Oxygen tension in the marrow is lower than in peripheral tissues, with hypoxic conditions (1% to 7% oxygen) helping maintain BM-MSC quiescence and stemness. Hypoxia-inducible factors (HIFs) mediate responses to low oxygen levels, promoting genes involved in self-renewal and metabolic adaptation.

Cellular interactions further shape BM-MSC function. Crosstalk with endothelial cells, osteoblasts, and pericytes influences their role in supporting hematopoiesis and tissue homeostasis. Endothelial cells secrete vascular endothelial growth factor (VEGF), enhancing BM-MSC survival and migration. Osteoblasts provide osteogenic signals that prime BM-MSCs for differentiation into bone-forming cells. Pericytes, which share similarities with BM-MSCs, contribute to vascular stability and regulate stem cell fate.

BM-MSCs are defined by a unique set of surface markers that distinguish them from other stromal and hematopoietic populations. Unlike HSCs, BM-MSCs lack CD34, CD45, and CD14, which are associated with blood cell lineages. Instead, they express CD73, CD90, and CD105, as established by the International Society for Cell and Gene Therapy (ISCT). These markers facilitate identification, isolation, and functional characterization.

CD73, also known as ecto-5-nucleotidase, catalyzes the conversion of extracellular AMP into adenosine, modulating microenvironmental signals. CD90, or Thy-1, is a glycoprotein involved in cell-cell and cell-matrix interactions, influencing BM-MSC proliferation and differentiation. CD105, or endoglin, serves as a co-receptor for transforming growth factor-beta (TGF-), maintaining BM-MSC multipotency and guiding lineage commitment.

Additional markers refine BM-MSC characterization. CD146, a pericyte-associated marker, is linked to heightened clonogenic potential. STRO-1, an early mesenchymal progenitor marker, correlates with enhanced osteogenic differentiation but diminishes with cell expansion. CD271, or low-affinity nerve growth factor receptor (LNGFR), has been proposed for isolating highly pure BM-MSC populations with superior regenerative properties.

Isolating and expanding BM-MSCs are critical for research and clinical applications. Various techniques selectively extract BM-MSCs while minimizing contamination from hematopoietic and other stromal cells.

Density gradient centrifugation separates mononuclear cells from other bone marrow components based on cell density. Ficoll-Paque and Percoll are commonly used media that enrich BM-MSCs by allowing lower-density mononuclear cells to form a distinct layer after centrifugation. This method is simple and cost-effective but does not exclusively isolate BM-MSCs, as the mononuclear fraction contains hematopoietic cells. To improve purity, plastic adherence-based selection is often employed, where BM-MSCs attach to tissue culture plastic while non-adherent cells are removed. However, this approach has limitations, including variability in yield and potential contamination.

Fluorescence-activated cell sorting (FACS) and magnetic-activated cell sorting (MACS) isolate BM-MSCs based on surface marker expression. FACS uses fluorescently labeled antibodies targeting BM-MSC markers such as CD73, CD90, and CD105, allowing high-purity selection through laser-based detection. MACS employs magnetic beads conjugated to antibodies, enabling rapid and scalable cell separation. While FACS provides greater resolution, it requires specialized equipment and is time-intensive. MACS, though less precise, is more accessible and suitable for large-scale cell enrichment.

Enzymatic digestion methods use proteolytic enzymes such as collagenase and trypsin to break down the extracellular matrix and release BM-MSCs. Collagenase digestion is commonly used to degrade collagen-rich structures while preserving viability. Trypsin, often combined with other enzymes, aids in cell detachment. While enzymatic dissociation enhances cell recovery, excessive enzyme exposure can compromise viability and surface marker integrity. This method is often combined with culture-based selection for further enrichment.

BM-MSCs can differentiate into osteoblasts, chondrocytes, and adipocytes. This process is governed by transcription factors and environmental cues that guide lineage commitment. The surrounding microenvironment, including mechanical forces and biochemical signals, influences differentiation outcomes.

