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Adult Cardiac Stem Cells Are Multipotent and Support …


The notion of the adult heart as terminally differentiated organ without self-renewal potential has been undermined by the existence of a subpopulation of replicating myocytes in normal and pathological states. The origin and significance of these cells has remained obscure for lack of a proper biological context. We report the existence of Lin c-kitPOS cells with the properties of cardiac stem cells. They are self-renewing, clonogenic, and multipotent, giving rise to myocytes, smooth muscle, and endothelial cells. When injected into an ischemic heart, these cells or their clonal progeny reconstitute well-differentiated myocardium, formed by blood-carrying new vessels and myocytes with the characteristics of young cells, encompassing 70% of the ventricle. Thus, the adult heart, like the brain, is mainly composed of terminally differentiated cells, but is not a terminally differentiated organ because it contains stem cells supporting its regeneration. The existence of these cells opens new opportunities for myocardial repair.

Until recently, the accepted paradigm in cardiac biology considered the adult mammalian heart to be a postmitotic organ without regenerative capacity. It has been assumed that from shortly after birth to adulthood and senescence the heart has a relatively stable but slowly diminishing number of myocytes. This static view of the myocardium implied that both myocyte death and myocyte regeneration had little role in cardiac cellular homeostasis. Although stem cells have been isolated from many adult tissues including the blood, skin, central nervous system, liver, gastrointestinal tract, and skeletal muscle (see Rosenthal, 2003), the search for a cardiac stem cell has been considered futile given the accepted lack of regenerative potential of this tissue.

Evidence challenging the accepted wisdom has been slowly accumulating McDonnell and Oberpriller 1984andRumyantsev and Broisov 1987. In the past few years, we have documented the existence of cycling ventricular myocytes in the normal and pathologic adult mammalian heart of several species, including humans Kajstura et al. 1998, Beltrami et al. 2001andQuaini et al. 2002. Although these data provided an alternative view of cardiac homeostasis, they also raised questions because it required reconciliation of two apparent contradictory bodies of evidence: the well-documented irreversible withdrawal of cardiac myocytes from the cell cycle soon after birth on one hand MacLellan and Schneider 2000andChien and Olson 2002, and the presence of cycling myocytes undergoing mitosis and cytokinesis on the other. These results raised the question as to the origin of the cycling myocytes and their dramatic increase in response to an acute work overload.

In cases of sex-mismatched cardiac transplants in humans, the female hearts in the male hosts had a significant number of Y positive myocytes and coronary vessels (Quaini et al., 2002). Most likely due to technical differences (Anversa and Nadal-Ginard, 2002a), there are some discrepancies among groups about the degree of cardiac chimerism Muller et al. 2002, Glaser et al. 2002andLaflamme et al. 2002. It is likely that these male cells colonized the female heart after the transplant and subsequently differentiated, although alternative explanations have been raised. These male cells in the female heart presuppose the existence of mobile stem-like cells able to differentiate into the three main cardiac cell types: myocytes, smooth, and endothelial vascular cells.

Primitive cells of donor and recipient origin that express stem cell-related surface antigensc-kit, Sca-1, and MDR1were identified in the recipient hearts. More importantly, identical cells were found in human control hearts Quaini et al. 2002andAnversa and Nadal-Ginard 2002b. It is well known that in early fetal life, c-kitPOS cells colonize the yolk sack, liver, and probably other organs. The colonized organs express stem cell factor (SCF), the ligand of the c-kit receptor (Teyssier-Le Discorde et al., 1999); SCF mRNA is also present in fetal and neonatal myocardium (Kunisada et al., 1998), raising the possibility that stem-like cells could have been in the heart from fetal life. The rapid induction of SCF during myocardial ischemia (Frangogiannis et al., 1998) could be involved in the activation of these cells and explain the significant increase in new myocyte formation (Beltrami et al., 2001). However, the origin of these primitive cells, their presence in normal and pathological hearts, together with the identification of some of them having initiated the cardiomyocyte gene expression program, is suggestive that they might be true cardiac stem cells that give rise to the cycling myocytes detected in the adult heart. If this were the case, their manipulation might provide the opportunity to stimulate myocardial regeneration with endogenous cells. For this reason, we endeavored to establish a precursor-product relationship between these primitive cells and the fully differentiated cardiac cells and to determine, in vitro and in vivo, whether they behave like true adult cardiac stem cells.

