Cardiac Stem Cells – Cedars-Sinai

By Dr. Matthew Watson

Preclinical Research

Scientists are developing novel therapeutics for the treatment of cardiovascular diseases using cardiac-derived stem cells in mice and large-animal models. Three current projects are studying:

ExosomesOur researchers are isolating exosomes from specialized human cardiac-derived stem cells and finding that they have the same beneficial effects as other types of stem cells. In mice models, our research shows that exosomes produce the same post-surgery benefits, such as decreasing scar size, increasing healthy heart tissue and reducing levels of chemicals that lead to inflammation. This research suggests that exosomes convey messages that reduce cell death, promote growth of new heart muscle cells and encourage the development of healthy blood vessels.

Mechanisms of Heart Regeneration by Cardiosphere-Derived CellsInvestigators seek to understand the basic mechanisms of coronary artery disease in preclinical disease models. We hope to gather novel mechanistic insights, enabling us to boost the efficacy of stem cell-based treatments by bolstering the regeneration of injured heart muscle.

Biological PacemakersUsing an engineered virus carrying T-box (TBx18), Cedars-Sinai researchers are reprogramming heart muscle cells (cardiomyoctes) into induced sinoatrial node cells in pigs. Cedars-Sinai research shows that these new cells generate electrical impulses spontaneously and are indistinguishable from sinoatrial node or native pacemaker cells. Investigators believe this could be a viable therapeutic avenue for pacemaker-dependent patients afflicted with device-related complications.

Researchers hope to someday incorporate therapeutic regeneration as a regular treatment option for a broad range of cardiovascular disorders, such as myocardial infarctions, heart failure, refractory angina and peripheral vascular disease. Through the Regenerative Medicine Clinic at the Cedars-Sinai Heart Institute, several cardiac stem cell trials are underway. They include:

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December 20th, 2018

Heart Failure Signs | Cardiac Stem Cell Therapies: Heart …

By JoanneRUSSELL25

Human life is dependent upon the hearts ability to pump forcefully and frequently enough, but heart failure signs can disturb its normal function. Most humans cannot live more than four minutes without a heartbeat or continuous blood-flow. At that time, brain cells begin to die because they lack adequately oxygenated blood-flow.

The human adult body requires, on average, 5.0 liters of re-circulated blood per minute. In the cardiology field, this metric is called the Cardiac Output, which is calculated as Stroke Volume (SV) x Heart Rate (HR). Another key metric is a patients Ejection-Fraction (EF %). A patients EF tells a cardiologist and other physicians if his or her heart is functioning normally or low normally. It is a measurement of ones heart contraction, with a normal EF range being 55-70%.

This number can also be combined with a patients heart rate to provide physicians with a baseline of a patients cardiac status. A normal range for an adult is 60-100 beats per minute, and this can be significantly higher during a normal pregnancy.

In this article:

For a cardiologist, cardiac metrics indicate if their services are required and allowthem to sign-off on pre-operative cardiac clearances. For other physicians, it tells them if the organ which they specialize in is being perfused adequately (for example, a nephrologist would be interested to know kidney perfusion). It can also indicate the degree to which decreased heart function may affect the severity or spread of disease.

When the heart fails to contract forcefully enough and its performance decreases to the point where its ability to circulate blood adequately is compromised (the EF% falls below 40%), this is considered heart failure. The clinical parameters of heart failure are clearly defined by the New York Heart Association (NYHA), which places patients in NYHA Class III & IV into the heart failure category.

An echocardiogram (often called an Echo), as opposed to an Electrocardiogram (EKG or ECG), allows technicians and physicians to visualize the beating heart. Video clips of the heart contracting are digitally recorded, and a patients EF and Cardiac Output (CO) can be measured with several diagnostic tools (Fractional Shortening via 2D or M-Mode measurements and Simpsons Method via 2D and 3D Quantification) on a cardiovascular ultrasound system.

When an experienced echo tech or cardiologist views a failing heart, it is immediately apparent. Based on my experience reading echocardiograms, I can see that the heart walls or heart muscles (myocardium) are not contracting as vigorously as they should.

For patients with a 5% EF range, any physical movement is extremely strenuous, and they can go into cardiac arrest at any moment, which is why they are usually on cardiac telemetry in a hospital setting. Most likely, a patient with 5% EF range would be awaiting a heart transplant, unless there is a medical condition preventing them from being eligible.

Once a patient falls into the heart failure range, they will be lethargic and have severe limits on activities. Other clinical manifestations of heart failure can include peripheral edema (i.e. swelling in the feet, legs, ankles, or stomach), pulmonary edema, and shortness of breath. In many cases, this can lead to depression.

In evaluating the frequency of heart failure in the U.S, statistics from the U.S. Centers for Disease Control (CDC) find that approximately 5.7 million adults are afflicted with this condition. Additionally, care for congestive heart failure costs an estimated $30.7B per year. Furthermore, the mortality rates of patients suffering from heart failure indicate its clinical severity, with 1 in 5 patients with this condition dying within a year of receiving the diagnosis.

A patient experiencing severe heart failure has limited treatment options, which are expensive, complicated, and have major lifestyle implications.

These limited options include:

Consequently, physicians need more effective weapons for treating heart failure in order to improve patients lives and reduce healthcare-related costs. CHF patients have disproportionate hospital readmission rates when compared to other major diseases.

Enter in the growing field of cardiac stem cell treatments, which introduce fundamentally new treatment options for heart failure patients. In cardiac stem cell treatments, stem cells are taken from a patients bone marrow or fat tissue in a sterile surgical procedure and injected via a catheter-wire into infarcted or poorly contracting muscular segments of the hearts main pumping chamber, the left ventricle (LV).

Over the course of a few months, the stem cells impact myocardial cells and begin to improve the contractility of the affected segments, most likely through paracrine signaling mechanisms and impacting the local microenvironment. This can bring a patients EF to low-normal or even normal levels. As a result, a patient can live a more normal life and return to many activities.

A very early clinical trial aimed at evaluating the potential and effectiveness of cardiac stem cell therapy in humans was conducted in 2006 utilizing a commercial product, VesCellTM. The parameters and results of this trial were documented in the American Heart Associations Circulation, Abstract 3682: Treatment of Patients with Severe Angina Pectoris Using Intracoronarily Injected Autologous Blood-Borne Angiogenic Cell Precursors.The subjects of this trial received an intracoronary injection of VesCellTM, an Autologous Angiogenic Cell Precursor (ACP)-based product.

The authors drew their conclusion regarding this study. VesCell therapy for chronic stable angina seems to be safe and improves anginal symptoms at 3 and 6 months. Larger studies are being initiated to evaluate the benefit of VesCell for the treatment of this and additional severe heart diseases. (Source: Tresukosol et al. Abstract 3682: Treatment of Patients with Severe Angina Pectoris Using Intracoronarily Injected Autologous Blood-Borne Angiogenic Cell Precursors. Circulation. October 31, 2006. Vol. 114, Issue Suppl 18. Link: http://circ.ahajournals.org/content/114/Suppl_18/II_786.4 )

Another early cardiac stem cell clinical trial was performed in 2009 by a Cedars-Sinai team based on technologies and discoveries made by Eduardo Marban, MD, PhD, and led by Raj Makkar, MD. In this study, they explored the safety of harvesting, expanding, and administering a patients cardiac stem cells to repair heart tissue injured by myocardial infarction.

Recently, the American College of Cardiology (ACC) also announced results of a ground-breaking clinical study to evaluate the efficacy and effectiveness of cardiac stem cell treatment for heart failure patients. As stated by Timothy Henry, M.D., Director of Cardiology at Cedars-Sinai Heart Institute and one of the studys lead authors, This is the largest double-blind, placebo-controlled stem cell trial for treatment of heart failure to be presentedBased on these positive results, we are encouraged that this is an attractive potential therapy for patients with class III and class IV heart failure.

Additionally, Dr. Charles Goldthwaite, Jr, published a whitepaper titled, Mending a Broken Heart: Stem Cells and Cardiac Repair, in which he draws the conclusion, Given the worldwide prevalence of cardiac dysfunction and the limited availability of tissue for cardiac transplantation, stem cells could ultimately fulfill a large-scale unmet clinical need and improve the quality of life for millions of people with CVD. However, the use of these cells in this setting is currently in its infancymuch remains to be learned about the mechanisms by which stem cells repair and regenerate myocardium, the optimal cell types, and modes of their delivery, and the safety issues that will accompany their use.

Clearly, there is a trend toward acceptance of cardiac stem cell therapies as an emerging treatment option. Several world-renowned institutes are now conducting clinical studies involving cardiac stem cell treatment, as well as applying for intellectual property protection (patents) pertaining to the techniques required in administrating the therapies.

The key questions at this point in time appear to be:

An important whitepaper pertaining to cardiac stem cells is Ischemic Cardiomyopathy Patients Treated with Autologous Angiogenic and Cardio-Regenerative Progenitor Cells, written by Dr. Athina Kyritsis, et al. In it, the physicians describe their objective as investigating the feasibility, safety, and clinical outcome of patients with Ischemic Cardiomyopathy treated with Autologous Angiogenic and Cardio-Regenerative Progenitor cells (ACPs).

The researchers state: In numerous human trials there is evidence of improvement in the ejection fractions of Cardiomyopathy patients treated with ACPs. Animal experiments not only show improvement in cardiac function, but also engraftment and differentiation of ACPs into cardiomyocytes, as well as neo-vascularization in infarcted myocardium. In our clinical experience, the process has shown to be safe as well as effective.

The authors also found that patients treated with this approach gained increases in cardiac ejection fraction from their starting measurements, with improvements in their cardiac ejection fraction of 21 points (75% increase) at rest and 28.5 points (80% increase) at stress. As a result of these finding, the authors conclude, ACPs can improve the ejection fraction in patients with severely reduced cardiac function with benefits sustained to six months.

In the practice of medicine, the focus should be on delivering excellent care to patients. If there are cardiac stem cell treatments available, then regulatory obstacles should be removed when sufficient clinical trial evidence has been provided to indicate safety and efficacy.

Cardiologist Zannos Grekos, MD, a pioneer in cardiac stem cell therapy since 2006, points to the vastly untapped promise of related therapies, commenting Those of us that have been involved with cardiac stem cell treatment for the last 10-plus years can see the incredible potential this approach has.

As of 2017, the U.S. healthcare system is under enormous pressure to deliver affordable healthcareto a growing population of patients, especially those who are fully or partially covered under Medicare or Medicaid (many have secondary coverage). Although we are in the infancy of its development, cardiac stem cell treatments represent a potentially powerful treatment alternative to patients with heart failure symptoms.

To learn more, view the resources below.

1) Regenocyte http://www.regenocyte.com

2) Cleveland Clinic Stem Cell Therapy for Heart Disease my.clevelandclinic.org/health/articles/stem-cell-therapy-heart-disease

3) Harvard Stem Cell Institute (HSCI) hsci.harvard.edu/heart-disease-0

4) Cedars Sinai Cardiac Stem Cell Treatment http://www.cedars-sinai.edu/Patients/Programs-and-Services/Heart-Institute/Clinical-Trials/Cardiac-Stem-Cell-Research.aspx

5) Johns Hopkins Medicine Cardiac Stem Cell Treatments http://www.hopkinsmedicine.org/stem_cell_research/cell_therapy/a_new_path_for_cardiac_stem_cells.html

What do you think about heart failure signs and cardiac stem cell therapies? Share your thoughts in the comments section below.

Up Next:European Society of Cardiology (ESC) Congress Presentation Reveals Results From Pre-Clinical Study Using CardioCells Stem Cells for Acute Myocardial Infarction

Guest Post: This is a guest article by Clifford M. Thornton, a Certified Cardiovascular Technologist, experienced Echocardiographer Technician, and journalist in the cardiac and medical device fields. His articles have been published in Inventors Digest, Global Innovation Magazine, and Modern Health Talk. He is enthusiastic about progress with cardiac stem cell therapies and their role in heart failure treatment.He can be reached byphone at 267-524-7144 or by email at[emailprotected].

Editors Note This post was originally published on March 14, 2017, and has been updated for quality and relevancy.

Heart Failure Signs | Cardiac Stem Cell Therapies for Heart Failure Treatment

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November 15th, 2018

Embryonic stem cell – Wikipedia

By daniellenierenberg

Embryonic stem cells (ES cells or ESCs) are pluripotent stem cells derived from the inner cell mass of a blastocyst, an early-stage pre-implantation embryo.[1][2] Human embryos reach the blastocyst stage 45 days post fertilization, at which time they consist of 50150 cells. Isolating the embryoblast, or inner cell mass (ICM) results in destruction of the blastocyst, a process which raises ethical issues, including whether or not embryos at the pre-implantation stage should have the same moral considerations as embryos in the post-implantation stage of development.[3][4] Researchers are currently focusing heavily on the therapeutic potential of embryonic stem cells, with clinical use being the goal for many labs. These cells are being studied to be used as clinical therapies, models of genetic disorders, and cellular/DNA repair. However, adverse effects in the research and clinical processes have also been reported.

Embryonic stem cells (ESCs), derived from the blastocyst stage of early mammalian embryos, are distinguished by their ability to differentiate into any cell type and by their ability to propagate. It is these traits that makes them valuable in the scientific/medical fields. ESC are also described as having a normal karyotype, maintaining high telomerase activity, and exhibiting remarkable long-term proliferative potential.[5]

Embryonic stem cells of the inner cell mass are pluripotent, meaning they are able to differentiate to generate primitive ectoderm, which ultimately differentiates during gastrulation into all derivatives of the three primary germ layers: ectoderm, endoderm, and mesoderm. These include each of the more than 220 cell types in the adult human body. Pluripotency distinguishes embryonic stem cells from adult stem cells, which are multipotent and can only produce a limited number of cell types.