Osteogenic differentiation is driven by RUNX2, which activates genes responsible for bone matrix deposition. Calcium, phosphate, and bone morphogenetic proteins (BMPs) reinforce osteogenesis by enhancing mineralization. Chondrogenic differentiation is regulated by SOX9, which promotes cartilage-specific proteins such as aggrecan and type II collagen. Hypoxic conditions sustain chondrocyte-like characteristics. Adipogenic differentiation is controlled by PPAR and C/EBP, which drive lipid accumulation and adipocyte-specific gene expression.

BM-MSC differentiation is regulated by signaling pathways that govern self-renewal, proliferation, and lineage commitment. The Notch, Wnt, and BMP pathways play key roles in directing fate decisions.

The Notch pathway influences BM-MSC proliferation and differentiation through cell-to-cell communication. Activation occurs when Notch ligands bind to receptors, triggering cleavage and release of the Notch intracellular domain (NICD). NICD translocates to the nucleus and modulates gene expression. Notch signaling maintains BM-MSCs in an undifferentiated state by suppressing osteogenic and adipogenic differentiation while promoting chondrogenesis. Sustained Notch activation enhances cartilage formation by upregulating SOX9, while inhibition facilitates osteogenesis by relieving suppression on RUNX2.

The Wnt signaling cascade affects BM-MSC fate through canonical and non-canonical pathways. In the canonical pathway, Wnt ligands bind to Frizzled receptors, stabilizing -catenin, which activates osteogenic genes. This pathway promotes bone formation by enhancing RUNX2 expression and matrix mineralization. The non-canonical pathway, independent of -catenin, regulates cytoskeletal organization and migration. Canonical Wnt signaling favors osteogenesis while inhibiting adipogenesis by suppressing PPAR, maintaining a balance in BM-MSC differentiation.

Bone morphogenetic proteins (BMPs) regulate BM-MSC differentiation, particularly in bone and cartilage formation. BMP ligands bind to receptors, triggering SMAD phosphorylation and transcriptional regulation. BMP2 and BMP7 induce osteogenesis by upregulating RUNX2 and enhancing extracellular matrix deposition. BMP signaling also synergizes with SOX9 to promote chondrogenesis. While BMPs favor skeletal differentiation, excessive signaling can lead to aberrant ossification.

BM-MSCs differ from other stem cell populations in differentiation potential, immunomodulatory effects, and tissue origin. Unlike HSCs, which primarily generate blood cells, BM-MSCs contribute to mesodermal-derived tissues such as bone, cartilage, and adipose. Their ability to differentiate into multiple skeletal and connective tissue types makes them valuable for regenerative applications.

Compared to embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), BM-MSCs have a more restricted differentiation capacity, as they do not generate cells from all three germ layers. However, this reduces the risk of teratoma formation, a concern with pluripotent stem cell-based therapies. BM-MSCs are also more accessible and ethically uncontroversial, as they can be harvested from adult bone marrow. Their immunomodulatory properties further distinguish them, as they modulate immune responses through cytokine secretion and direct interactions, making them useful in inflammatory and autoimmune conditions.

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Bone Marrow Mesenchymal Stem Cells: Key Insights and Functions

New Gene Therapy Reverses Three Diseases With Shots to the Bloodstream  SingularityHub

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New Gene Therapy Reverses Three Diseases With Shots to the Bloodstream - SingularityHub

Newborn Mice May Hold the Key to Simpler Gene Therapy  the-scientist.com

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Newborn Mice May Hold the Key to Simpler Gene Therapy - the-scientist.com

In vivo haemopoietic stem cell gene therapy enabled by postnatal trafficking  Nature

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In vivo haemopoietic stem cell gene therapy enabled by postnatal trafficking - Nature

U achieves first successful allogenic stem cell transplant using graft from deceased donor  The University of Utah

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U achieves first successful allogenic stem cell transplant using graft from deceased donor - The University of Utah

Delivery of bone marrow mesenchymal stem cell-derived exosomes into fibroblasts attenuates intestinal fibrosis by weakening its transdifferentiation via the CCN2-TGF- axis  Nature

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Delivery of bone marrow mesenchymal stem cell-derived exosomes into fibroblasts attenuates intestinal fibrosis by weakening its transdifferentiation...