To determine whether the putative cardiac stem cells detected in human heart transplants and their controls are bona fide stem cells with cardiogenic potential, we isolated them to test their differentiation potential in vivo and in vitro. For experimental convenience, we chose the rat as the animal model system. We first analyzed whether cells with the cell surface markers commonly expressed by other stem cells could be identified in the adult rat myocardium. Based on the postulated higher number of proliferating stem and precursor cells with age (Morrison et al., 1996), we analyzed the myocardium from older animals. Histological sections of myocardium from Fisher rats 2023 months of age were examined by confocal microscopy for the presence of cells negative for the expression of blood lineage markers (Lin) but positive for the common stem cell markers c-kit (Kondo et al., 2003), Sca-1 (Morrison et al., 1997), and MDR-1 (Sellers et al., 2001). Small Lin cells with a very high nucleus/cytoplasm ratio and positive for each of the above markers were distributed throughout the ventricular and atrial myocardium with a higher density in the atria and the ventricular apex. Because of the role of bone marrow-derived Lin c-kitPOS cells in myocardial regeneration (Orlic et al., 2001), the mesodermal origin of both the heart and the bone marrow, and the use of c-kit as a hematopoietic stem cell marker Morrison et al. 1997, Weissman et al. 2001andKondo et al. 2003, we decided to concentrate on the cardiac cells expressing this marker, the receptor for SCF. Although the density of these cells varied among different regions of the heart, on average we identified one Lin c-kitPOS cell every 1 104 myocytes. It should be noted that most, if not all, of the detected c-kitPOS cells were negative for the pan leukocyte marker CD45 and the endothelial/hematopoietic progenitor marker CD34.

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Adult Cardiac Stem Cells Are Multipotent and Support …

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Jan. 29, 2016 The mechanism used by specialized enzymes to remodel the extremely condensed genetic material in the nucleus of cells in order to control which genes can be used has been discovered. The research … read more Ultrasound-Based Therapy for Cardiac Stem Cells Recovery Jan. 29, 2016 When cardiac stem cells undergo low-intensity pulsed ultrasound treatment, these cells can perform continuing modifications, tissue remodeling and regeneration of damaged cardiac tissue after a heart … read more Assessing Stem Cells: New Biomarker Developed Jan. 29, 2016 A research team has found a way to assess the viability of ‘manufactured’ stem cells known as induced pluripotent stem cells (iPSCs). The team’s discovery offers a new way to … read more Jan. 29, 2016 Industry 4.0 requires comprehensive data collection in order to control highly automated process sequences in complex production environments. One example is the cultivation of living cells. But … read more Protein Combination Improves Bone Regeneration, Study Shows Jan. 29, 2016 A combination of proteins that could improve clinical bone restoration, and could lead towards the development of therapeutic treatments for skeletal defects, bone loss and osteoporosis, report … read more Cancer’s Surprise Origins, Caught in Action Jan. 28, 2016 For the first time, researchers have visualized the origins of cancer from the first affected cell and watched its spread in a live animal. This work could change the way scientists understand … read more Research Hints at a Nutritional Strategy for Reducing Autism Risk Jan. 28, 2016 Folic acid has long been touted as an important supplement for women of childbearing age for its ability to prevent defects in the baby’s developing brain and spinal cord. In fact, folic acid is … read more CRISPR Used to Repair Blindness-Causing Genetic Defect in Patient-Derived Stem Cells Jan. 28, 2016 Scientists have used a new gene-editing technology called CRISPR, to repair a genetic mutation responsible for retinitis pigmentosa (RP), an inherited condition that causes the retina to degrade and … read more Jan. 27, 2016 The Achilles heel of hepatocellular carcinoma, a leading cause of cancer deaths worldwide, has been discovered by researchers. The key to disrupting chemo-resistant stem cells that become liver … read more Scientists Make an Important Contribution to Decoding the Language of Cells Jan. 27, 2016 There are astonishing similarities between molecular mechanisms in neural stem cells and pancreatic islet cells, new research shows. This may lead to new forms of therapy, particularly for … read more Jan. 25, 2016 A molecule that interrupts biochemical signals essential for the survival of a certain type of cancer stem cell has been discovered by … read more How to Detect and Preserve Human Stem Cells in the Lab Jan. 22, 2016 Human stem cells that are capable of becoming any other kind of cell in the body have previously only been acquired and cultivated with difficulty. Scientists have now presented details of a method … read more Jan. 21, 2016 A research team has now discovered how human macrophages can divide and self-renew almost indefinitely. As the researchers show in their new report, the macrophages achieve this by activating a gene … read more Jan. 20, 2016 In 1917, Florence Sabin, the first female member of the US National Academy of Sciences, discovered hemangioblasts, the common precursor cells for blood cells and blood vessel endothelia. Her … read more Breakthrough in Human Cell Transformation Could Revolutionize Regenerative Medicine Jan. 19, 2016 A breakthrough in the transformation of human cells by an international team of researchers could open the door to a new range of treatments for a variety of medical … read more Jan. 19, 2016 Electrical stimulation of human heart muscle cells engineered from human stem cells aids their development and function, researchers have demonstrated for the first time. They used electrical … read more Broken UV Light Leads to Key Heart Muscle Cell Discovery Jan. 18, 2016 For a team of investigators trying to generate heart muscle cells from stem cells, a piece of broken equipment turned out to be a good thing. The faulty equipment pushed the researchers to try a … read more Jan. 14, 2016 Where and when do stem cells first appear during development? Researchers investigated this question by examining how cells organize as the hair follicle first appears in mouse embryos. They … read more Donor’s Genotype Controls Differentiation of Induced Pluripotent Stem Cells Jan. 14, 2016 Pluripotent stem cells derived from different cell types are equally susceptible to reprogramming, indicates a recent study. However, the genotype of the donor strongly influences the differentiation … read more Mechanism That Controls Neuron Production from Stem Cells Revealed Jan. 13, 2016 The discovery of a mechanism enabling the production of cellular diversity in the developing nervous system has been announced by scientists. This discovery could improve the protocols to … read more