Under defined conditions, embryonic stem cells are capable of propagating indefinitely in an undifferentiated state. Conditions must either prevent the cells from clumping, or maintain an environment that supports an unspecialized state.[2] While being able to remain undifferentiated, ESCs also have the capacity, when provided with the appropriate signals, to differentiate (presumably via the initial formation of precursor cells) into nearly all mature cell phenotypes.[6]

Due to their plasticity and potentially unlimited capacity for self-renewal, embryonic stem cell therapies have been proposed for regenerative medicine and tissue replacement after injury or disease. Pluripotent stem cells have shown potential in treating a number of varying conditions, including but not limited to: spinal cord injuries, age related macular degeneration, diabetes, neurodegenerative disorders (such as Parkinson's disease), AIDS, etc.[7] In addition to their potential in regenerative medicine, embryonic stem cells provide an alternative source of tissue/organs which serves as a possible solution to the donor shortage dilemma. Not only that, but tissue/organs derived from ESCs can be made immunocompatible with the recipient. Aside from these uses, embryonic stem cells can also serve as tools for the investigation of early human development, study of genetic disease and as in vitro systems for toxicology testing.[5]

According to a 2002 article in PNAS, "Human embryonic stem cells have the potential to differentiate into various cell types, and, thus, may be useful as a source of cells for transplantation or tissue engineering."[8]

However, embryonic stem cells are not limited to cell/tissue engineering.

Current research focuses on differentiating ESCs into a variety of cell types for eventual use as cell replacement therapies (CRTs). Some of the cell types that have or are currently being developed include cardiomyocytes (CM), neurons, hepatocytes, bone marrow cells, islet cells and endothelial cells.[9] However, the derivation of such cell types from ESCs is not without obstacles, therefore current research is focused on overcoming these barriers. For example, studies are underway to differentiate ESCs in to tissue specific CMs and to eradicate their immature properties that distinguish them from adult CMs.[10]

Besides becoming an important alternative to organ transplants, ESCs are also being used in field of toxicology and as cellular screens to uncover new chemical entities (NCEs) that can be developed as small molecule drugs. Studies have shown that cardiomyocytes derived from ESCs are validated in vitro models to test drug responses and predict toxicity profiles.[9] ES derived cardiomyocytes have been shown to respond to pharmacological stimuli and hence can be used to assess cardiotoxicity like Torsades de Pointes.[17]

ESC-derived hepatocytes are also useful models that could be used in the preclinical stages of drug discovery. However, the development of hepatocytes from ESCs has proven to be challenging and this hinders the ability to test drug metabolism. Therefore, current research is focusing on establishing fully functional ESC-derived hepatocytes with stable phase I and II enzyme activity.[18]

Several new studies have started to address the concept of modeling genetic disorders with embryonic stem cells. Either by genetically manipulating the cells, or more recently, by deriving diseased cell lines identified by prenatal genetic diagnosis (PGD), modeling genetic disorders is something that has been accomplished with stem cells. This approach may very well prove invaluable at studying disorders such as Fragile-X syndrome, Cystic fibrosis, and other genetic maladies that have no reliable model system.

Yury Verlinsky, a Russian-American medical researcher who specialized in embryo and cellular genetics (genetic cytology), developed prenatal diagnosis testing methods to determine genetic and chromosomal disorders a month and a half earlier than standard amniocentesis. The techniques are now used by many pregnant women and prospective parents, especially couples who have a history of genetic abnormalities or where the woman is over the age of 35 (when the risk of genetically related disorders is higher). In addition, by allowing parents to select an embryo without genetic disorders, they have the potential of saving the lives of siblings that already had similar disorders and diseases using cells from the disease free offspring.[19]

Differentiated somatic cells and ES cells use different strategies for dealing with DNA damage. For instance, human foreskin fibroblasts, one type of somatic cell, use non-homologous end joining (NHEJ), an error prone DNA repair process, as the primary pathway for repairing double-strand breaks (DSBs) during all cell cycle stages.[20] Because of its error-prone nature, NHEJ tends to produce mutations in a cells clonal descendants.

ES cells use a different strategy to deal with DSBs.[21] Because ES cells give rise to all of the cell types of an organism including the cells of the germ line, mutations arising in ES cells due to faulty DNA repair are a more serious problem than in differentiated somatic cells. Consequently, robust mechanisms are needed in ES cells to repair DNA damages accurately, and if repair fails, to remove those cells with un-repaired DNA damages. Thus, mouse ES cells predominantly use high fidelity homologous recombinational repair (HRR) to repair DSBs.[21] This type of repair depends on the interaction of the two sister chromosomes formed during S phase and present together during the G2 phase of the cell cycle. HRR can accurately repair DSBs in one sister chromosome by using intact information from the other sister chromosome. Cells in the G1 phase of the cell cycle (i.e. after metaphase/cell division but prior the next round of replication) have only one copy of each chromosome (i.e. sister chromosomes arent present). Mouse ES cells lack a G1 checkpoint and do not undergo cell cycle arrest upon acquiring DNA damage.[22] Rather they undergo programmed cell death (apoptosis) in response to DNA damage.[23] Apoptosis can be used as a fail-safe strategy to remove cells with un-repaired DNA damages in order to avoid mutation and progression to cancer.[24] Consistent with this strategy, mouse ES stem cells have a mutation frequency about 100-fold lower than that of isogenic mouse somatic cells.[25]

On January 23, 2009, Phase I clinical trials for transplantation of oligodendrocytes (a cell type of the brain and spinal cord) derived from human ES cells into spinal cord-injured individuals received approval from the U.S. Food and Drug Administration (FDA), marking it the world's first human ES cell human trial.[26] The study leading to this scientific advancement was conducted by Hans Keirstead and colleagues at the University of California, Irvine and supported by Geron Corporation of Menlo Park, CA, founded by Michael D. West, PhD. A previous experiment had shown an improvement in locomotor recovery in spinal cord-injured rats after a 7-day delayed transplantation of human ES cells that had been pushed into an oligodendrocytic lineage.[27] The phase I clinical study was designed to enroll about eight to ten paraplegics who have had their injuries no longer than two weeks before the trial begins, since the cells must be injected before scar tissue is able to form. The researchers emphasized that the injections were not expected to fully cure the patients and restore all mobility. Based on the results of the rodent trials, researchers speculated that restoration of myelin sheathes and an increase in mobility might occur. This first trial was primarily designed to test the safety of these procedures and if everything went well, it was hoped that it would lead to future studies that involve people with more severe disabilities.[28] The trial was put on hold in August 2009 due to FDA concerns regarding a small number of microscopic cysts found in several treated rat models but the hold was lifted on July 30, 2010.[29]

In October 2010 researchers enrolled and administered ESTs to the first patient at Shepherd Center in Atlanta.[30] The makers of the stem cell therapy, Geron Corporation, estimated that it would take several months for the stem cells to replicate and for the GRNOPC1 therapy to be evaluated for success or failure.

In November 2011 Geron announced it was halting the trial and dropping out of stem cell research for financial reasons, but would continue to monitor existing patients, and was attempting to find a partner that could continue their research.[31] In 2013 BioTime (AMEX:BTX), led by CEO Dr. Michael D. West, acquired all of Geron's stem cell assets, with the stated intention of restarting Geron's embryonic stem cell-based clinical trial for spinal cord injury research.[32]

BioTime company Asterias Biotherapeutics (NYSE MKT: AST) was granted a $14.3 million Strategic Partnership Award by the California Institute for Regenerative Medicine (CIRM) to re-initiate the worlds first embryonic stem cell-based human clinical trial, for spinal cord injury. Supported by California public funds, CIRM is the largest funder of stem cell-related research and development in the world.[33]

The award provides funding for Asterias to reinitiate clinical development of AST-OPC1 in subjects with spinal cord injury and to expand clinical testing of escalating doses in the target population intended for future pivotal trials.[33]

AST-OPC1 is a population of cells derived from human embryonic stem cells (hESCs) that contains oligodendrocyte progenitor cells (OPCs). OPCs and their mature derivatives called oligodendrocytes provide critical functional support for nerve cells in the spinal cord and brain. Asterias recently presented the results from phase 1 clinical trial testing of a low dose of AST-OPC1 in patients with neurologically-complete thoracic spinal cord injury. The results showed that AST-OPC1 was successfully delivered to the injured spinal cord site. Patients followed 23 years after AST-OPC1 administration showed no evidence of serious adverse events associated with the cells in detailed follow-up assessments including frequent neurological exams and MRIs. Immune monitoring of subjects through one year post-transplantation showed no evidence of antibody-based or cellular immune responses to AST-OPC1. In four of the five subjects, serial MRI scans performed throughout the 23 year follow-up period indicate that reduced spinal cord cavitation may have occurred and that AST-OPC1 may have had some positive effects in reducing spinal cord tissue deterioration. There was no unexpected neurological degeneration or improvement in the five subjects in the trial as evaluated by the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) exam.[33]

The Strategic Partnership III grant from CIRM will provide funding to Asterias to support the next clinical trial of AST-OPC1 in subjects with spinal cord injury, and for Asterias product development efforts to refine and scale manufacturing methods to support later-stage trials and eventually commercialization. CIRM funding will be conditional on FDA approval for the trial, completion of a definitive agreement between Asterias and CIRM, and Asterias continued progress toward the achievement of certain pre-defined project milestones.[33]

The major concern with the possible transplantation of ESC into patients as therapies is their ability to form tumors including teratoma.[34] Safety issues prompted the FDA to place a hold on the first ESC clinical trial, however no tumors were observed.

The main strategy to enhance the safety of ESC for potential clinical use is to differentiate the ESC into specific cell types (e.g. neurons, muscle, liver cells) that have reduced or eliminated ability to cause tumors. Following differentiation, the cells are subjected to sorting by flow cytometry for further purification. ESC are predicted to be inherently safer than IPS cells created with genetically-integrating viral vectors because they are not genetically modified with genes such as c-Myc that are linked to cancer. Nonetheless, ESC express very high levels of the iPS inducing genes and these genes including Myc are essential for ESC self-renewal and pluripotency,[35] and potential strategies to improve safety by eliminating c-Myc expression are unlikely to preserve the cells' "stemness". However, N-myc and L-myc have been identified to induce iPS cells instead of c-myc with similar efficiency.[36]More recent protocols to induce pluripotency bypass these problems completely by using non-integrating RNA viral vectors such as sendai virus or mRNA transfection.

Due to the nature of embryonic stem cell research, there is a lot of controversial opinions on the topic. Since harvesting embryonic stem cells necessitates destroying the embryo from which those cells are obtained, the moral status of the embryo comes into question. Scientists argue that the 5-day old mass of cells is too young to achieve personhood or that the embryo, if donated from an IVF clinic (which is where labs typically acquire embryos from), would otherwise go to medical waste anyway. Opponents of ESC research counter that any embryo has the potential to become a human, therefore destroying it is murder and the embryo must be protected under the same ethical view as a developed human being.[37]

In vitro fertilization generates multiple embryos. The surplus of embryos is not clinically used or is unsuitable for implantation into the patient, and therefore may be donated by the donor with consent. Human embryonic stem cells can be derived from these donated embryos or additionally they can also be extracted from cloned embryos using a cell from a patient and a donated egg.[49] The inner cell mass (cells of interest), from the blastocyst stage of the embryo, is separated from the trophectoderm, the cells that would differentiate into extra-embryonic tissue. Immunosurgery, the process in which antibodies are bound to the trophectoderm and removed by another solution, and mechanical dissection are performed to achieve separation. The resulting inner cell mass cells are plated onto cells that will supply support. The inner cell mass cells attach and expand further to form a human embryonic cell line, which are undifferentiated. These cells are fed daily and are enzymatically or mechanically separated every four to seven days. For differentiation to occur, the human embryonic stem cell line is removed from the supporting cells to form embryoid bodies, is co-cultured with a serum containing necessary signals, or is grafted in a three-dimensional scaffold to result.[50]

Embryonic stem cells are derived from the inner cell mass of the early embryo, which are harvested from the donor mother animal. Martin Evans and Matthew Kaufman reported a technique that delays embryo implantation, allowing the inner cell mass to increase. This process includes removing the donor mother's ovaries and dosing her with progesterone, changing the hormone environment, which causes the embryos to remain free in the uterus. After 46 days of this intrauterine culture, the embryos are harvested and grown in in vitro culture until the inner cell mass forms egg cylinder-like structures, which are dissociated into single cells, and plated on fibroblasts treated with mitomycin-c (to prevent fibroblast mitosis). Clonal cell lines are created by growing up a single cell. Evans and Kaufman showed that the cells grown out from these cultures could form teratomas and embryoid bodies, and differentiate in vitro, all of which indicating that the cells are pluripotent.[41]

Gail Martin derived and cultured her ES cells differently. She removed the embryos from the donor mother at approximately 76 hours after copulation and cultured them overnight in a medium containing serum. The following day, she removed the inner cell mass from the late blastocyst using microsurgery. The extracted inner cell mass was cultured on fibroblasts treated with mitomycin-c in a medium containing serum and conditioned by ES cells. After approximately one week, colonies of cells grew out. These cells grew in culture and demonstrated pluripotent characteristics, as demonstrated by the ability to form teratomas, differentiate in vitro, and form embryoid bodies. Martin referred to these cells as ES cells.[42]

It is now known that the feeder cells provide leukemia inhibitory factor (LIF) and serum provides bone morphogenetic proteins (BMPs) that are necessary to prevent ES cells from differentiating.[51][52] These factors are extremely important for the efficiency of deriving ES cells. Furthermore, it has been demonstrated that different mouse strains have different efficiencies for isolating ES cells.[53] Current uses for mouse ES cells include the generation of transgenic mice, including knockout mice. For human treatment, there is a need for patient specific pluripotent cells. Generation of human ES cells is more difficult and faces ethical issues. So, in addition to human ES cell research, many groups are focused on the generation of induced pluripotent stem cells (iPS cells).[54]

On August 23, 2006, the online edition of Nature scientific journal published a letter by Dr. Robert Lanza (medical director of Advanced Cell Technology in Worcester, MA) stating that his team had found a way to extract embryonic stem cells without destroying the actual embryo.[55] This technical achievement would potentially enable scientists to work with new lines of embryonic stem cells derived using public funding in the USA, where federal funding was at the time limited to research using embryonic stem cell lines derived prior to August 2001. In March, 2009, the limitation was lifted.[56]

The iPSC technology was pioneered by Shinya Yamanakas lab in Kyoto, Japan, who showed in 2006 that the introduction of four specific genes encoding transcription factors could convert adult cells into pluripotent stem cells.[57] He was awarded the 2012 Nobel Prize along with Sir John Gurdon "for the discovery that mature cells can be reprogrammed to become pluripotent." [58]

In 2007 it was shown that pluripotent stem cells highly similar to embryonic stem cells can be generated by the delivery of three genes (Oct4, Sox2, and Klf4) to differentiated cells.[59] The delivery of these genes "reprograms" differentiated cells into pluripotent stem cells, allowing for the generation of pluripotent stem cells without the embryo. Because ethical concerns regarding embryonic stem cells typically are about their derivation from terminated embryos, it is believed that reprogramming to these "induced pluripotent stem cells" (iPS cells) may be less controversial. Both human and mouse cells can be reprogrammed by this methodology, generating both human pluripotent stem cells and mouse pluripotent stem cells without an embryo.[60]

This may enable the generation of patient specific ES cell lines that could potentially be used for cell replacement therapies. In addition, this will allow the generation of ES cell lines from patients with a variety of genetic diseases and will provide invaluable models to study those diseases.