Gene therapy: a first of its kind at Sainte-Justine Hospital  CityNews Montreal

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Gene therapy: a first of its kind at Sainte-Justine Hospital - CityNews Montreal

Embryonic macrophages orchestrate niche cell homeostasis for the establishment of the definitive hematopoietic stem cell pool  Nature

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Embryonic macrophages orchestrate niche cell homeostasis for the establishment of the definitive hematopoietic stem cell pool - Nature

Stem cells that give rise to other blood cells

Hematopoietic stem cells (HSCs) are the stem cells[1] that give rise to other blood cells. This process is called haematopoiesis.[2] In vertebrates, the first definitive HSCs arise from the ventral endothelial wall of the embryonic aorta within the (midgestational) aorta-gonad-mesonephros region, through a process known as endothelial-to-hematopoietic transition.[3][4] In adults, haematopoiesis occurs in the red bone marrow, in the core of most bones. The red bone marrow is derived from the layer of the embryo called the mesoderm.

Haematopoiesis is the process by which all mature blood cells are produced. It must balance enormous production needs (the average person produces more than 500 billion blood cells every day) with the need to regulate the number of each blood cell type in the circulation. In vertebrates, the vast majority of hematopoiesis occurs in the bone marrow and is derived from a limited number of hematopoietic stem cells that are multipotent and capable of extensive self-renewal.

Hematopoietic stem cells give rise to different types of blood cells, in lines called myeloid and lymphoid. Myeloid and lymphoid lineages both are involved in dendritic cell formation. Myeloid cells include monocytes, macrophages, neutrophils, basophils, eosinophils, erythrocytes, and megakaryocytes to platelets. Lymphoid cells include T cells, B cells, natural killer cells, and innate lymphoid cells.

The definition of hematopoietic stem cell has developed since they were first discovered in 1961.[5] The hematopoietic tissue contains cells with long-term and short-term regeneration capacities and committed multipotent, oligopotent, and unipotent progenitors. Hematopoietic stem cells constitute 1:10,000 of cells in myeloid tissue.

HSC transplants are used in the treatment of cancers and other immune system disorders[6] due to their regenerative properties.[7]

They are round, non-adherent, with a rounded nucleus and low cytoplasm-to-nucleus ratio. In shape, hematopoietic stem cells resemble lymphocytes.

The very first hematopoietic stem cells during (mouse and human) embryonic development are found in aorta-gonad-mesonephros region and the vitelline and umbilical arteries.[8][9][10] Slightly later, HSCs are also found in the placenta, yolk sac, embryonic head, and fetal liver.[3][11]

Stem and progenitor cells can be taken from the pelvis, at the iliac crest, using a needle and syringe.[12] The cells can be removed as liquid (to perform a smear to look at the cell morphology) or they can be removed via a core biopsy (to maintain the architecture or relationship of the cells to each other and to the bone).[citation needed]

A colony-forming unit is a subtype of HSC. (This sense of the term is different from colony-forming units of microbes, which is a cell counting unit.) There are various kinds of HSC colony-forming units:

The above CFUs are based on the lineage. Another CFU, the colony-forming unitspleen (CFU-S), was the basis of an in vivo clonal colony formation, which depends on the ability of infused bone marrow cells to give rise to clones of maturing hematopoietic cells in the spleens of irradiated mice after 8 to 12 days. It was used extensively in early studies, but is now considered to measure more mature progenitor or transit-amplifying cells rather than stem cells[citation needed].

Since hematopoietic stem cells cannot be isolated as a pure population, it is not possible to identify them in a microscope.[citation needed] Hematopoietic stem cells can be identified or isolated by the use of flow cytometry where the combination of several different cell surface markers (particularly CD34) are used to separate the rare hematopoietic stem cells from the surrounding blood cells. Hematopoietic stem cells lack expression of mature blood cell markers and are thus called Lin-. Lack of expression of lineage markers is used in combination with detection of several positive cell-surface markers to isolate hematopoietic stem cells. In addition, hematopoietic stem cells are characterised by their small size and low staining with vital dyes such as rhodamine 123 (rhodamine lo) or Hoechst 33342 (side population).