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Cardiac muscle cell – Wikipedia, the free encyclopedia

Cardiac muscle cells or cardiomyocytes (also known as myocardiocytes[1] or cardiac myocytes[2]) are the muscle cells (myocytes) that make up the cardiac muscle. Each myocardial cell contains myofibrils, which are specialized organelles consisting of long chains of sarcomeres, the fundamental contractile units of muscle cells. Cardiomyocytes show striations similar to those on skeletal muscle cells. Unlike multinucleated skeletal cells, the majority of cardiomyocytes contain only one nucleus, although they may have as many as four.[3] Cardiomyocytes have a high mitochondrial density, which allows them to produce adenosine triphosphate (ATP) quickly, making them highly resistant to fatigue.

There are two types of cells within the heart: the cardiomyocytes and the cardiac pacemaker cells. Cardiomyocytes make up the atria (the chambers in which blood enters the heart) and the ventricles (the chambers where blood is collected and pumped out of the heart). These cells must be able to shorten and lengthen their fibers and the fibers must be flexible enough to stretch. These functions are critical to the proper form during the beating of the heart.[4]

Cardiac pacemaker cells carry the impulses that are responsible for the beating of the heart. They are distributed throughout the heart and are responsible for several functions. First, they are responsible for being able to spontaneously generate and send out electrical impulses. They also must be able to receive and respond to electrical impulses from the brain. Lastly, they must be able to transfer electrical impulses from cell to cell.[5]

All of these cells are connected by cellular bridges. Porous junctions called intercalated discs form junctions between the cells. They permit sodium, potassium and calcium to easily diffuse from cell to cell. This makes it easier for depolarization and repolarization in the myocardium. Because of these junctions and bridges the heart muscle is able to act as a single coordinated unit.[6][7]

Cardiac action potential consists of two cycles, a rest phase and an active phase. These two phases are commonly understood as systole and diastole. The rest phase is considered polarized. The resting potential during this phase of the beat separates the ions such as sodium, potassium and calcium. Myocardial cells possess the property of automaticity or spontaneous depolarization. This is the direct result of a membrane which allows sodium ions to slowly enter the cell until the threshold is reached for depolarization. Calcium ions follow and extend the depolarization even further. Once calcium stops moving inward, potassium ions move out slowly to produce repolarization. The very slow repolarization of the CMC membrane is responsible for the long refractory period.[8][9]

Myocardial infarction, commonly known as a heart attack, occurs when the heart’s supplementary blood vessels are obstructed by an unstable build-up of white blood cells, cholesterol, and fat. With no blood flow, the cells die, causing whole portions of cardiac tissue to die. Once these tissues are lost, they cannot be replaced, thus causing permanent damage. Current research indicates, however, that it may be possible to repair damaged cardiac tissue with stem cells,[10] as human embryonic stem cells can differentiate into cardiomyocytes under appropriate conditions.[11]