However, as a first indication that the induced pluripotent stem cell (iPS) cell technology can in rapid succession lead to new cures, it was used by a research team headed by Rudolf Jaenisch of the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, to cure mice of sickle cell anemia, as reported by Science journal's online edition on December 6, 2007.[61][62]

On January 16, 2008, a California-based company, Stemagen, announced that they had created the first mature cloned human embryos from single skin cells taken from adults. These embryos can be harvested for patient matching embryonic stem cells.[63]

The online edition of Nature Medicine published a study on January 24, 2005, which stated that the human embryonic stem cells available for federally funded research are contaminated with non-human molecules from the culture medium used to grow the cells.[64] It is a common technique to use mouse cells and other animal cells to maintain the pluripotency of actively dividing stem cells. The problem was discovered when non-human sialic acid in the growth medium was found to compromise the potential uses of the embryonic stem cells in humans, according to scientists at the University of California, San Diego.[65]

However, a study published in the online edition of Lancet Medical Journal on March 8, 2005 detailed information about a new stem cell line that was derived from human embryos under completely cell- and serum-free conditions. After more than 6 months of undifferentiated proliferation, these cells demonstrated the potential to form derivatives of all three embryonic germ layers both in vitro and in teratomas. These properties were also successfully maintained (for more than 30 passages) with the established stem cell lines.[66]

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Embryonic stem cell - Wikipedia

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September 23rd, 2018

stem cell | Definition, Types, Uses, Research, & Facts …

By Sykes24Tracey

Stem cell, an undifferentiated cell that can divide to produce some offspring cells that continue as stem cells and some cells that are destined to differentiate (become specialized). Stem cells are an ongoing source of the differentiated cells that make up the tissues and organs of animals and plants. There is great interest in stem cells because they have potential in the development of therapies for replacing defective or damaged cells resulting from a variety of disorders and injuries, such as Parkinson disease, heart disease, and diabetes. There are two major types of stem cells: embryonic stem cells and adult stem cells, which are also called tissue stem cells.

Adult Cardiac Stem Cells Don’t Exist: Study | The …

By Sykes24Tracey

Cardiac stem cell research has a turbulent history. Studies revealing the presence of regenerative progenitors in adult rodents hearts formed the basis of numerous clinical trials, but several experiments have cast doubt on these cells ability to produce new tissue. Some scientists are now lauding the results of a report published in April in Circulation as undeniable evidence against the idea that resident stem cells can give rise to new cardiomyocytes.

The concept of [many] clinical trials arose from the basic science in labs of a few individuals more than 15 years ago, and that basic science is whats now being called into question, says Jeffery Molkentin, a cardiovascular biologist at Cincinnati Childrens Hospital who penned an editorial about the latest work.

The first evidence supporting the notion of cardiac stem cells in adults emerged in the early 2000s, when researchers reported that cells derived from bone marrow or adult heart expressing the protein c-kit could give rise to new muscle tissue when injected into damaged myocardium in rodents. These studies caused some controversy right from the start, Molkentin says. The main reason that this struck a raw nerve with people is because we already know that heart, in human patients, doesnt regenerate itself after an infarct.

Early skepticism arose in 2004, when two separate groups of researchers published back-to-back papers refuting the claims that bone marrowderived c-kit cells could regenerate damaged heart tissue. Still, the concept of endogenous cardiac stem cells remained a mainstream idea until Molkentin and his colleagues published a study in 2014 reporting that c-kit cells in the adult mouse heart almost never produced new cardiomyocytes, says Bin Zhou, a cell biologist at the Chinese Academy of Sciences and a coauthor of the new study.

Although Molkentins findings were replicated shortly afterwards by two independent groups (including Zhous), some researchers held fast to the idea that cardiac progenitors could regenerate injured heart tissue. Earlier this year, a team of researchersincluding Bernardo Nadal-Ginard and Daniele Torella of Magna Graecia University in Italy and several other scientists who conducted the early work on c-kit cellspublished a paper reporting the flaws in the cell lineage tracing technique employed by Molkentin, Zhou, and their colleagues. For example, they noted that the method, which involved tagging c-kitexpressing cells and their progeny with a fluorescent marker, compromised the gene required to express the c-kit protein, impairing the progenitors regenerative abilities.

In the new Circulationstudy, Zhou and his colleagues used a different approach to examine endogenous stem cell populations in mice. Instead of tagging c-kit cells, the team applied a technique that would fluorescently label nonmyocytes and newly generated muscle cells a different color from existing myocytes. This method allowed the researchers to investigate all proposed stem cell populations, rather than specifically addressing c-kit cells. We wanted to ask the broader question of whether there are any stem cells in the adult heart, Zhou says.

These experiments revealed that, while nonmyocytes generate cardiomyocytes in mouse embryos, they do not give rise to new muscle cells in adult rodents hearts. The results also address the concerns raised about c-kit lineage tracing, Zhou tells The Scientist. We think our system can conclude that nonmyocytes cannot become myocytes in adults in homeostasis and after injury.

Torella says that hes not convinced by Zhous evidence. The main issue, he explains, is that the researchers did not explicitly test whether cardiac stem cells were indeed labeled as nonmyocytes to ensure that they were not inadvertently tagging them as myocytes instead.

Molkentin disagrees with this critique, stating that the only way the system would label a myocyte progenitor as a myocyte is if it was no longer a true stem cell, but instead an immature myocyte. Zhous group uses an exhausting and very rigorous genetic approach, he adds. My opinion is that we need to go back to the bench and conduct additional research to truly understand the mechanisms at play to better inform how we design the next generation of clinical trials.

Other scientists note that stem cells may not need to become new myocytes to help repair the injured heart. According to Phillip Yang, a cardiologist at Stanford University who did not take part in the work, many scientists now agree that stem cells are not regenerating damaged cardiomyocytes. Instead, he explains, a growing body of research now supports an alternative theory, which posits that progenitor cells secrete small molecules called paracrine factors that help repair injured heart cells. (Yang is involved in several stem cell clinical trials).

When you inject these stem cells, its pretty incontrovertible that they help heart function in a mouse injury model, Yang says. But the truth is, most of these cells are dead upon arrival [to the site of injury]. So the question is: Why is heart function still improving if these cells are dying?

Y. Li et al., Genetic lineage tracing of nonmyocyte population by dual recombinases, Circulation, 138:793-805, 2018.

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September 8th, 2018

Susan Solomon: The promise of research with stem cells …

By daniellenierenberg

There was a very sad example of this in the last decade.There's a wonderful drug, and a class of drugs actually,but the particular drug was Vioxx, andfor people who were suffering from severe arthritis pain,the drug was an absolute lifesaver,but unfortunately, for another subset of those people,they suffered pretty severe heart side effects,and for a subset of those people, the side effects wereso severe, the cardiac side effects, that they were fatal.But imagine a different scenario,where we could have had an array, a genetically diverse array,of cardiac cells, and we could have actually testedthat drug, Vioxx, in petri dishes, and figured out,well, okay, people with this genetic type are going to havecardiac side effects, people with these genetic subgroupsor genetic shoes sizes, about 25,000 of them,are not going to have any problems.The people for whom it was a lifesavercould have still taken their medicine.The people for whom it was a disaster, or fatal,would never have been given it, andyou can imagine a very different outcome for the company,who had to withdraw the drug.

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August 23rd, 2018

Stem Cell Therapy and Stem Cell Injection Provider Finder …

By raymumme

Stem cell therapy can be described as a means or process by which stem cells are used for the prevention, treatment or the cure of diseases. Stem cells are a special kind of cells that have features other types of cells dont have. As an illustration, stem cells are capable of proliferation. This implies that they can develop into any type of cell, and grow to start performing the functions of the tissue. In addition, they can regenerate. This means they can multiply themselves. This is most important when a new tissue has to be formed. Also, they modulate immune reactions. This has made them useful for the treatment of autoimmune diseases, especially those that affect the musculoskeletal system such as rheumatoid arthritis, systemic lupus erythematosus and so on. Stem cells can be derrived from different sources. They can be extracted from the body, and in some specific parts of the body. This includes the blood, bone marrow, umbilical cord in newborns, adipose tissue, and from embryos. There are 2 main types of stem cell transplant. These are autologous stem cell transplant, and allogeneic stem cell transplant. The autologous stem cell transplant means that stem cells are extracted from the patient, processed, and then transplanted back to the patient, for therapeutic purposes. On the other hand, allogeneic stem cell transplant means the transplant of stem cells or from another individual, known as the donor, to another person, or recipient. Some treatments must be given to the receiver to prevent any cases of rejections, and other complications. The autologous is usually the most preferred type of transplant because of its almost zero side effects. Below are some of the stem cell treatments. Our goal is to provide education, research and an opportunity to connect with Stem Cell Doctors, as well as provide stem cell reviews

Adipose Stem Cell TreatmentsAdipose stem cell treatment is one of the most commonly used. This is because large quantities of stem cells can be derrived from them. According to statistics, the number of stem cells in adipose tissue are usually hundreds of times higher than what can be obtained from other sources, such as the bone marrow stem cells. Adipose stem cells have taken the center stage in the world of stem cell therapy. Apart from the ease that comes with the harvesting of these cells from the adipose tissue, they also have some special features, that separates them from other types of cells. Adipose stem cells are capable of regulating and modulating the immune system. This includes immune suppression, which is important for the treatment of autoimmune diseases. In addition, adipose stem cells can differentiate to form other types of cells. Some of them include the bone forming cells, cardiomyocytes, and cells of the nervous system.

This process can be divided into four parts. These are

Stem cell joint injection is fast becoming the new treatment of joint diseases. Stem cells derived from bone marrow, adipose and mesenchymal stem cells are the most commonly used. The stem cells are injected into the joints, and they proceed to repair and replace the damaged tissues. The cells also modulate the inflammatory process going on. Overall, stem cell joint injections significantly reduce the recovery time of patients and also eliminates pain and risks associated with surgery. Examples of diseases where this treatment is used include osteoarthritis, rheumatoid arthritis, and so on. Researchers and physicians have rated this procedure to be the future of joint therapy.

Losing a tooth as a kid isnt news because youd eventually grow them back, but losing one as an adult isnt a pleasant experience. Youd have to go through the pains of getting a replacement from your dentist. Apart from the cost of these procedures, the pain and number of days youd have to stay at home nursing the pain is also a problem. Nevertheless, there are great teeth replacement therapies available for all kinds of dental problems. Although there are already good dental treatment methods, stem cell therapy might soon become the future of dental procedures. Currently, a lot of research is being done on how stem cells can be used to develop teeth naturally, especially in patients with dental problems. The aim of the project is to develop a method whereby peoples stem cells are used in regenerating their own teeth and within the shortest time possible. Some of the benefits of the stem cell tooth would be:

The quality of life of those that underwent serious procedures, especially those that had an allogeneic hematopoietic stem cell transplantation done was studied. It was discovered that this set of people had to cope with some psychological problems, even years after the procedure. In addition, allogeneic stem cell transplantation often comes with some side effects. However, this a small price to pay, considering that the adverse effects are not usually life-threatening. Also theses types of procedures are used for severe disorders or even terminal diseases. On the other hand, autologous stem cell transplantation bears the minimum to no side effects. Patients do have a great quality of life, both in the short term and in the long term.

This is one of the many uses of stem cells. The stem cell gun is a device that is used in treating people with wounds or burns. This is done by simply triggering it, and it sprays stem cells on the affected part. This kind of treatment is crucial for victims of a severe burn. Usually, people affected by severe burns would have to endure excruciating pain. The process of recovery is usually long, which might vary from weeks to months, depending on the severity of the burn. Even after treatment, most patients are left with scars forever. However, the stem cell gun eliminates these problems, the skin can be grown back in just a matter of days. The new skin also grows evenly and blends perfectly with the other part of the body. This process is also without the scars that are usually associated with the traditional burns therapy. The stem cell gun is without any side effects.

There is one company that focuses on the production of stem cell supplements. These stem cells are usually natural ingredients that increase the development of stem cells, and also keeps them healthy. The purpose of the stem cell supplements is to help reduce the aging process and make people look younger. These supplements work by replacing the dead or repairing the damaged tissues of the body. There have been a lot of testimonials to the efficacy of these supplements.

It is the goal of researchers to make stem cell therapy a good alternative for the millions of patients suffering from cardiac-related diseases. According to some experiments carried out in animals, stem cells were injected into the ones affected by heart diseases. A large percentage of them showed great improvement, even within just a few weeks. However, when the trial was carried out in humans, some stem cells went ahead to develop into heart muscles, but overall, the heart function was generally improved. The reason for the improvement has been attributed to the formation of new vessels in the heart. The topic that has generated a lot of arguments have been what type of cells should be used in the treatment of heart disorders. Stem cells extracted from the bone marrow, embryo have been in use, although bone marrow stem cells are the most commonly used. Stem cells extracted from bone marrow can differentiate into cardiac cells, while studies have shown that other stem cells cannot do the same. Even though the stem cell therapy has a lot of potential in the future, more research and studies have to be done to make that a reality.

The use of stem cells for the treatment of hair loss has increased significantly. This can be attributed to the discovery of stem cells in bone marrow, adipose cells, umbilical cord, and so on. Stem cells are extracted from the patient, through any of the sources listed above. Adipose tissue stem cells are usually the most convenient in this scenario, as they do not require any special extraction procedure. Adipose tissue is harvested from the abdominal area. The stem cells are then isolated from the other cells through a process known as centrifugation. The stem cells are then activated and are now ready for use. The isolated stem cells are then introduced into the scalp, under local anesthesia. The entire process takes about three hours. Patients are free to go home, after the procedure. Patients would begin to see improvements in just a few months, however, this depends largely on the patients ability to heal. Every patient has a different outcome.