Hematopoietic stem cells are essential to haematopoiesis, the formation of the cells within blood. Hematopoietic stem cells can replenish all blood cell types (i.e., are multipotent) and self-renew. A small number of hematopoietic stem cells can expand to generate a very large number of daughter hematopoietic stem cells. This phenomenon is used in bone marrow transplantation,[13] when a small number of hematopoietic stem cells reconstitute the hematopoietic system. This process indicates that, subsequent to bone marrow transplantation, symmetrical cell divisions into two daughter hematopoietic stem cells must occur.

Stem cell self-renewal is thought to occur in the stem cell niche in the bone marrow, and it is reasonable to assume that key signals present in this niche will be important in self-renewal.[2] There is much interest in the environmental and molecular requirements for HSC self-renewal, as understanding the ability of HSC to replenish themselves will eventually allow the generation of expanded populations of HSC in vitro that can be used therapeutically.

Hematopoietic stem cells, like all adult stem cells, mostly exist in a state of quiescence, or reversible growth arrest. The altered metabolism of quiescent HSCs helps the cells survive for extended periods of time in the hypoxic bone marrow environment.[14] When provoked by cell death or damage, Hematopoietic stem cells exit quiescence and begin actively dividing again. The transition from dormancy to propagation and back is regulated by the MEK/ERK pathway and PI3K/AKT/mTOR pathway.[15] Dysregulation of these transitions can lead to stem cell exhaustion, or the gradual loss of active Hematopoietic stem cells in the blood system.[15]

Hematopoietic stem cells have a higher potential than other immature blood cells to pass the bone marrow barrier, and, thus, may travel in the blood from the bone marrow in one bone to another bone. If they settle in the thymus, they may develop into T cells. In the case of fetuses and other extramedullary hematopoiesis. Hematopoietic stem cells may also settle in the liver or spleen and develop.

This enables Hematopoietic stem cells to be harvested directly from the blood.

Hematopoietic stem cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood.[16][17][13] It may be autologous (the patient's own stem cells are used), allogeneic (the stem cells come from a donor) or syngeneic (from an identical twin).[16][17]

It is most often performed for patients with certain cancers of the blood or bone marrow, such as multiple myeloma or leukemia.[17] In these cases, the recipient's immune system is usually destroyed with radiation or chemotherapy before the transplantation. Infection and graft-versus-host disease are major complications of allogeneic HSCT.[17]

In order to harvest stem cells from the circulating peripheral blood, blood donors are injected with a cytokine, such as granulocyte-colony stimulating factor (G-CSF), that induces cells to leave the bone marrow and circulate in the blood vessels.[18]In mammalian embryology, the first definitive Hematopoietic stem cells are detected in the AGM (aorta-gonad-mesonephros), and then massively expanded in the fetal liver prior to colonising the bone marrow before birth.[11]

Hematopoietic stem cell transplantation remains a dangerous procedure with many possible complications; it is reserved for patients with life-threatening diseases. As survival following the procedure has increased, its use has expanded beyond cancer to autoimmune diseases[19][20] and hereditary skeletal dysplasias; notably malignant infantile osteopetrosis[21][22] and mucopolysaccharidosis.[23]

Stem cells can be used to regenerate different types of tissues. HCT is an established as therapy for chronic myeloid leukemia, acute lymphatic leukemia, aplastic anemia, and hemoglobinopathies, in addition to acute myeloid leukemia and primary immune deficiencies. Hematopoietic system regeneration is typically achieved within 24 weeks post-chemo- or irradiation therapy and HCT. HSCs are being clinically tested for their use in non-hematopoietic tissue regeneration.[24]

DNA strand breaks accumulate in long term hematopoietic stem cells during aging.[25] This accumulation is associated with a broad attenuation of DNA repair and response pathways that depends on HSC quiescence.[25] Non-homologous end joining (NHEJ) is a pathway that repairs double-strand breaks in DNA. NHEJ is referred to as "non-homologous" because the break ends are directly ligated without the need for a homologous template. The NHEJ pathway depends on several proteins including ligase 4, DNA polymerase mu and NHEJ factor 1 (NHEJ1, also known as Cernunnos or XLF).