Humans are born with a set number of heart muscle cells, or cardiomyocytes, which increase in size as our heart grows larger during childhood development. Recent evidence suggests that cardiomyocytes are actually slowly turned over as we age, but that less than 50% of the cardiomyocytes we are born with are replaced during a normal life span.[12] The growth of individual cardiomyocytes not only occurs during normal heart development, it also occurs in response to extensive exercise (athletic heart syndrome), heart disease, or heart muscle injury such as after a myocardial infarction. A healthy adult cardiomyocyte has a cylindrical shape that is approximately 100m long and 10-25m in diameter. Cardiomyocyte hypertrophy occurs through sarcomerogenesis, the creation of new sarcomere units in the cell. During heart volume overload, cardiomyocytes grow through eccentric hypertrophy.[13] The cardiomyocytes extend lengthwise but have the same diameter, resulting in ventricular dilation. During heart pressure overload, cardiomyocytes grow through concentric hypertrophy.[13] The cardiomyocytes grow larger in diameter but have the same length, resulting in heart wall thickening.

Cardiac muscle cell – Wikipedia, the free encyclopedia

Regenocyte, Stem Cells Used To Treat Cardiovascular Disease

About 128 million people suffer from diseases that might be cured or treated through stem cell therapy. About 58 million of these people suffer from cardiovascular disease.

Cardiovascular disease can manifest itself in many different ways because the blood vessels transport blood to every single part of the body. The heart is the organ that pumps the blood around the body, and it also receives nutrients from the blood vessels (via the coronary vessels). Any interruption of the supply of blood containing nutrients and oxygen to one of the bodys organs leads to functional impairment and, in the worst case scenario, the death of the tissue. One typical example is cardiac arrest, which occurs when the blood supply to the heart muscle is restricted.

Cardiovascular disease can have any number of causes. Some people are born with a susceptibility to vascular disease (e.g. varicose veins), which can be alleviated by taking medication. Other peoples heart and blood vessels can be damaged by external factors. The majority of vascular diseases these days, however, are caused by our modern-day lifestyles. The walls of the blood vessel are always in contact with the blood which flows through them, so they are most commonly affected by unhealthy lifestyles. If someone has an unfavorable haemogram, i.e. if their blood contains too much glucose, cholesterol, triglycerides (fats) or nicotine, this can put the blood vessels under an enormous amount of stress. Glucose adheres to the walls of the blood vessels and the blood constituents, and cholesterol and triglycerides also accumulate on the blood vessel walls. As a result, the blood clumps, the blood vessel walls calcify, turning porous and can no longer perform their biological function properly. Nicotine also constricts the blood vessels, so they narrow and the amount of blood circulating the body is reduced.

If the condition is aggravated by a lack of vessel-protecting substances, the damaged vessels lose their ability to regenerate. The consequences include arteriosclerosis, leg ulceration, dilation of the abdominal artery (aneurysm), cardiac insufficiency, cardiac arrest and stroke. Cardiovascular disease is still the number one cause of death in many other western industrial nations.

Adult Stem Cells derived from the patients own blood are potent and effective to treat heart disease.Patients who have severe cardiac disease with a history of coronary infarction, congestive heart failure, those with previous bypass surgery and stents, cardiomyopathy, and individuals with low ejection fraction (the rate at which the heart pumps) are candidates for this procedure. Patients that survive myocardial infarction have diminished cardiac reserve putting them at risk for subsequent heart failure. Doctors and scientists throughout the world now understand that myocardial repair and regeneration are possible and attainable.

Watch this informative video that highlights one of our patients and how their heart was treated with Stem Cell Therapy. Stem Cell Treatment for the heart saved this patients life.

Regenocyte generates healthy heart muscle cells in the laboratory and then transplants those cells into patients with chronic heart disease. Stem cells cultivated from the patients own blood and transplanted into a damaged heart, can generate new collateral vessels.

Treatment is non-invasive consisting of an intravenous infusion of precursor cardiomyocyte stem cells derived from a patients own blood through a specially designed catheter. This approach increases the engraftment, survival and proliferation of the stem cells to the heart muscle.

To find out more about how stem cells can treat the heart,click hereor call us at (866) 216-5710

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Regenocyte, Stem Cells Used To Treat Cardiovascular Disease

Challenges in identifying the best source of stem cells …

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Challenges in identifying the best source of stem cells …

Endogenous cardiac stem cell – Wikipedia, the free …

Endogenous cardiac stem cells (eCSCs) are tissue-specific stem progenitor cells harboured within the adult mammalian heart.