Human umbilical stem cells are cells extracted from the umbilical cord of a healthy baby, shortly after birth. Umbilical cord tissue is abundant in stem cells, and the stem cells can differentiate into many types of cells such as red blood cells, white blood cells, and platelets. They are also capable of differentiating into non-blood cells such as muscle cells, cartilage cells and so on. These cells are usually preferred because its' extraction is minimally non invasive. It also is nearly painless. It also has zero risks of rejecting, as it does not require any form of matching or typing.Human umbilical stem cell injections are used for the treatment of spinal cord injuries. A trial was done on twenty-five patients that had late-stage spinal cord injuries. They were placed on human umbilical stem cell therapy, while another set of 25 patients were simultaneously placed on the usual rehabilitation therapy. The two groups were studied for the next twelve months. The results of the trial showed that those people placed on stem cell therapy by administering the human umbilical cell tissue injections had a significant recovery, as compared to the other group that underwent the traditional rehabilitation therapy. It was concluded that human umbilical tissue injections applied close to the injured part gives the best outcomes.

Stem cell therapy has been used for the treatment of many types diseases. This ranges from terminal illnesses such as cancer, joint diseases such as arthritis, and also autoimmune diseases. Stem cell therapy is often a better alternative to most traditional therapy today. This is because stem cell procedure is minimally invasive when compared to chemotherapy and so on. It harnesses the bodys own ability to heal. The stem cells are extracted from other parts of the body and then transplanted to other parts of the body, where they would repair and maintain the tissues. They also perform the function of modulating the immune system, which makes them important for the treatment of autoimmune diseases. Below are some of the diseases that stem cell therapies have been used successfully:

A stem cell bank can be described as a facility where stem cells are stored for future purposes. These are mostly amniotic stem cells, which are derived from the amnion fluid. Umbilical cord stem cells are also equally important as it is rich in stem cells and can be used for the treatment of many diseases. Examples of these diseases include cancer, blood disorders, autoimmune diseases, musculoskeletal diseases and so on. According to statistics, umbilical stem cells can be used for the treatment of over eighty diseases. Storing your stem cells should be seen as an investment in your health for future sake. Parents do have the option of either throwing away their babys umbilical cord or donating it to stem cell banks.

The adipose tissue contains a lot of stem cells, that has the ability to transform into other cells such as muscle, cartilage, neural cells. They are also important for the treatment of some cardiovascular diseases. This is what makes it important for people to want to store their stem cells. The future health benefit is huge. The only way adults can store their stem cells in sufficient amounts is to extract the stem cells from their fat tissues. This process is usually painless and fast. Although, the extraction might have to be done between 3 to 5 times before the needed quantity is gotten. People that missed the opportunity to store their stem cells, using their cord cells, can now store it using their own adipose tissues. This can be used at any point in time.

Side effects often accompany every kind of treatment. However, this depends largely on the individual. While patients might present with side effects, some other people wouldnt. Whether a patient will present with adverse effects, depends on the following factors;

Some of the common side effects of stem cell transplant are;

Stem cell treatment has been largely successful so far, however, more studies and research needs to be done. Stem cell therapy could be the future.

Stem cells are unique cells that have some special features such as self-regeneration, tissue repair, and modulation of the immune system. These are the features that are employed in the treatment of diseases.

Our doctors are certified by iSTEMCELL but operate as part of a medical group or as independent business owners and as such are free to charge what the feel to be the right fit for their practice and clients. We have seen Stem Cell Treatment costs range from $3500 upwards of $30,000 depending on the condition and protocol required for intended results. Find the Best Stem Cell Doctor Near me If you are interested in saving money, try our STEM CELL COUPON!

Travel Medcations are becoming very popular around the globe for several reasons but not for what one might think. It is not about traveling to Mexico to save money, but to get procedures or protocols that are not yet available in your home country. Many procedures are started in your home country, then the tissue is set to the tissue lab where it is then grown in a process to maximize live cells, then sent to a hospital in Mexico designed to treat or provide different therapies for different conditions. If you're ready to take a medical vacation call 972-800-6670 for our"WHITE GLOVE" service.

Chen, C. and Hou, J. (2016). Mesenchymal stem cell-based therapy in kidney transplantation. Stem Cell Research & Therapy, 7(1).

Donnelly, A., Johar, S., OBrien, T. and Tuan, R. (2010). Welcome to Stem Cell Research & Therapy. Stem Cell Research & Therapy, 1(1), p.1.

Groothuis, S. (2015). Changes in Stem Cell Research. Stem Cell Research, 14(1), p.130.

Rao, M. (2012). Stem cells and regenerative medicine. Stem Cell Research & Therapy, 3(4), p.27.

Vunjak-Novakovic, G. (2013). Physical influences on stem cells. Stem Cell Research & Therapy, 4(6), p.153.

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August 19th, 2018

Myocyte – Wikipedia

By raymumme

"Muscle fiber" and "Myofiber" redirect here. For protein structures inside cells, see Myofibril.

A myocyte (also known as a muscle cell)[1] is the type of cell found in muscle tissue. Myocytes are long, tubular cells that develop from myoblasts to form muscles in a process known as myogenesis.[2] There are various specialized forms of myocytes: cardiac, skeletal, and smooth muscle cells, with various properties. The striated cells of cardiac and skeletal muscles are referred to as muscle fibers.[3] Cardiomyocytes are the muscle fibres that form the chambers of the heart, and have a single central nucleus.[4] Skeletal muscle fibers help support and move the body and tend to have peripheral nuclei.[5][6] Smooth muscle cells control involuntary movements such as the peristalsis contractions in the oesophagus and stomach.

The unusual microstructure of muscle cells has led cell biologists to create specialized terminology. However, each term specific to muscle cells has a counterpart that is used in the terminology applied to other types of cells:

The sarcoplasm is the cytoplasm of a muscle fiber. Most of the sarcoplasm is filled with myofibrils, which are long protein cords composed of myofilaments. The sarcoplasm is also composed of glycogen, a polysaccharide of glucose monomers, which provides energy to the cell with heightened exercise, and myoglobin, the red pigment that stores oxygen until needed for muscular activity.[7]

There are three types of myofilaments:[7]

Together, these myofilaments work to produce a muscle contraction.

The sarcoplasmic reticulum, a specialized type of smooth endoplasmic reticulum, forms a network around each myofibril of the muscle fiber. This network is composed of groupings of two dilated end-sacs called terminal cisternae, and a single transverse tubule, or T tubule, which bores through the cell and emerge on the other side; together these three components form the triads that exist within the network of the sarcoplasmic reticulum, in which each T tubule has two terminal cisternae on each side of it. The sarcoplasmic reticulum serves as reservoir for calcium ions, so when an action potential spreads over the T tubule, it signals the sarcoplasmic reticulum to release calcium ions from the gated membrane channels to stimulate a muscle contraction.[7][8]

The sarcolemma is the cell membrane of a striated muscle fiber and receives and conducts stimuli. At the end of each muscle fiber, the outer layer of the sarcolemma combines with tendon fibers.[9] Within the muscle fiber pressed against the sarcolemma are multiple flattened nuclei; this multinuclear condition results from multiple myoblasts fusing to produce each muscle fiber, where each myoblast contributes one nucleus.[7]

The cell membrane of a myocyte has several specialized regions, which may include the intercalated disk and the transverse tubular system. The cell membrane is covered by a lamina coat which is approximately 50nm wide. The laminar coat is separable into two layers; the lamina densa and lamina lucida. In between these two layers can be several different types of ions, including calcium.[10]

The cell membrane is anchored to the cell's cytoskeleton by anchor fibers that are approximately 10nm wide. These are generally located at the Z lines so that they form grooves and transverse tubules emanate. In cardiac myocytes this forms a scalloped surface.[10]

The cytoskeleton is what the rest of the cell builds off of and has two primary purposes; the first is to stabilize the topography of the intracellular components and the second is to help control the size and shape of the cell. While the first function is important for biochemical processes, the latter is crucial in defining the surface to volume ratio of the cell. This heavily influences the potential electrical properties of excitable cells. Additionally deviation from the standard shape and size of the cell can have negative prognostic impact.[10]

Each muscle fiber contains myofibrils, which are very long chains of sarcomeres, the contractile units of the cell. A cell from the biceps brachii muscle may contain 100,000 sarcomeres.[11][verification needed] The myofibrils of smooth muscle cells are not arranged into sarcomeres. The sarcomeres are composed of thin and thick filaments. Thin filaments are made of actin and attach at Z lines which help them line up correctly with each other.[12] Troponins are found at intervals along the thin filaments. Thick filaments are made of the elongated protein myosin.[13] The sarcomere does not contain organelles or a nucleus. Sarcomeres are marked by Z lines which show the beginning and the end of a sarcomere. Individual myocytes are surrounded by endomysium.

Myocytes are bound together by perimysium into bundles called fascicles; the bundles are then grouped together to form muscle tissue, which is enclosed in a sheath of epimysium. The perimysium contains blood vessels and nerves which provide for the muscle fibers. Muscle spindles are distributed throughout the muscles and provide sensory feedback information to the central nervous system. Myosin is shaped like a long shaft with a rounded end pointed out towards the surface. This structure forms the cross bridge that connects with the thin filaments.[13]

A myoblast is a type of embryonic progenitor cell that differentiates to give rise to muscle cells.[14] Differentiation is regulated by myogenic regulatory factors, including MyoD, Myf5, myogenin, and MRF4.[15] GATA4 and GATA6 also play a role in myocyte differentiation.[16]

Skeletal muscle fibers are made when myoblasts fuse together; muscle fibers therefore are cells with multiple nuclei, known as myonuclei, with each cell nucleus originating from a single myoblast. The fusion of myoblasts is specific to skeletal muscle (e.g., biceps brachii) and not cardiac muscle or smooth muscle.

Myoblasts in skeletal muscle that do not form muscle fibers dedifferentiate back into myosatellite cells. These satellite cells remain adjacent to a skeletal muscle fiber, situated between the sarcolemma and the basement membrane[17] of the endomysium (the connective tissue investment that divides the muscle fascicles into individual fibers). To re-activate myogenesis, the satellite cells must be stimulated to differentiate into new fibers.

Myoblasts and their derivatives, including satellite cells, can now be generated in vitro through directed differentiation of pluripotent stem cells.[18]

Kindlin-2 plays a role in developmental elongation during myogenesis.[19]

Muscle fibers grow when exercised and shrink when not in use. This is due to the fact that exercise stimulates the increase in myofibrils which increase the overall size of muscle cells. Well exercised muscles can not only add more size but can also develop more mitochondria, myoglobin, glycogen and a higher density of capillaries. However muscle cells cannot divide to produce new cells, and as a result we have fewer muscle cells as an adult than a newborn.[20]

When contracting, thin and thick filaments slide with respect to each other by using adenosine triphosphate. This pulls the Z discs closer together in a process called sliding filament mechanism. The contraction of all the sarcomeres results in the contraction of the whole muscle fiber. This contraction of the myocyte is triggered by the action potential over the cell membrane of the myocyte. The action potential uses transverse tubules to get from the surface to the interior of the myocyte, which is continuous within the cell membrane. Sarcoplasmic reticula are membranous bags that transverse tubules touch but remain separate from. These wrap themselves around each sarcomere and are filled with Ca2+.[13]

Excitation of a myocyte causes depolarization at its synapses, the neuromuscular junctions, which triggers action potential. With a singular neuromuscular junction, each muscle fiber receives input from just one somatic efferent neuron. Action potential in a somatic efferent neuron causes the release of the neurotransmitter acetylcholine.[21]

When the acetylcholine is released it diffuses across the synapse and binds to a receptor on the sarcolemma, a term unique to muscle cells that refers to the cell membrane. This initiates an impulse that travels across the sarcolemma.[20]

When the action potential reaches the sarcoplasmic reticulum it triggers the release of Ca2+ from the Ca2+ channels. The Ca2+ flows from the sarcoplasmic reticulum into the sarcomere with both of its filaments. This causes the filaments to start sliding and the sarcomeres to become shorter. This requires a large amount of ATP, as it is used in both the attachment and release of every myosin head. Very quickly Ca2+ is actively transported back into the sarcoplasmic reticulum, which blocks the interaction between the thin and thick filament. This in turn causes the muscle cell to relax.[20]

There are four main different types of muscle contraction: twitch, treppe, tetanus and isometric/isotonic. Twitch contraction is the process previously described, in which a single stimulus signals for a single contraction. In twitch contraction the length of the contraction may vary depending on the size of the muscle cell. During treppe (or summation) contraction muscles do not start at maximum efficiency; instead they achieve increased strength of contraction due to repeated stimuli. Tetanus involves a sustained contraction of muscles due to a series of rapid stimuli, which can continue until the muscles fatigue. Isometric contractions are skeletal muscle contractions that do not cause movement of the muscle. However, isotonic contractions are skeletal muscle contractions that do cause movement.[20]

Specialized cardiomyocytes located in the sinoatrial node are responsible for generating the electrical impulses that control the heart rate. These electrical impulses coordinate contraction throughout the remaining heart muscle via the electrical conduction system of the heart. Sinoatrial node activity is modulated, in turn, by nerve fibres of both the sympathetic and parasympathetic nervous systems. These systems act to increase and decrease, respectively, the rate of production of electrical impulses by the sinoatrial node.

There are numerous methods employed for fiber-typing, and confusion between the methods is common among non-experts. Two commonly confused methods are histochemical staining for myosin ATPase activity and immunohistochemical staining for Myosin heavy chain (MHC) type. Myosin ATPase activity is commonlyand correctlyreferred to as simply "fiber type", and results from the direct assaying of ATPase activity under various conditions (e.g. pH).[22] Myosin heavy chain staining is most accurately referred to as "MHC fiber type", e.g. "MHC IIa fibers", and results from determination of different MHC isoforms.[22] These methods are closely related physiologically, as the MHC type is the primary determinant of ATPase activity. Note, however, that neither of these typing methods is directly metabolic in nature; they do not directly address oxidative or glycolytic capacity of the fiber. When "type I" or "type II" fibers are referred to generically, this most accurately refers to the sum of numerical fiber types (I vs. II) as assessed by myosin ATPase activity staining (e.g. "type II" fibers refers to type IIA + type IIAX + type IIXA... etc.).