DNA ligase 4 (Lig4) has a highly specific role in the repair of double-strand breaks by NHEJ. Lig4 deficiency in the mouse causes a progressive loss of hematopoietic stem cells during aging.[26] Deficiency of lig4 in pluripotent stem cells results in accumulation of DNA double-strand breaks and enhanced apoptosis.[27]

In polymerase mu mutant mice, hematopoietic cell development is defective in several peripheral and bone marrow cell populations with about a 40% decrease in bone marrow cell number that includes several hematopoietic lineages.[28] Expansion potential of hematopoietic progenitor cells is also reduced. These characteristics correlate with reduced ability to repair double-strand breaks in hematopoietic tissue.

Deficiency of NHEJ factor 1 in mice leads to premature aging of hematopoietic stem cells as indicated by several lines of evidence including evidence that long-term repopulation is defective and worsens over time.[29] Using a human induced pluripotent stem cell model of NHEJ1 deficiency, it was shown that NHEJ1 has an important role in promoting survival of the primitive hematopoietic progenitors.[30] These NHEJ1 deficient cells possess a weak NHEJ1-mediated repair capacity that is apparently incapable of coping with DNA damages induced by physiological stress, normal metabolism, and ionizing radiation.[30]

The sensitivity of hematopoietic stem cells to Lig4, DNA polymerase mu and NHEJ1 deficiency suggests that NHEJ is a key determinant of the ability of stem cells to maintain themselves against physiological stress over time.[26] Rossi et al.[31] found that endogenous DNA damage accumulates with age even in wild type Hematopoietic stem cells, and suggested that DNA damage accrual may be an important physiological mechanism of stem cell aging.

A study shows the clonal diversity of hematopoietic stem cells gets drastically reduced around age 70 , substantiating a novel theory of ageing which could enable healthy aging.[32][33] Of note, the shift in clonal diversity during aging was previously reported in 2008[34] for the murine system by the Christa Muller-Sieburg laboratory in San Diego, California.

A cobblestone area-forming cell (CAFC) assay is a cell culture-based empirical assay. When plated onto a confluent culture of stromal feeder layer,[35] a fraction of hematopoietic stem cells creep between the gaps (even though the stromal cells are touching each other) and eventually settle between the stromal cells and the substratum (here the dish surface) or trapped in the cellular processes between the stromal cells. Emperipolesis is the in vivo phenomenon in which one cell is completely engulfed into another (e.g. thymocytes into thymic nurse cells); on the other hand, when in vitro, lymphoid lineage cells creep beneath nurse-like cells, the process is called pseudoemperipolesis. This similar phenomenon is more commonly known in the HSC field by the cell culture terminology cobble stone area-forming cells (CAFC), which means areas or clusters of cells look dull cobblestone-like under phase contrast microscopy, compared to the other hematopoietic stem cells, which are refractile. This happens because the cells that are floating loosely on top of the stromal cells are spherical and thus refractile. However, the cells that creep beneath the stromal cells are flattened and, thus, not refractile. The mechanism of pseudoemperipolesis is only recently coming to light. It may be mediated by interaction through CXCR4 (CD184) the receptor for CXC Chemokines (e.g., SDF1) and 41 integrins.[36]

Hematopoietic stem cells (HSC) cannot be easily observed directly, and, therefore, their behaviors need to be inferred indirectly. Clonal studies are likely the closest technique for single cell in vivo studies of HSC. Here, sophisticated experimental and statistical methods are used to ascertain that, with a high probability, a single HSC is contained in a transplant administered to a lethally irradiated host. The clonal expansion of this stem cell can then be observed over time by monitoring the percent donor-type cells in blood as the host is reconstituted. The resulting time series is defined as the repopulation kinetic of the HSC.