They were first discovered in 2003 by Bernardo Nadal-Ginard, Piero Anversa and colleagues [1][2] in the adult rat heart and since then have been identified and isolated from mouse, dog, porcine and human hearts.[3][4]

The adult heart was previously thought to be a post mitotic organ without any regenerative capability. The identification of eCSCs has provided an explanation for the hitherto unexplained existence of a subpopulation of immature cycling myocytes in the adult myocardium. Indeed, recent evidence from a genetic fate-mapping study established that stem cells replenish adult mammalian cardiomyocytes lost by cardiac wear and tear and injury throughout the adult life.[5] Moreover, it is now accepted that myocyte death and myocyte renewal are the two sides of the proverbial coin of cardiac homeostasis in which the eCSCs play a central role.[6] These findings produced a paradigm shift in cardiac biology and opened new opportunities and approaches for future treatment of cardiac diseases by placing the heart squarely amongst other organs with regenerative potential such as the liver, skin, muscle, CNS. However, they have not changed the well-established fact that the working myocardium is mainly constituted of terminally differentiated contractile myocytes. This fact does not exclude, but is it fully compatible with the heart being endowed with a robust intrinsic regenerative capacity which resides in the presence of the eCSCs throughout the individual lifespan.

Briefly, eCSCs have been first identified through the expression of c-kit, the receptor of the stem cell factor and the absence of common hematopoietic markers, like CD45. Afterwards, different membrane markers (Sca-1, Abcg-2, Flk-1) and transcription factors (Isl-1, Nkx2.5, GATA4) have been employed to identify and characterize these cells in the embryonic and adult life.[7] eCSCs are clonogenic, self renewing and multipotent in vitro and in vivo,[8] capable of generating the 3 major cell types of the myocardium: myocytes, smooth muscle and endothelial vascular cells.[9] They express several markers of stemness (i.e. Oct3/4, Bmi-1, Nanog) and have significant regenerative potential in vivo.[10] When cloned in suspension they form cardiospheres,[11] which when cultured in a myogenic differentiation medium, attach and differentiate into beating cardiomyocytes.

In 2012, it was proposed that Isl-1 is not a marker for endogenous cardiac stem cells.[12] That same year, a different group demonstrated that Isl-1 is not restricted to second heart field progenitors in the developing heart, but also labels cardiac neural crest.[13] It has also been reported that Flk-1 is not a specific marker for endogenous and mouse ESC-derived Isl1+ CPCs. While some eCSC discoveries have been brought into question, there has been success with other membrane markers. For instance, it was demonstrated that the combination of Flt1+/Flt4+ membrane markers identifies an Isl1+/Nkx2.5+ cell population in the developing heart. It was also shown that endogenous Flt1+/Flt4+ cells could be expanded in vitro and displayed trilineage differentiation potential. Flt1+/Flt4+ CPCs derived from iPSCs were shown to engraft into the adult myocardium and robustly differentiate into cardiomyocytes with phenotypic and electrophysiologic characteristics of adult cardiomyocytes.[14]

With the myocardium now recognized as a tissue with limited regenerating potential,[15] harbouring eCSCs that can be isolated and amplified in vitro [16] for regenerative protocols of cell transplantation or stimulated to replicate and differentiate in situ in response to growth factors,[17] it has become reasonable to exploit this endogenous regenerative potential to replace lost/damaged cardiac muscle with autologous functional myocardium.

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Endogenous cardiac stem cell – Wikipedia, the free …

Heart Stem Cell Trial: Interview With Researcher Roberto …

An interview with Roberto Bolli, MD.

University of Louisville cardiologist Roberto Bolli, MD, led the stem cell study that tested using patients’ own heart stem cells to help their hearts recover from heart failure. Though that trial was preliminary, the results look promising — and may one day lead to a cure for heart failure.

Here, Bolli talks about what this work means and when it might become an option for patients.

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“Realistically, this will not come… for another three or four years, at least,” Bolli says. “It may be longer, depending on the results of the next trial, of course.”

Larger studies are needed to confirm the procedure’s safety and effectiveness. If those succeed, it could be “the biggest advance in cardiovascular medicine in my lifetime,” Bolli says.

A total of 20 patients took part in the initial study.

All of them experienced significant improvement in their heart failure and now function better in daily life, according to Bolli. “The patients can do more, there’s more ability to exercise, and the quality of life improves markedly,” Bolli says.

Bolli’s team published its findings on how the patients were doing one year after stem cell treatment in November 2011 in the Lancet, a British medical journal.