Below is a table showing the relationship between these two methods, limited to fiber types found in humans. Note the sub-type capitalization used in fiber typing vs. MHC typing, and that some ATPase types actually contain multiple MHC types. Also, a subtype B or b is not expressed in humans by either method.[23] Early researchers believed humans to express a MHC IIb, which led to the ATPase classification of IIB. However, later research showed that the human MHC IIb was in fact IIx,[23] indicating that the IIB is better named IIX. IIb is expressed in other mammals, so is still accurately seen (along with IIB) in the literature. Non human fiber types include true IIb fibers, IIc, IId, etc.

Further fiber typing methods are less formally delineated, and exist on more of a spectrum. They tend to be focused more on metabolic and functional capacities (i.e., oxidative vs. glycolytic, fast vs. slow contraction time). As noted above, fiber typing by ATPase or MHC does not directly measure or dictate these parameters. However, many of the various methods are mechanistically linked, while others are correlated in vivo.[26][27] For instance, ATPase fiber type is related to contraction speed, because high ATPase activity allows faster crossbridge cycling.[22] While ATPase activity is only one component of contraction speed, type I fibers are "slow", in part, because they have low speeds of ATPase activity in comparison to type II fibers. However, measuring contraction speed is not the same as ATPase fiber typing.

Because of these types of relationships, Type I and Type II fibers have relatively distinct metabolic, contractile, and motor-unit properties. The table below differentiates these types of properties. These types of propertieswhile they are partly dependent on the properties of individual fiberstend to be relevant and measured at the level of the motor unit, rather than individual fiber.[22]

Traditionally, fibers were categorized depending on their varying color, which is a reflection of myoglobin content. Type I fibers appear red due to the high levels of myoglobin. Red muscle fibers tend to have more mitochondria and greater local capillary density. These fibers are more suited for endurance and are slow to fatigue because they use oxidative metabolism to generate ATP (adenosine triphosphate). Less oxidative type II fibers are white due to relatively low myoglobin and a reliance on glycolytic enzymes.

Fibers can also be classified on their twitch capabilities, into fast and slow twitch. These traits largely, but not completely, overlap the classifications based on color, ATPase, or MHC.

Some authors define a fast twitch fiber as one in which the myosin can split ATP very quickly. These mainly include the ATPase type II and MHC type II fibers. However, fast twitch fibers also demonstrate a higher capability for electrochemical transmission of action potentials and a rapid level of calcium release and uptake by the sarcoplasmic reticulum. The fast twitch fibers rely on a well-developed, short term, glycolytic system for energy transfer and can contract and develop tension at 23 times the rate of slow twitch fibers. Fast twitch muscles are much better at generating short bursts of strength or speed than slow muscles, and so fatigue more quickly.[28]

The slow twitch fibers generate energy for ATP re-synthesis by means of a long term system of aerobic energy transfer. These mainly include the ATPase type I and MHC type I fibers. They tend to have a low activity level of ATPase, a slower speed of contraction with a less well developed glycolytic capacity. They contain high mitochondrial volumes, and the high levels of myoglobin that give them a red pigmentation. They have been demonstrated to have high concentrations of mitochondrial enzymes, thus they are fatigue resistant. Slow twitch muscles fire more slowly than fast twitch fibers, but are able to contract for a longer time before fatiguing.[28]

Individual muscles tend to be a mixture of various fiber types, but their proportions vary depending on the actions of that muscle and the species. For instance, in humans, the quadriceps muscles contain ~52% type I fibers, while the soleus is ~80% type I.[29] The orbicularis oculi muscle of the eye is only ~15% type I.[29] Motor units within the muscle, however, have minimal variation between the fibers of that unit. It is this fact that makes the size principal of motor unit recruitment viable.

The total number of skeletal muscle fibers has traditionally been thought not to change.It is believed there are no sex or age differences in fiber distribution; however, proportions of fiber types vary considerably from muscle to muscle and person to person.Sedentary men and women (as well as young children) have 45% type II and 55% type I fibers.[citation needed]People at the higher end of any sport tend to demonstrate patterns of fiber distribution e.g. endurance athletes show a higher level of type I fibers.Sprint athletes, on the other hand, require large numbers of type IIX fibers.Middle distance event athletes show approximately equal distribution of the two types. This is also often the case for power athletes such as throwers and jumpers.It has been suggested that various types of exercise can induce changes in the fibers of a skeletal muscle.[30]It is thought that if you perform endurance type events for a sustained period of time, some of the type IIX fibers transform into type IIA fibers. However, there is no consensus on the subject.It may well be that the type IIX fibers show enhancements of the oxidative capacity after high intensity endurance training which brings them to a level at which they are able to perform oxidative metabolism as effectively as slow twitch fibers of untrained subjects. This would be brought about by an increase in mitochondrial size and number and the associated related changes, not a change in fiber type.

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July 31st, 2018

Cardiac stem cells rejuvenate rats’ aging hearts … – CNN

By JoanneRUSSELL25

The old rats appeared newly invigorated after receiving their injections. As hoped, the cardiac stem cells improved heart function yet also provided additional benefits. The rats' fur fur, shaved for surgery, grew back more quickly than expected, and their chromosomal telomeres, which commonly shrink with age, lengthened.

The old rats receiving the cardiac stem cells also had increased stamina overall, exercising more than before the infusion.

"It's extremely exciting," said Dr. Eduardo Marbn, primary investigator on the research and director of the Cedars-Sinai Heart Institute. Witnessing "the systemic rejuvenating effects," he said, "it's kind of like an unexpected fountain of youth."

"We've been studying new forms of cell therapy for the heart for some 12 years now," Marbn said.

Some of this research has focused on cardiosphere-derived cells.

"They're progenitor cells from the heart itself," Marbn said. Progenitor cells are generated from stem cells and share some, but not all, of the same properties. For instance, they can differentiate into more than one kind of cell like stem cells, but unlike stem cells, progenitor cells cannot divide and reproduce indefinitely.

Since heart failure with preserved ejection fraction is similar to aging, Marbn decided to experiment on old rats, ones that suffered from a type of heart problem "that's very typical of what we find in older human beings: The heart's stiff, and it doesn't relax right, and it causes fluid to back up some," Marbn explained.

He and his team injected cardiosphere-derived cells from newborn rats into the hearts of 22-month-old rats -- that's elderly for a rat. Similar old rats received a placebo injection of saline solution. Then, Marbn and his team compared both groups to young rats that were 4 months old. After a month, they compared the rats again.

Even though the cells were injected into the heart, their effects were noticeable throughout the body, Marbn said

"The animals could exercise further than they could before by about 20%, and one of the most striking things, especially for me (because I'm kind of losing my hair) the animals ... regrew their fur a lot better after they'd gotten cells" compared with the placebo rats, Marbn said.

The rats that received cardiosphere-derived cells also experienced improved heart function and showed longer heart cell telomeres.

Why did it work?

The working hypothesis is that the cells secrete exosomes, tiny vesicles that "contain a lot of nucleic acids, things like RNA, that can change patterns of the way the tissue responds to injury and the way genes are expressed in the tissue," Marbn said.

It is the exosomes that act on the heart and make it better as well as mediating long-distance effects on exercise capacity and hair regrowth, he explained.

Looking to the future, Marbn said he's begun to explore delivering the cardiac stem cells intravenously in a simple infusion -- instead of injecting them directly into the heart, which would be a complex procedure for a human patient -- and seeing whether the same beneficial effects occur.

Dr. Gary Gerstenblith, a professor of medicine in the cardiology division of Johns Hopkins Medicine, said the new study is "very comprehensive."

"Striking benefits are demonstrated not only from a cardiac perspective but across multiple organ systems," said Gerstenblith, who did not contribute to the new research. "The results suggest that stem cell therapies should be studied as an additional therapeutic option in the treatment of cardiac and other diseases common in the elderly."

Todd Herron, director of the University of Michigan Frankel Cardiovascular Center's Cardiovascular Regeneration Core Laboratory, said Marbn, with his previous work with cardiac stem cells, has "led the field in this area."

"The novelty of this bit of work is, they started to look at more precise molecular mechanisms to explain the phenomenon they've seen in the past," said Herron, who played no role in the new research.

One strength of the approach here is that the researchers have taken cells "from the organ that they want to rejuvenate, so that makes it likely that the cells stay there in that tissue," Herron said.

He believes that more extensive study, beginning with larger animals and including long-term followup, is needed before this technique could be used in humans.

"We need to make sure there's no harm being done," Herron said, adding that extending the lifetime and improving quality of life amounts to "a tradeoff between the potential risk and the potential good that can be done."

Capicor hasn't announced any plans to do studies in aging, but the possibility exists.

After all, the cells have been proven "completely safe" in "over 100 human patients," so it would be possible to fast-track them into the clinic, Marbn explained: "I can't tell you that there are any plans to do that, but it could easily be done from a safety viewpoint."

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July 24th, 2018

iPSC | Induced Pluripotent Stem Cells | Human | HiPSC …

By daniellenierenberg

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Human Induced Pluripotent Stem Cells (HiPSC)Top:HiPSC express pluriotency markers OCT4, Nanog, LIN28 and SSEA-4.Bottom:HiPSC differentiate into cell derivatives from the 3 embryonic layers: Neuronal marker beta III tubulin (TUJ1), Smooth Muscle Actin (SMA) and Hepatocyte Nuclear Factor 3 Beta (HNF3b).

Cutting-edge development and manufacturing provides high quality, thoroughly-characterized HiPSC cells to researchers around the world. HiPSC are generated from somatic cells, eliminating ethical considerations associated with scientific work based on embryonic stem cells. Furthermore, being donor/patient-specific, they open possibilities for a wide variety of studies in biomedical research. Donor somatic cells carry the genetic makeup of the diseased patient, hence HiPSC can be used directly to model disease on a dish.

Thus, one of the main uses of HiPSC has been in genetic disease modeling in organs and tissues, such as the brain (Alzheimers, Autism Spectrum Disorders), heart (Familial Hypertrophic, Dilated, and Arrhythmogenic Right Ventricular Cardiomyopathies), and skeletal muscle (Amyotrophic Lateral Sclerosis, Spinal Muscle Atrophy). The combination of HiPSC technology and gene editing strategies such as the CRISPR/Cas9 system creates a powerful platform in which disease-causing mutations can be created on demand and sets of isogenic cell lines (with and without mutations) serve as convenient tools for disease modeling studies.

Other applications of HiPSC and iPSC-differentiated cells include drug screening, development, efficacy and toxicity assessment. As an example, through the FDA-backed CiPA (Comprehensive in vitro Pro-Arrhythmia Assessment) initiative, HiPSC-derived cardiac muscle cells (cardiomyocytes) are poised to constitute a new standard model for the evaluation of cardiotoxicity of new drugs, which is the main reason of drug withdrawal from the market. Finally, HiPSC-differentiated cells are being used in early stage technology development for applications in regenerative medicine. Bio-printing and tissue constructs have also been considered as attractive applications for HiPSC.

Human iPSC and Derived Cells are forResearch Use Only (RUO). Not for human clinical or therapeutic use.

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July 13th, 2018

Mending a Broken Heart: Stem Cells and Cardiac Repair …

By Sykes24Tracey

Charles A. Goldthwaite, Jr., Ph.D.

Cardiovascular disease (CVD), which includes hypertension, coronary heart disease (CHD), stroke, and congestive heart failure (CHF), has ranked as the number one cause of death in the United States every year since 1900 except 1918, when the nation struggled with an influenza epidemic.1 In 2002, CVD claimed roughly as many lives as cancer, chronic lower respiratory diseases, accidents, diabetes mellitus, influenza, and pneumonia combined. According to data from the 19992002 National Health and Nutrition Examination Survey (NHANES), CVD caused approximately 1.4 million deaths (38.0 percent of all deaths) in the U.S. in 2002. Nearly 2600 Americans die of CVD each day, roughly one death every 34 seconds. Moreover, within a year of diagnosis, one in five patients with CHF will die. CVD also creates a growing economic burden; the total health care cost of CVD in 2005 was estimated at $393.5 billion dollars.

Given the aging of the U.S. population and the relatively dramatic recent increases in the prevalence of cardiovascular risk factors such as obesity and type 2 diabetes,2,3 CVD will continue to be a significant health concern well into the 21st century. However, improvements in the acute treatment of heart attacks and an increasing arsenal of drugs have facilitated survival. In the U.S. alone, an estimated 7.1 million people have survived a heart attack, while 4.9 million live with CHF.1 These trends suggest an unmet need for therapies to regenerate or repair damaged cardiac tissue.

Ischemic heart failure occurs when cardiac tissue is deprived of oxygen. When the ischemic insult is severe enough to cause the loss of critical amounts of cardiac muscle cells (cardiomyocytes), this loss initiates a cascade of detrimental events, including formation of a non-contractile scar, ventricular wall thinning (see Figure 6.1), an overload of blood flow and pressure, ventricular remodeling (the overstretching of viable cardiac cells to sustain cardiac output), heart failure, and eventual death.4 Restoring damaged heart muscle tissue, through repair or regeneration, therefore represents a fundamental mechanistic strategy to treat heart failure. However, endogenous repair mechanisms, including the proliferation of cardiomyocytes under conditions of severe blood vessel stress or vessel formation and tissue generation via the migration of bone-marrow-derived stem cells to the site of damage, are in themselves insufficient to restore lost heart muscle tissue (myocardium) or cardiac function.5 Current pharmacologic interventions for heart disease, including beta-blockers, diuretics, and angiotensin-converting enzyme (ACE) inhibitors, and surgical treatment options, such as changing the shape of the left ventricle and implanting assistive devices such as pacemakers or defibrillators, do not restore function to damaged tissue. Moreover, while implantation of mechanical ventricular assist devices can provide long-term improvement in heart function, complications such as infection and blood clots remain problematic.6 Although heart transplantation offers a viable option to replace damaged myocardium in selected individuals, organ availability and transplant rejection complications limit the widespread practical use of this approach.