The reconstitution kinetics are very heterogeneous. However, using symbolic dynamics, one can show that they fall into a limited number of classes.[37] To prove this, several hundred experimental repopulation kinetics from clonal Thy-1lo SCA-1+ lin(B220, CD4, CD8, Gr-1, Mac-1 and Ter-119)[38] c-kit+ HSC were translated into symbolic sequences by assigning the symbols "+", "-", "~" whenever two successive measurements of the percent donor-type cells have a positive, negative, or unchanged slope, respectively. By using the Hamming distance, the repopulation patterns were subjected to cluster analysis yielding 16 distinct groups of kinetics. To finish the empirical proof, the Laplace add-one approach was used to determine that the probability of finding kinetics not contained in these 16 groups is very small. By corollary, this result shows that the hematopoietic stem cell compartment is also heterogeneous by dynamical criteria.

It was originally believed that all hematopoietic stem cells were alike in their self-renewal and differentiation abilities. This view was first challenged by the 2002 discovery by the Muller-Sieburg group in San Diego, who illustrated that different stem cells can show distinct repopulation patterns that are epigenetically predetermined intrinsic properties of clonal Thy-1lo Sca-1+ lin c-kit+ HSC.[39][40][41] The results of these clonal studies led to the notion of lineage bias. Using the ratio = L / M {displaystyle rho =L/M} of lymphoid (L) to myeloid (M) cells in blood as a quantitative marker, the stem cell compartment can be split into three categories of HSC. Balanced (Bala) hematopoietic stem cells repopulate peripheral white blood cells in the same ratio of myeloid to lymphoid cells as seen in unmanipulated mice (on average about 15% myeloid and 85% lymphoid cells, or 3 10). Myeloid-biased (My-bi) hematopoietic stem cells give rise to very few lymphocytes resulting in ratios 0 < < 3, while lymphoid-biased (Ly-bi) hematopoietic stem cells generate very few myeloid cells, which results in lymphoid-to-myeloid ratios of > 10. All three types are normal types of HSC, and they do not represent stages of differentiation. Rather, these are three classes of HSC, each with an epigenetically fixed differentiation program. These studies also showed that lineage bias is not stochastically regulated or dependent on differences in environmental influence. My-bi HSC self-renew longer than balanced or Ly-bi HSC. The myeloid bias results from reduced responsiveness to the lymphopoetin interleukin 7 (IL-7).[40]

Subsequently, other groups confirmed and highlighted the original findings.[42] For example, the Eaves group confirmed in 2007 that repopulation kinetics, long-term self-renewal capacity, and My-bi and Ly-bi are stably inherited intrinsic HSC properties.[43] In 2010, the Goodell group provided additional insights about the molecular basis of lineage bias in side population (SP) SCA-1+ lin c-kit+ HSC.[44] As previously shown for IL-7 signaling, it was found that a member of the transforming growth factor family (TGF-beta) induces and inhibits the proliferation of My-bi and Ly-bi HSC, respectively.

From Greek haimato-, combining form of haima 'blood', and from the Latinized form of Greek poietikos 'capable of making, creative, productive', from poiein 'to make, create'.[45]

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Hematopoietic stem cell - Wikipedia

A step closer to the confident production of blood stem cells for regenerative medicine  Medical Xpress

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A step closer to the confident production of blood stem cells for regenerative medicine - Medical Xpress

Circadian rhythm and aryl hydrocarbon receptor crosstalk in bone marrow adipose tissue and implications in leukemia  Nature

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Circadian rhythm and aryl hydrocarbon receptor crosstalk in bone marrow adipose tissue and implications in leukemia - Nature

Dr (Brig) Anil Kumar Dhar is one of the top medical oncologists in Gurugram. He has a vast experience of more than 30 years in the field of Medical oncology. He his specialised in treating leukemia,lymphoma, hematological oncology and other complex oncology cases . He is also specialised in Bone Marrow Transplantation (BMT) treatment. He is working as a Senior Consultant, HOD, Medical Oncologist in American Oncology Institute, Gurugram.

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Bone Marrow vs. Stem Cell Transplants | A Comprehensive Guide

Inside incredible cutting edge therapy that's curing patients of 'untreatable' diseases after Selma Blair brea  Daily Mail

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Inside incredible cutting edge therapy that's curing patients of 'untreatable' diseases after Selma Blair brea - Daily Mail