Each patient was infused with about 1 million of his or her own cardiac stem cells, which could eventually produce an estimated 4 trillion new cardiac cells, Bolli says. His team plans to follow each patient for two years after their stem cell procedure.

Keep in mind that this was a phase I study. Those focus on safety more than effectiveness.

The results were “much more striking” than past stem cell trials to heal the heart, Bolli says.

This trial was the first in the world to use stem cells derived from the heart. Earlier studies used stem cells gleaned from different bodily sources, including bone marrow, adipose (fat) tissue, and circulating blood. Those showed either no improvement or only modest gains in a patient’s left ventricular ejection fraction, a measure of the heart’s pumping ability.

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Heart Stem Cell Trial: Interview With Researcher Roberto …

Cardiac muscle – Wikipedia, the free encyclopedia

An isolated cardiac muscle cell, beating

Cardiac muscle (heart muscle) is involuntary striated muscle that is found in the walls and histological foundation of the heart, specifically the myocardium. Cardiac muscle is one of three major types of muscle, the others being skeletal and smooth muscle. These three types of muscle all form in the process of myogenesis. The cells that constitute cardiac muscle, called cardiomyocytes or myocardiocytes, contain only three nuclei.[1][2][pageneeded] The myocardium is the muscle tissue of the heart, and forms a thick middle layer between the outer epicardium layer and the inner endocardium layer.

Coordinated contractions of cardiac muscle cells in the heart propel blood out of the atria and ventricles to the blood vessels of the left/body/systemic and right/lungs/pulmonary circulatory systems. This complex mechanism illustrates systole of the heart.

Cardiac muscle cells, unlike most other tissues in the body, rely on an available blood and electrical supply to deliver oxygen and nutrients and remove waste products such as carbon dioxide. The coronary arteries help fulfill this function.

Cardiac muscle has cross striations formed by rotating segments of thick and thin protein filaments. Like skeletal muscle, the primary structural proteins of cardiac muscle are myosin and actin. The actin filaments are thin, causing the lighter appearance of the I bands in striated muscle, whereas the myosin filament is thicker, lending a darker appearance to the alternating A bands as observed with electron microscopy. However, in contrast to skeletal muscle, cardiac muscle cells are typically branch-like instead of linear.

Another histological difference between cardiac muscle and skeletal muscle is that the T-tubules in the cardiac muscle are bigger and wider and track laterally to the Z-discs. There are fewer T-tubules in comparison with skeletal muscle. The diad is a structure in the cardiac myocyte located at the sarcomere Z-line. It is composed of a single T-tubule paired with a terminal cisterna of the sarcoplasmic reticulum. The diad plays an important role in excitation-contraction coupling by juxtaposing an inlet for the action potential near a source of Ca2+ ions. This way, the wave of depolarization can be coupled to calcium-mediated cardiac muscle contraction via the sliding filament mechanism. Cardiac muscle forms these instead of the triads formed between the sarcoplasmic reticulum in skeletal muscle and T-tubules. T-tubules play critical role in excitation-contraction coupling (ECC). Recently, the action potentials of T-tubules were recorded optically by Guixue Bu et al.[3]

The cardiac syncytium is a network of cardiomyocytes connected to each other by intercalated discs that enable the rapid transmission of electrical impulses through the network, enabling the syncytium to act in a coordinated contraction of the myocardium. There is an atrial syncytium and a ventricular syncytium that are connected by cardiac connection fibres.[4] Electrical resistance through intercalated discs is very low, thus allowing free diffusion of ions. The ease of ion movement along cardiac muscle fibers axes is such that action potentials are able to travel from one cardiac muscle cell to the next, facing only slight resistance. Each syncyntium obeys the all or none law.[5]

Intercalated discs are complex adhering structures that connect the single cardiomyocytes to an electrochemical syncytium (in contrast to the skeletal muscle, which becomes a multicellular syncytium during mammalian embryonic development). The discs are responsible mainly for force transmission during muscle contraction. Intercalated discs are described to consist of three different types of cell-cell junctions: the actin filament anchoring adherens junctions, the intermediate filament anchoring desmosomes , and gap junctions. They allow action potentials to spread between cardiac cells by permitting the passage of ions between cells, producing depolarization of the heart muscle. However, novel molecular biological and comprehensive studies unequivocally showed that intercalated discs consist for the most part of mixed-type adhering junctions named area composita (pl. areae compositae) representing an amalgamation of typical desmosomal and fascia adhaerens proteins (in contrast to various epithelia).[6][7][8] The authors discuss the high importance of these findings for the understanding of inherited cardiomyopathies (such as arrhythmogenic right ventricular cardiomyopathy).