Figure 6.1. Normal vs. Infarcted Heart. The left ventricle has a thick muscular wall, shown in cross-section in A. After a myocardial infarction (heart attack), heart muscle cells in the left ventricle are deprived of oxygen and die (B), eventually causing the ventricular wall to become thinner (C).

2007 Terese Winslow

The difficulty in regenerating damaged myocardial tissue has led researchers to explore the application of embryonic and adult-derived stem cells for cardiac repair. A number of stem cell types, including embryonic stem (ES) cells, cardiac stem cells that naturally reside within the heart, myoblasts (muscle stem cells), adult bone marrow-derived cells, mesenchymal cells (bone marrow-derived cells that give rise to tissues such as muscle, bone, tendons, ligaments, and adipose tissue), endothelial progenitor cells (cells that give rise to the endothelium, the interior lining of blood vessels), and umbilical cord blood cells, have been investigated to varying extents as possible sources for regenerating damaged myocardium. All have been tested in mouse or rat models, and some have been tested in large animal models such as pigs. Preliminary clinical data for many of these cell types have also been gathered in selected patient populations.

However, clinical trials to date using stem cells to repair damaged cardiac tissue vary in terms of the condition being treated, the method of cell delivery, and the primary outcome measured by the study, thus hampering direct comparisons between trials.7 Some patients who have received stem cells for myocardial repair have reduced cardiac blood flow (myocardial ischemia), while others have more pronounced congestive heart failure and still others are recovering from heart attacks. In some cases, the patient's underlying condition influences the way that the stem cells are delivered to his/her heart (see the section, quot;Methods of Cell Deliveryquot; for details). Even among patients undergoing comparable procedures, the clinical study design can affect the reporting of results. Some studies have focused on safety issues and adverse effects of the transplantation procedures; others have assessed improvements in ventricular function or the delivery of arterial blood. Furthermore, no published trial has directly compared two or more stem cell types, and the transplanted cells may be autologous (i.e., derived from the person on whom they are used) or allogeneic (i.e., originating from another person) in origin. Finally, most of these trials use unlabeled cells, making it difficult for investigators to follow the cells' course through the body after transplantation (see the section quot;Considerations for Using These Stem Cells in the Clinical Settingquot; at the end of this article for more details).

Despite the relative infancy of this field, initial results from the application of stem cells to restore cardiac function have been promising. This article will review the research supporting each of the aforementioned cell types as potential source materials for myocardial regeneration and will conclude with a discussion of general issues that relate to their clinical application.

In 2001, Menasche, et.al. described the successful implantation of autologous skeletal myoblasts (cells that divide to repair and/or increase the size of voluntary muscles) into the post-infarction scar of a patient with severe ischemic heart failure who was undergoing coronary artery bypass surgery.8 Following the procedure, the researchers used imaging techniques to observe the heart's muscular wall and to assess its ability to beat. When they examined patients 5 months after treatment, they concluded that treated hearts pumped blood more efficiently and seemed to demonstrate improved tissue health. This case study suggested that stem cells may represent a viable resource for treating ischemic heart failure, spawning several dozen clinical studies of stem cell therapy for cardiac repair (see Boyle, et.al.7 for a complete list) and inspiring the development of Phase I and Phase II clinical trials. These trials have revealed the complexity of using stem cells for cardiac repair, and considerations for using stem cells in the clinical setting are discussed in a subsequent section of this report.

The mechanism by which stem cells promote cardiac repair remains controversial, and it is likely that the cells regenerate myocardium through several pathways. Initially, scientists believed that transplanted cells differentiated into cardiac cells, blood vessels, or other cells damaged by CVD.911 However, this model has been recently supplanted by the idea that transplanted stem cells release growth factors and other molecules that promote blood vessel formation (angiogenesis) or stimulate quot;residentquot; cardiac stem cells to repair damage.1214 Additional mechanisms for stem-cell mediated heart repair, including strengthening of the post-infarct scar15 and the fusion of donor cells with host cardiomyocytes,16 have also been proposed.

Regardless of which mechanism(s) will ultimately prove to be the most significant in stem-cell mediated cardiac repair, cells must be successfully delivered to the site of injury to maximize the restored function. In preliminary clinical studies, researchers have used several approaches to deliver stem cells. Common approaches include intravenous injection and direct infusion into the coronary arteries. These methods can be used in patients whose blood flow has been restored to their hearts after a heart attack, provided that they do not have additional cardiac dysfunction that results in total occlusion or poor arterial flow.12, 17 Of these two methods, intracoronary infusion offers the advantage of directed local delivery, thereby increasing the number of cells that reach the target tissue relative to the number that will home to the heart once they have been placed in the circulation. However, these strategies may be of limited benefit to those who have poor circulation, and stem cells are often injected directly into the ventricular wall of these patients. This endomyocardial injection may be carried out either via a catheter or during open-heart surgery.18

To determine the ideal site to inject stem cells, doctors use mapping or direct visualization to identify the locations of scars and viable cardiac tissue. Despite improvements in delivery efficiency, however, the success of these methods remains limited by the death of the transplanted cells; as many as 90% of transplanted cells die shortly after implantation as a result of physical stress, myocardial inflammation, and myocardial hypoxia.4 Timing of delivery may slow the rate of deterioration of tissue function, although this issue remains a hurdle for therapeutic approaches.

Embryonic and adult stem cells have been investigated to regenerate damaged myocardial tissue in animal models and in a limited number of clinical studies. A brief review of work to date and specific considerations for the application of various cell types will be discussed in the following sections.

Because ES cells are pluripotent, they can potentially give rise to the variety of cell types that are instrumental in regenerating damaged myocardium, including cardiomyocytes, endothelial cells, and smooth muscle cells. To this end, mouse and human ES cells have been shown to differentiate spontaneously to form endothelial and smooth muscle cells in vitro19 and in vivo,20,21 and human ES cells differentiate into myocytes with the structural and functional properties of cardiomyocytes.2224 Moreover, ES cells that were transplanted into ischemically-injured myocardium in rats differentiated into normal myocardial cells that remained viable for up to four months,25 suggesting that these cells may be candidates for regenerative therapy in humans.

However, several key hurdles must be overcome before human ES cells can be used for clinical applications. Foremost, ethical issues related to embryo access currently limit the avenues of investigation. In addition, human ES cells must go through rigorous testing and purification procedures before the cells can be used as sources to regenerate tissue. First, researchers must verify that their putative ES cells are pluripotent. To prove that they have established a human ES cell line, researchers inject the cells into immunocompromised mice; i.e., mice that have a dysfunctional immune system. Because the injected cells cannot be destroyed by the mouse's immune system, they survive and proliferate. Under these conditions, pluripotent cells will form a teratoma, a multi-layered, benign tumor that contains cells derived from all three embryonic germ layers. Teratoma formation indicates that the stem cells have the capacity to give rise to all cell types in the body.

The pluripotency of ES cells can complicate their clinical application. While undifferentiated ES cells may possibly serve as sources of specific cell populations used in myocardial repair, it is essential that tight quality control be maintained with respect to the differentiated cells. Any differentiated cells that would be used to regenerate heart tissue must be purified before transplantation can be considered. If injected regenerative cells are accidentally contaminated with undifferentiated ES cells, a tumor could possibly form as a result of the cell transplant.4 However, purification methodologies continue to improve; one recent report describes a method to identify and select cardiomyocytes during human ES cell differentiation that may make these cells a viable option in the future.26

This concern illustrates the scientific challenges that accompany the use of all human stem cells, whether derived from embryonic or adult tissues. Predictable control of cell proliferation and differentiation requires additional basic research on the molecular and genetic signals that regulate cell division and specialization. Furthermore, long-term cell stability must be well understood before human ES-derived cells can be used in regenerative medicine. The propensity for genetic mutation in the human ES cells must be determined, and the survival of differentiated, ES-derived cells following transplantation must be assessed. Furthermore, once cells have been transplanted, undesirable interactions between the host tissue and the injected cells must be minimized. Cells or tissues derived from ES cells that are currently available for use in humans are not tissue-matched to patients and thus would require immunosuppression to limit immune rejection.18

While skeletal myoblasts (SMs) are committed progenitors of skeletal muscle cells, their autologous origin, high proliferative potential, commitment to a myogenic lineage, and resistance to ischemia promoted their use as the first stem cell type to be explored extensively for cardiac application. Studies in rats and humans have demonstrated that these cells can repopulate scar tissue and improve left ventricular function following transplantation.27 However, SM-derived cardiomyocytes do not function in complete concert with native myocardium. The expression of two key proteins involved in electromechanical cell integration, N-cadherin and connexin 43, are downregulated in vivo,28 and the engrafted cells develop a contractile activity phenotype that appears to be unaffected by neighboring cardiomyocytes.29

To date, the safety and feasibility of transplanting SM cells have been explored in a series of small studies enrolling a collective total of nearly 100 patients. Most of these procedures were carried out during open-heart surgery, although a couple of studies have investigated direct myocardial injection and transcoronary administration. Sustained ventricular tachycardia, a life-threatening arrhythmia and unexpected side-effect, occurred in early implantation studies, possibly resulting from the lack of electrical coupling between SM-derived cardiomyocytes and native tissue.30,31 Changes in preimplantation protocols have minimized the occurrence of arrhythmias in conjunction with the use of SM cells, and Phase II studies of skeletal myoblast therapy are presently underway.

In 2001, Jackson, et.al. demonstrated that cardiomyocytes and endothelial cells could be regenerated in a mouse heart attack model through the introduction of adult mouse bone marrow-derived stem cells.9 That same year, Orlic and colleagues showed that direct injection of mouse bone marrow-derived cells into the damaged ventricular wall following an induced heart attack led to the formation of new cardiomyocytes, vascular endothelium, and smooth muscle cells.11 Nine days after transplanting the stem cells, the newly-formed myocardium occupied nearly 70 percent of the damaged portion of the ventricle, and survival rates were greater in mice that received these cells than in those that did not. While several subsequent studies have questioned whether these cells actually differentiate into cardiomyocytes,32,33 the evidence to support their ability to prevent remodeling has been demonstrated in many laboratories.7

Based on these findings, researchers have investigated the potential of human adult bone marrow as a source of stem cells for cardiac repair. Adult bone marrow contains several stem cell populations, including hematopoietic stem cells (which differentiate into all of the cellular components of blood), endothelial progenitor cells, and mesenchymal stem cells; successful application of these cells usually necessitates isolating a particular cell type on the basis of its' unique cell-surface receptors. In the past three years, the transplantation of bone marrow mononuclear cells (BMMNCs), a mixed population of blood and cells that includes stem and progenitor cells, has been explored in more patients and clinical studies of cardiac repair than any other type of stem cell.7

The results from clinical studies of BMMNC transplantation have been promising but mixed. However, it should be noted that these studies have been conducted under a variety of conditions, thereby hampering direct comparison. The cells have been delivered via open-heart surgery and endomyocardial and intracoronary catheterization. Several studies, including the Bone Marrow Transfer to Enhance ST-Elevation Infarct Regeneration (BOOST) and the Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI) trials, have shown that intracoronary infusion of BMMNCs following a heart attack significantly improves the left ventricular (LV) ejection fraction, or the volume of blood pumped out of the left ventricle with each heartbeat.3436 However, other studies have indicated either no improvement in LV ejection fraction upon treatment37 or an increased LV ejection fraction in the control group.38 An early study that used endomyocardial injection to enhance targeted delivery indicated a significant improvement in overall LV function.39 Discrepancies such as these may reflect differences in cell preparation protocols or baseline patient statistics. As larger trials are developed, these issues can be explored more systematically.

Mesenchymal stem cells (MSCs) are precursors of non-hematopoietic tissues (e.g., muscle, bone, tendons, ligaments, adipose tissue, and fibroblasts) that are obtained relatively easily from autologous bone marrow. They remain multipotent following expansion in vitro, exhibit relatively low immunogenicity, and can be frozen easily. While these properties make the cells amenable to preparation and delivery protocols, scientists can also culture them under special conditions to differentiate them into cells that resemble cardiac myocytes. This property enables their application to cardiac regeneration. MSCs differentiate into endothelial cells when cultured with vascular endothelial growth factor40 and cardiomyogenic (CMG) cells when treated with the dna-demethylating agent, 5-azacytidine.41 More important, however, is the observation that MSCs can differentiate into cardiomyocytes and endothelial cells in vivo when transplanted to the heart following myocardial infarct (MI) or non-injury in pig, mouse, or rat models.4245 Additionally, the ability of MSCs to restore functionality may be enhanced by the simultaneous transplantation of other stem cell types.43

Several animal model studies have shown that treatment with MSCs significantly increases myocardial function and capillary formation.5,41 One advantage of using these cells in human studies is their low immunogenicity; allogeneic MSCs injected into infarcted myocardium in a pig model regenerated myocardium and reduced infarct size without evidence of rejection.46 A randomized clinical trial implanting MSCs after MI has demonstrated significant improvement in global and regional LV function,47 and clinical trials are currently underway to investigate the application of allogeneic and autologous MSCs for acute MI and myocardial ischemia, respectively.

Recent evidence suggests that the heart contains a small population of endogenous stem cells that most likely facilitate minor repair and turnover-mediated cell replacement.7 These cells have been isolated and characterized in mouse, rat, and human tissues.48,49 The cells can be harvested in limited quantity from human endomyocardial biopsy specimens50 and can be injected into the site of infarction to promote cardiomyocyte formation and improvements in systolic function.49 Separation and expansion ex vivo over a period of weeks are necessary to obtain sufficient quantities of these cells for experimental purposes. However, their potential as a convenient resource for autologous stem cell therapy has led the National Heart, Lung, and Blood Institute to fund forthcoming clinical trials that will explore the use of cardiac stem cells for myocardial regeneration.

The endothelium is a layer of specialized cells that lines the interior surface of all blood vessels (including the heart). This layer provides an interface between circulating blood and the vessel wall. Endothelial progenitor cells (EPCs) are bone marrow-derived stem cells that are recruited into the peripheral blood in response to tissue ischemia.4 EPCs are precursor cells that express some cell-surface markers characteristic of mature endothelium and some of hematopoietic cells.19,5153 EPCs home in on ischemic areas, where they differentiate into new blood vessels; following a heart attack, intravenously injected EPCs home to the damaged region within 48 hours.12 The new vascularization induced by these cells prevents cardiomyocyte apoptosis (programmed cell death) and LV remodeling, thereby preserving ventricular function.13 However, no change has been observed in non-infarcted regions upon EPC administration. Clinical trials are currently underway to assess EPC therapy for growing new blood vessels and regenerating myocardium.

Several other cell populations, including umbilical cord blood (UCB) stem cells, fibroblasts (cells that synthesize the extracellular matrix of connective tissues), and peripheral blood CD34+ cells, have potential therapeutic uses for regenerating cardiac tissue. Although these cell types have not been investigated in clinical trials of heart disease, preliminary studies in animal models indicate several potential applications in humans.

Umbilical cord blood contains enriched populations of hematopoietic stem cells and mesencyhmal precursor cells relative to the quantities present in adult blood or bone marrow.54,55 When injected intravenously into the tail vein in a mouse model of MI, human mononuclear UCB cells formed new blood vessels in the infarcted heart.56 A human DNA assay was used to determine the migration pattern of the cells after injection; although they homed only to injured areas within the heart, they were also detected in the marrow, spleen, and liver. When injected directly into the infarcted area in a rat model of MI, human mononuclear UCB cells improved ventricular function.57 Staining for CD34 and other markers found on the cell surface of hematopoietic stem cells indicated that some of the cells survived in the myocardium. Results similar to these have been observed following the injection of human unrestricted somatic stem cells from UCB into a pig MI model.58

Adult peripheral blood CD34+ cells offer the advantage of being obtained relatively easily from autologous sources.59 Although some studies using a mouse model of MI claim that these cells can transdifferentiate into cardiomyocytes, endothelial cells, and smooth muscle cells at the site of tissue injury,60 this conclusion is highly contested. Recent studies that involve the direct injection of blood-borne or bone marrow-derived hematopoietic stem cells into the infarcted region of a mouse model of MI found no evidence of myocardial regeneration following injection of either cell type.33 Instead, these hematopoietic stem cells followed traditional differentiation patterns into blood cells within the microenvironment of the injured heart. Whether these cells will ultimately find application in myocardial regeneration remains to be determined.

Autologous fibroblasts offer a different strategy to combat myocardial damage by replacing scar tissue with a more elastic, muscle-like tissue and inhibiting host matrix degradation.4 The cells may be manipulated to express muscle-specific transcription factors that promote their differentiation into myotubes such as those derived from skeletal myoblasts.61 One month after these cells were implanted into the post-infarction scar in a rat model of MI, they occupied a large portion of the scar but were not functionally integrated.61 Although the effects on ventricular function were not evaluated in this study, authors noted that modified autologous fibroblasts may ultimately prove useful in elderly patients who have a limited population of autologous skeletal myoblasts or bone marrow stem cells.

As these examples indicate, many types of stem cells have been applied to regenerate damaged myocardium. In select applications, stem cells have demonstrated sufficient promise to warrant further exploration in large-scale, controlled clinical trials. However, the current breadth of application of these cells has made it difficult to compare and contextualize the results generated by the various trials. Most studies published to date have enrolled fewer than 25 patients, and the studies vary in terms of cell types and preparations used, methods of delivery, patient populations, and trial outcomes. However, the mixed results that have been observed in these studies do not necessarily argue against using stem cells for cardiac repair. Rather, preliminary results illuminate the many gaps in understanding of the mechanisms by which these cells regenerate myocardial tissue and argue for improved characterization of cell preparations and delivery methods to support clinical applications.

Future clinical trials that use stem cells for myocardial repair must address two concerns that accompany the delivery of these cells: 1) safety and 2) tracking the cells to their ultimate destination(s). Although stem cells appear to be relatively safe in the majority of recipients to date, an increased frequency of non-sustained ventricular tachycardia, an arrhythmia, has been reported in conjunction with the use of skeletal myoblasts.30,6264 While this proarrhythmic effect occurs relatively early after cell delivery and does not appear to be permanent, its presence highlights the need for careful safety monitoring when these cells are used. Additionally, animal models have demonstrated that stem cells rapidly diffuse from the heart to other organs (e.g., lungs, kidneys, liver, spleen) within a few hours of transplantation,65,66 an effect observed regardless of whether the cells are injected locally into the myocardium. This migration may or may not cause side-effects in patients; however, it remains a concern related to the delivery of stem cells in humans. (Note: Techniques to label stem cells for tracking purposes and to assess their safety are discussed in more detail in other articles in this publication).

In addition to safety and tracking, several logistical issues must also be addressed before stem cells can be used routinely in the clinic. While cell tracking methodologies allow researchers to determine migration patterns, the stem cells must target their desired destination(s) and be retained there for a sufficient amount of time to achieve benefit. To facilitate targeting and enable clinical use, stem cells must be delivered easily and efficiently to their sites of application. Finally, the ease by which the cells can be obtained and the cost of cell preparation will also influence their transition to the clinic.

The evidence to date suggests that stem cells hold promise as a therapy to regenerate damaged myocardium. Given the worldwide prevalence of cardiac dysfunction and the limited availability of tissue for cardiac transplantation, stem cells could ultimately fulfill a large-scale unmet clinical need and improve the quality of life for millions of people with CVD. However, the use of these cells in this setting is currently in its infancymuch remains to be learned about the mechanisms by which stem cells repair and regenerate myocardium, the optimal cell types and modes of their delivery, and the safety issues that will accompany their use. As the results of large-scale clinical trials become available, researchers will begin to identify ways to standardize and optimize the use of these cells, thereby providing clinicians with powerful tools to mend a broken heart.

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June 21st, 2018

Combination of Mesenchymal and C-kit+ Cardiac Stem Cells …

By LizaAVILA

Brief Summary:

This is a phase II, randomized, placebo-controlled clinical trial designed to assess feasibility, safety, and effect of autologous bone marrow-derived mesenchymal stem cells (MSCs) and c-kit+ cardiac stem cells (CSCs) both alone and in combination (Combo), compared to placebo (cell-free Plasmalyte-A medium) as well as each other, administered by transendocardial injection in subjects with ischemic cardiomyopathy.

This is a randomized, placebo-controlled clinical trial designed to evaluate the feasibility, safety, and effect of Combo, MSCs alone, and CSCs alone compared with placebo as well as each other in subjects with heart failure of ischemic etiology. Following a successful lead-in phase, a total of one hundred forty-four (144) subjects will be randomized (1:1:1:1) to receive Combo, MSCs, CSCs, or placebo. After randomization, baseline imaging, relevant harvest procedures, and study product injection, subjects will be followed up at 1 day, 1 week, 1 month, 3 months, 6 months and 12 months post study product injection. All subjects will receive study product injection (cells or placebo) using the NOGA XP Mapping and Navigation System. Subjects will have delayed-enhanced magnetic resonance imaging (DEMRI) scans to assess scar size and LV function and structure at baseline and at 6 and 12 months post study product administration. All endpoints will be assessed at the 6 and 12 month visits which will occur 180 30 days and 365 30 days respectively from the day of study product injection (Day 0). For the purpose of the endpoint analysis and safety evaluations, the Investigators will utilize an "intention-to-treat" study population, however an as treated analysis will also be conducted.

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June 21st, 2018

Next Steps for Cardiac Stem Cells – MedStar Heart …

By Sykes24Tracey

To determine why the first stem cell trials were not providing the anticipated therapeutic potential, all variables, such as which stem cells were used, and how they were developed and administered, were open to consideration, says Dr. Epstein.

A key issue was the use of autologous stem cells in all previous studies. Studies demonstrated these old stem cells are functionally defective when compared to stem cells obtained from young healthy individuals. So harvesting a healthy young donors bone marrow and growing the resident stem cells might produce more robust cells.

However, giving a patient allogenic stem cells raised an important issue: whether such cells will be rejected by an immune response. But research showed mesenchymal stem cells (MSCs), a type of adult stem cell, have been designed by nature to be stealth bombers, explainsDr. Epstein. They express molecules on their surface that prevent the body from recognizing the cells as foreign, so the patient does not reject the donated MSCs.

To further explore and refine potential stem cell cardiovascular therapies, MHVI expanded the translational research team to include Michael Lipinski, MD, PhD, an expert in molecular biology and scientific lead for preclinical research at the MedStar Cardiovascular Research Network, and Dror Luger, PhD, an expert in immunology and inflammatory responses. By bringing together these diverse areas of expertise, we forged a team with the potential to produce research that could lead to important breakthroughs in understanding how stem cells might work and thereby provide more successful treatment of patients with cardiac disease, says Dr. Epstein.

CardioCell, a San Diego-based stem cell company focused on stem cell therapy for cardiovascular disease, found that MSCs grew faster and showed improved function when cultured in a reduced oxygen environment. Stem cells typically grow in the body, in bone marrow and other tissues, in a low oxygen environmentonly five percent oxygen, as opposed to room air, which is about 20 percent, explains Dr. Lipinski. All previous stem cell trials used cells exposed to, and grown under, room air oxygen conditions.

Using CardioCells low oxygen-grown MSCs, the MHVI scientists demonstrated biologically important effects occurred, even when the MSCs were administered intravenously. This mode of administration was previously rejected by scientists who thought cells would be trapped in the first capillary bed they traversedthe lungsand never reach the heart.

However, the MHVI team demonstrated a small percentage of these IV administered MSCs did reach the heart, where they could exert beneficial effects. The cells seek out inflamed cardiac tissue after a heart attack because they upregulate receptors that allow them to be attracted to and penetrate inflamed tissue in high numbers, says Dr. Luger.

The investigators also found the cells residing in other tissues could provide other benefits. It has been shown that a heart attack activates the immune and inflammatory systems, including those in the spleen, explains Dr. Luger. The systemic anti-inflammatory effects produced by MSCs in the spleen, lungs and other tissues caused by the molecules secreted by the MSCs could exert positive effects as well. Dr. Epstein added that such anti-inflammatory effects could also benefit the excessive inflammatory activities that exist in many heart failure patients.

For the clinical heart failure trial, MHVI is partnering with CardioCell, which will grow and provide stem cells already used in Phase I and 2a clinical trials and approved by the Food and Drug Administration.

As an extension of their stem cell work, the MHVI investigators are building on the fact that any beneficial effect of adult stem cells will not derive from their transformation into heart muscle, but rather from the molecules they secrete; these, in turn, stimulate pathways favoring tissue healing. The team is investigating the use of liposomes as therapeutic delivery vehicles for these secreted products, which include those with anti-inflammatory and angiogenesis activities.

If successful, using MSCs for anti-inflammatory and immune-modulatory effects could have implicationsfor many different diseases, including arthritis and autoimmune diseases like rheumatoid arthritis. Dr. Epstein cautions that a great deal of research is yet to be done before such applications can be routinely used to treat patients with these conditions. For now, they hope the current studies in heart failure patients will demonstrate effectiveness. If so, Dr. Epstein says, it changes the whole playing field for stem cells.

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June 11th, 2018

Studies: Stem cells reverse heart damage – CNN

By LizaAVILA

Story highlights

On a June day in 2009, a 39-year-old man named Ken Milles lay on an exam table at Cedars-Sinai Medical Center in Los Angeles. A month earlier, he'd suffered a massive heart attack that destroyed nearly a third of his heart.

"The most difficult part was the uncertainty," he recalls. "Your heart is 30% damaged, and they tell you this could affect you the rest of your life." He was about to receive an infusion of stem cells, grown from cells taken from his own heart a few weeks earlier. No one had ever tried this before.

About three weeks later, in Kentucky, a patient named Mike Jones underwent a similar procedure at the University of Louisville's Jewish Hospital. Jones suffered from advanced heart failure, the result of a heart attack years earlier. Like Milles, he received an infusion of stem cells, grown from his own heart tissue.

"Once you reach this stage of heart disease, you don't get better," says Dr. Robert Bolli, who oversaw Jones' procedure, explaining what doctors have always believed and taught. "You can go down slowly, or go down quickly, but you're going to go down."

Conventional wisdom took a hit Monday, as Bolli's group and a team from Cedars-Sinai each reported that stem cell therapies were able to reverse heart damage, without dangerous side effects, at least in a small group of patients.

In Bolli's study, published in The Lancet, 16 patients with severe heart failure received a purified batch of cardiac stem cells. Within a year, their heart function markedly improved. The heart's pumping ability can be quantified through the "Left Ventricle Ejection Fraction," a measure of how much blood the heart pumps with each contraction. A patient with an LVEF of less than 40% is considered to suffer severe heart failure. When the study began, Bolli's patients had an average LVEF of 30.3%. Four months after receiving stem cells, it was 38.5%. Among seven patients who were followed for a full year, it improved to an astounding 42.5%. A control group of seven patients, given nothing but standard maintenance medications, showed no improvement at all.

"We were surprised by the magnitude of improvement," says Bolli, who says traditional therapies, such as placing a stent to physically widen the patient's artery, typically make a smaller difference. Prior to treatment, Mike Jones couldn't walk to the restroom without stopping for breath, says Bolli. "Now he can drive a tractor on his farm, even play basketball with his grandchildren. His life was transformed."

At Cedars-Sinai, 17 patients, including Milles, were given stem cells approximately six weeks after suffering a moderate to major heart attack. All had lost enough tissue to put them "at big risk" of future heart failure, according to Dr. Eduardo Marban, the director of the Cedars-Sinai Heart Institute, who developed the stem cell procedure used there.

The results were striking. Not only did scar tissue retreat -- shrinking 40% in Ken Milles, and between 30% and 47% in other test subjects -- but the patients actually generated new heart tissue. On average, the stem cell recipients grew the equivalent of 600 million new heart cells, according to Marban, who used MRI imaging to measure changes. By way of perspective, a major heart attack might kill off a billion cells.

"This is unprecedented, the first time anyone has grown living heart muscle," says Marban. "No one else has demonstrated that. It's very gratifying, especially when the conventional teaching has been that the damage is irreversible."

Perhaps even more important, no treated patient in either study suffered a significant health setback.

The twin findings are a boost to the notion that the heart contains the seeds of its own rebirth. For years, doctors believed that heart cells, once destroyed, were gone forever. But in a series of experiments, researchers including Bolli's collaborator, Dr. Piero Anversa, found that the heart contains a type of stem cell that can develop into either heart muscle or blood vessel components -- in essence, whatever the heart requires at a particular point in time. The problem for patients like Mike Jones or Ken Milles is that there simply aren't enough of these repair cells waiting around. The experimental treatments involve removing stem cells through a biopsy, and making millions of copies in a laboratory.