Under light microscopy, intercalated discs appear as thin, typically dark-staining lines dividing adjacent cardiac muscle cells. The intercalated discs run perpendicular to the direction of muscle fibers. Under electron microscopy, an intercalated disc’s path appears more complex. At low magnification, this may appear as a convoluted electron dense structure overlying the location of the obscured Z-line. At high magnification, the intercalated disc’s path appears even more convoluted, with both longitudinal and transverse areas appearing in longitudinal section.[9]

In contrast to skeletal muscle, cardiac muscle requires extracellular calcium ions for contraction to occur. Like skeletal muscle, the initiation and upshoot of the action potential in ventricular muscle cells is derived from the entry of sodium ions across the sarcolemma in a regenerative process. However, an inward flux of extracellular calcium ions through L-type calcium channels sustains the depolarization of cardiac muscle cells for a longer duration. The reason for the calcium dependence is due to the mechanism of calcium-induced calcium release (CICR) from the sarcoplasmic reticulum that must occur under normal excitation-contraction (EC) coupling to cause contraction. Once the intracellular concentration of calcium increases, calcium ions bind to the protein troponin, which initiate extracellular fluid and intracellular stores, and skeletal muscle, which is only activated by calcium stored in the sarcoplasmic reticulum.

Until recently, it was commonly believed that cardiac muscle cells could not be regenerated. However, a study reported in the April 3, 2009 issue of Science contradicts that belief.[10] Olaf Bergmann and his colleagues at the Karolinska Institute in Stockholm tested samples of heart muscle from people born before 1955 who had very little cardiac muscle around their heart, many showing with disabilities from this abnormality. By using DNA samples from many hearts, the researchers estimated that a 20-year-old renews about 1% of heart muscle cells per year, and about 45 percent of the heart muscle cells of a 50-year-old were generated after he or she was born.

One way that cardiomyocyte regeneration occurs is through the division of pre-existing cardiomyocytes during the normal aging process.[11] The division process of pre-existing cardiomyocytes has also been shown to increase in areas adjacent to sites of myocardial injury. In addition, certain growth factors promote the self-renewal of endogenous cardiomyocytes and cardiac stem cells. For example, insulin-like growth factor 1, hepatocyte growth factor, and high-mobility group protein B1 increase cardiac stem cell migration to the affected area, as well as the proliferation and survival of these cells.[12] Some members of the fibroblast growth factor family also induce cell-cycle re-entry of small cardiomyocytes. Vascular endothelial growth factor also plays an important role in the recruitment of native cardiac cells to an infarct site in addition to its angiogenic effect.

Based on the natural role of stem cells in cardiomyocyte regeneration, researchers and clinicians are increasingly interested in using these cells to induce regeneration of damaged tissue. Various stem cell lineages have been shown to be able to differentiate into cardiomyocytes, including bone marrow stem cells. For example, in one study, researchers transplanted bone marrow cells, which included a population of stem cells, adjacent to an infarct site in a mouse model. Nine days after surgery, the researchers found a new band of regenerating myocardium.[13] However, this regeneration was not observed when the injected population of cells was devoid of stem cells, which strongly suggests that it was the stem cell population that contributed to the myocardium regeneration. Other clinical trials have shown that autologous bone marrow cell transplants delivered via the infarct-related artery decreases the infarct area compared to patients not given the cell therapy.[14]

Occlusion (blockage) of the coronary arteries by atherosclerosis and/or thrombosis can lead to myocardial infarction (heart attack), where part of the myocardium is injured due to ischemia (not receiving enough oxygen). This occurs because coronary arteries are functional end arteries – i.e. there is almost no overlap in the areas supplied by different arteries (anastomoses) so that if one fails, others cannot adequately perfuse the region, unlike in other tissues.

Certain viruses lead to myocarditis (inflammation of the myocardium). Cardiomyopathies are inherent diseases of the myocardium, many of which are caused by genetic mutations.

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Cardiac muscle – Wikipedia, the free encyclopedia

Injecting the Heart With Stem Cells Helps Chest Pain – ABC …

George Reed’s heart wasn’t doing so well: He’s 71, and after suffering a heart attack years earlier, Reed had undergone open heart surgery and was put on multiple medications. But nothing seemed to help the dizziness and chest pain he experienced daily.