The Bolli/Anversa group and Marban's team both used cardiac stem cells, but Bolli and Anversa "purified" the CSCs, so that more than 90% of the infusion was actual stem cells. Marban, on the other hand, used a mixture of stem cells and other types of cells extracted from the patient's heart. "We've found that the mixture is more potent than any subtype we've been able to isolate," he says. He says the additional cells may help by providing a supportive environment for the stem cells to multiply.

Other scientists, including Dr. Douglas Losordo, have produced improvements in cardiac patients using stem cells derived from bone marrow. "The body contains cells that seem to be pre-programmed for repair," explains Losordo. "The consistent thing about all these approaches is that they're leveraging what seems to be the body's own repair mechanism."

Losordo praised the Lancet paper, and recalls the skepticism that met Anversa's initial claims, a decade ago, that there were stem cells in the adult heart. "Some scientists are always resistant to that type of novelty. You know the saying: First they ignore you, then they attack you and finally they imitate you."

Denis Buxton, who oversees stem cell research at the National Heart, Lung and Blood Institute at the National Institutes of Health, calls the new studies "a paradigm shift, harnessing the heart's own regenerative processes." But he says he would like to see more head-to-head comparisons to determine which type of cells are most beneficial.

Questions also remain about timing. Patients who suffer large heart attacks are prone to future damage, in part because the weakened heart tries to compensate by dilating -- swelling -- and by changing shape. In a vicious circle, the changes make the heart a less efficient pump, which leads to more overcompensation, and so on, until the end result is heart failure. Marban's study aimed to treat patients before they could develop heart failure in the first place.

In a third study released Monday, researchers treated patients with severe heart failure with stem cells derived from bone marrow. In a group of 60 patients, those receiving the treatment had fewer heart problems over the course of a year, as well as improved heart function.

A fourth study also used cells derived from bone marrow, but injected them into patients two to three weeks after a heart attack. Previous studies, with the cells given just days afterward, found a modest improvement in heart function. But Monday, the lead researcher, Dr. Dan Simon of UH Case Medical Center, reported that with the three-week delay, patients did not see the same benefit.

With other methods, there may be a larger window of opportunity. At least in initial studies, Losordo's bone marrow treatments helped some patients with long-standing heart problems. Bolli's Lancet paper suggests that CSCs, too, might help patients with advanced disease. "These patients had had heart failure for several years. They were a wreck!" says Bolli. "But we found their stem cells were still very competent." By that, he means the cells were still capable of multiplying and of turning into useful muscle and blood vessel walls.

Marban has an open mind on the timing issue. In fact, one patient from his control group e-mailed after the study was complete, saying he felt terrible and pleading for an infusion of stem cells. At Marban's request, the FDA granted special approval to treat him. "He had a very nice response. That was 14 months after his heart attack. Of course that's just one person, and we need bigger studies," says Marban.

For Ken Milles, the procedure itself wasn't painful, but it was unsettling. The biopsy to harvest the stem cells felt "weird," he recalls, as he felt the doctor poking around inside his heart. The infusion, a few weeks later, was harder. The procedure -- basically the same as an angioplasty -- involved stopping blood flow through the damaged artery for three minutes, while the stem cells were infused. "It felt exacfly like I was having a heart attack again," Milles remembers.

Milles had spent the first weeks after his heart attack just lying in bed re-watching his "Sopranos" DVDs, but within a week of the stem cell infusion, he says, "I was reinvigorated." Today he's back at work full time, as an accounting manager at a construction company. He's cut out fast food and shed 50 pounds. His wife and two teenage sons are thrilled.

Denis Buxton says the new papers could prove a milestone. "We don't have anything else to actually regenerate the heart. These stem cell therapies have the possibility of actually reversing damage."

Bolli says he'll have to temper his enthusiasm until he can duplicate the results in larger studies, definitive enough to get stem cell therapy approved as a standard treatment. "If a phase 3 study confirmed this, it would be the biggest advance in cardiology in my lifetime. We would possibly be curing heart failure. It would be a revolution."

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April 2nd, 2018

STEM CELLS – Issue – Wiley Online Library

By raymumme

Stem Cells May Help Improve Corneal Wound Healing

Stem Cell Treatment Has Potential to Help Parkinsons Disease Unexpected Brain Area

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Video abstract from Drs. Banerjee, Surendran, Bharti, Morishita, Varshney, and Pal on their recently published STEM CELLS paper entitled, "Long non-coding RNA RP11-380D23.2 drives distal-proximal patterning of the lung by regulating PITX2 expression." Read the paper here.

Video abstract from Drs. Sayed, Ospino, Himmati, Lee, Chanda, Mocarski, and Cooke on their recently published STEM CELLS paper entitled, "Retinoic Acid Inducible Gene 1 Protein (RIG1)-like Receptor Pathway is Required for Efficient Nuclear Reprogramming." Read the paper here.

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March 16th, 2018

Induced Pluripotent Stem Cells for Cardiovascular …

By LizaAVILA

Nearly 500,000 people in the US die of sudden cardiac death each year, and long QT syndrome (LQTS) is a major form of sudden cardiac death. LQTS can be triggered by drug exposure or stresses. Drug-induced LQTS is the single most common reason for drugs to be withdrawn from clinical trials, causing major setbacks to drug discovery efforts and exposing people to dangerous drugs. In most cases, the mechanism of drug-induced LQTS is unknown. However, there are genetic forms of LQTS that should allow us to make iPS cellderived heart cells that have the key features of LQTS. Our objective is to produce a cell-based test for LQTS with induced pluripotent stem (iPS) cell technology, which allows adult cells to be reprogrammed to be stem celllike cells.Despite the critical need, current tests for drug-induced LQTS are far from perfect. As a result, potentially unsafe drugs enter clinical trials, endangering people and wasting millions of dollars in research funds. When drugs that cause LQTS, such as terfenadine (Seldane), enter the market, millions of people are put at serious risk. Unfortunately, it is very difficult to know when a drug will cause LQTS, since most people who develop LQTS have no known genetic risk factors. The standard tests for LQTS use animal models or hamster cells that express human heart genes at high levels. Unfortunately, cardiac physiology in animal models (rabbits and dogs) differs from that in humans, and hamster cells lack many key features of human heart cells. Human embryonic stem cells (hESCs) can be differentiated into heart cells, but we do not know the culture conditions that would make the assay most similar to LQTS in a living person. These problems could be solved if we had a method to grow human heart cells from people with genetic LQTS mutations, so that we know the exact test conditions that would reflect the human disease. This test would be much more accurate than currently available tests and would help enable the development of safer human pharmaceuticals.Our long-term goal is to develop a panel of iPS cell lines that better represent the genetic diversity of the human population. Susceptibility to LQTS varies, and most people who have life-threatening LQTS have no known genetic risk factors. We will characterize iPS cells with well-defined mutations that have clinically proven responses to drugs that cause LQTS. These iPS cell lines will be used to refine testing conditions. To validate the iPS cellbased test, the results will be directly compared to the responses in people. These studies will provide the foundation for an expanded panel of iPS cell lines from people with other genetic mutations and from people who have no genetically defined risk factor but still have potentially fatal drug-induced LQTS. This growing panel of iPS cell lines should allow for testing drugs for LQTS more effectively and accurately than any current test.To meet these goals, we made a series of iPS cells that harbor different LQTS mutations. These iPS cells differentiate into beating cardiomyocytes. We are now evaluating these LQTS cell lines in cellular assays. We are hopeful that our studies will meet or exceed all the aims of our original proposal.

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March 16th, 2018

Development of 3D Bioprinting Techniques using Human …

By LizaAVILA

In this project, we aim to develop a 3D bioprinting technology to create functional cardiac tissues via encapsulation of cardiomyocytes derived from hESCs. To further improve their viability and cardiac functionality, we are developing a new vascularization technique to enhance the cardiac tissue model through the incorporation of functional vasculature using 3D bioprinting. In Specific Aim 1, we have successfully developed and optimized a rapid 3D bioprinting technique to create biomimetic 3D micro-architectures using hyaluronic acid (HA)-based biomaterials and hESC-derived cardiomyocytes. A protocol for the synthesis of the photopolymeriable hydrogel biomaterial (hyaluronic acid-glycidyl methacrylate (HA-GM)) proposed for use with the 3D bioprinting platform has been created and refined. HA-GM chemical synthesis efficiency was evaluated. H7 human embryonic stem cells (hESC) were used. These hESC derived cardiomyoctes (hESC-CMs) were shown to be well differentiated based on examining surface markers (Nkx2.5 & cardiac troponin T) and mRNA expression (Nkx2.5, ISL1, MYL2, and MYL7). These cells have been encapsulated within a 3D vasculature pattern of photopolymerized HA-GM hydrogel biomaterial. Digital images derived from a 3D model of the heart have been printed and the direct printing of biomaterials and cell-laden materials has been successfully achieved. Fluorescent staining showed encapsulated cell survival of this structure after 2-weeks of incubation. We have successfully measured the physiological function of cells embedded within the hydrogel constructs. We assessed changes in the cell viability, alignment and function of cells within hydrogel constructs. We successfully characterized electrical function of cardiomyocytes by optical mapping of Spontaneous Beats in unpatterned and patterned tissue constructs. We further measured mechanical function in the tissue constructs by cantilever displacement. We have also measured calcium transients in our 3D printed tissue constructs by live confocal imaging at varying frequencies. In Specific Aim 2, we have created an advanced vascularization technique for 3D pre-vascularized cardiac tissues with precise control of spatial organization. Human umbilical vein endothelial cells (HUVECs) were encapsulated within a mesh of hexagonal channels and cardiomyocytes were encapsulated within islands between these channels to demonstrate the capability of spatially printing distinct cell populations into a simple prevascularized co-culture model. Cells in this bioprinted configuration showed proliferation and viability. To investigate the formation of the endothelial network, we performed immunofluorescence staining on the prevascularized tissues after 1-week culture in vitro. Human-specific CD31 staining (green) in confocal microscopy shows the conjunctive network formation of HUVECs at different patterned channel widths.

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March 10th, 2018

Home – STEM CELL SCIENCE

By LizaAVILA

Stem cell can be isolated from the the bone marrow and adipose tissue in the abdomen that are capable of forming new blood vessels and heart muscle cells. The cell number is so small in the tissues that the cells should be grown for several weeks before there is enough for the treatment of patients.

We have conducted three clinical stem cell therapy studies in which patients with coronary artery disease havebeen treated with their own mesenchymal stem cells from either the bone marrow or adipose tissue. Encouraging results are available from two studies and there is ongoing follow-up in the third study. Treatments with stem cells have in all previous studies been without any side effects.

During the course of the SCIENCE study a total of 138 patients with heart failure will be included and treated in a so-called blinded placebo-controlled design. This means that 92 patients will receive stem cells and 46 patients placebo (inactive medication, saline). Choice of treatment will be done by drawing lots. The study is carried out by an international collaboration between cardiac centers in Denmark, Poland, Germany, Netherlands, Austria and Sloveniaand the industrial partners Terumo BCT and COOK Tegentec.

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February 13th, 2018

Autologous cardiac-derived cells for advanced ischemic …

By raymumme

Disease Team Award DR1-01461, autologous cardiac-derived cells for advanced ischemic cardiomyopathy, is targeted at developing novel therapies for the treatment of heart failure, a condition which afflicts 7 million Americans. Heart failure, when symptomatic, has a mortality exceeding that of many malignant tumors; new therapies are desperately needed. In the second year of CIRM support, pivotal pre-clinical studies have been completed. We have found that dose-optimized injection of CSps preserves systolic function, attenuates remodeling, decreases scar size and increases viable myocardium in a porcine model of ischemic cardiomyopathy. The 3D microtissues engraft efficiently in preclinical models of heart failure, as expected from prior work indicating their complex multi-layer nature combining cardiac progenitors, supporting cells and derivatives into the cardiomyocyte and endothelial lineages. Analysis of the MRI data continues. We have developed standard operating procedures for cardiosphere manufacturing and release criteria, product and freezing/thawing stability testing have been completed for the 3D microtissue development candidate. We have identified two candidate potency assays for future development. The disease team will evaluate the results of the safety study (immunology, histology, and markers of ischemic injury) and complete the pivotal pig study in Q1 2012. With data in hand, full efforts will be placed on preparation of the IND for Q2 2012 submission.

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February 5th, 2018

Allogeneic Cardiac-Derived Stem Cells for Patients …

By NEVAGiles23

This project aims to demonstrate both safety and efficacy of a heart-derived cell product in patients who have experienced a heart attack either recently or in the past by conducting a mid-stage (Phase II) clinical trial. The cell product is manufactured using heart tissue obtained from a healthy donor and can be used in most other individuals. Its effect is thought to be long-lasting (months-years) although it is expected to be cleared from the body relatively quickly (weeks-months). Treatment is administered during a single brief procedure, requiring a local anesthetic and insertion of a tube (or catheter) into the heart. The overriding goal for the product is to prevent patients who have had a heart attack from deteriorating over time and developing heart failure, a condition which is defined by the hearts inability to pump blood efficiently and one which affects millions of Americans. At the outset of the project, a Phase I trial was underway. The Phase II trial was initiated at the beginning of the current reporting period, and all subjects enrolled in Phase I completed follow up during the current reporting period. Fourteen patients were treated with the heart-derived cell product as part of Phase I. The safety endpoint for the trial was pre-defined and took into consideration the following: inflammation in the heart accompanied by an immune response, death due to abnormal heart rhythms, sudden death, repeat heart attack, treatment for symptoms of heart failure, need for a heart assist device, and need for a heart transplant. Both an independent Data and Safety Monitoring Board (DSMB) and CIRM agreed that Phase I met its safety endpoint. Preliminary efficacy data from Phase I collected during the current reporting period showed evidence of improvements in scar size, a measure of damage in the heart, and ejection fraction, a measure of the hearts ability to pump blood. At the end of the current reporting period, Phase II is still enrolling subjects and clinical trial sites are still being brought on for participation in the trial. Meanwhile, the manufacturing processes established continue to be employed to create cell products for use in Phase II. Manufacturing data and trial status updates were also provided to the Food and Drug Administration (FDA) as part of standard annual reporting.

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January 27th, 2018

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