“I’d get dizzy and just fall over — sometimes twice a day. I would run my head into the concrete. I was a bloody mess,” the Perry, Ohio, native says. Despite his doctor’s best efforts, Reed continued to experience angina, a type of chest pain that occurs when the heart doesn’t get enough oxygen-rich blood; it can be accompanied by dizziness. So when he was recommended for an experimental study that would inject his own stem cells into his damaged heart, Perry signed on. “I needed something to change,” he says.

Researchers gave Reed a drug commonly used in bone marrow transplants that stimulates the marrow to make more stem cells. Then they removed some of Reed’s blood, isolated the stem cells and injected them into and around the damaged areas of his heart.

“The goal was to grow new blood vessels with stem cells from the patient’s own body,” says Dr. Tim Henry, a co-author of the study and director of research at the Minneapolis Heart Institute Foundation.

Within a few months, Reed, along with many of the other 100 or so patients at 26 hospital centers who’d received this stem cell treatment, reported feeling better than he had in years.

“When it started kicking in, I felt like a kid. I felt good,” Reed says. He wasn’t passing out and falling down anymore.

For Jay Homstad, 49, who was part of the Minnesota branch of the study, he felt the changes most in his ability to walk and be active.

“My activity level increased tenfold. Before, I struggled with chest pain every day. My activity level was about as close to zero as you could get. Now I can participate … just in life. It may sound silly, but the best part is that in the wintertime I could go out and walk with my dog along the Red River. When you’re walking through snow that is waist deep, you can tell there’s a difference,” Homstad says.

Homstad had had about a dozen surgeries and nine stents put in before he enrolled in the study, but he still struggled with angina daily. Within a few months of the stem cell shots, he could walk farther, and his chest pain subsided and was kept at bay for nearly four years.

“These are people for whom other treatment hasn’t worked. They’re debilitated by their chest pain, but their other options are really limited, that’s why we picked them,” says Henry. If the positive results seen in this study hold up in the next phase of the study, which is set to begin enrollment in the fall, this type of cardiac stem cell injection could be added to the arsenal of weapons against angina. The upcoming phase three trial has already been approved by the Food and Drug Administration.

Shot to the Heart, Before It’s too Late

While several smaller studies have suggested that injecting stem cells into damaged heart tissue might be effective, this study, in its scope and rigor, was the first of its kind. A total of 167 patients were recruited and randomly assigned to receive a lower dose of stem cells, a higher dose or a placebo. The patients didn’t know who got what treatment, and neither did the doctors treating them.

When tracked for a year after the injection, patients who received the lower dose of stem cells could last longer during a treadmill exercise than those who had received the placebo, and they averaged seven fewer episodes of chest pain in a week. To put this in perspective, a popular drug to treat angina, Ranolazine, reduced chest pain by fewer than two episodes a week in clinical trials.

Although the goal of the stem cell shots was to grow new blood vessels, it’s impossible to tell if these stem cells were actually growing into blood vessels or if they were just triggering some other kind of healing process in the body, Henry says. Tests in animal models, however, do suggest that new blood vessels are forming, says Dr. Marco Costa, a co-author of the study and George Reed’s doctor at UH Case Medical Center in Cleveland.

For now, the only gauge of the injections is improvement in symptoms.

Despite the positive results of the study, cardiologists remain “cautiously optimistic” about stem cells as a treatment for angina.

“The number of patients is relatively small, so this trial would probably not carry much scientific weight,” says Dr. Jeff Brinker, a professor of cardiology at Johns Hopkins University. The results did justify the next, larger trial, he says, which would offer more answers as to whether this treatment is actually working the way researchers suspect.

The fact that lower doses of stem cells were puzzlingly more effective than larger ones is cause for caution, says Dr. Steve Nissen, chairman of the department of cardiovascular medicine at the Cleveland Clinic.

“The jury is still out for stem cell therapies to treat heart disease,” says Dr. Cam Paterson, a cardiologist at the University of North Carolina at Chapel Hill.

But the results so far provide cautious hope for heart patients like George Reed and Jay Homstad.

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Injecting the Heart With Stem Cells Helps Chest Pain – ABC …

Stem Cell Therapy for Heart Disease – Cleveland Clinic

Stem Cell Therapy: Helping the Body Heal Itself

Stem cells are natures own transformers. When the body is injured, stem cells travel the scene of the accident. Some come from the bone marrow, a modest number of others, from the heart itself. Additionally, theyre not all the same. There, they may help heal damaged tissue. They do this by secreting local hormones to rescue damaged heart cells and occasionally turning into heart muscle cells themselves. Stem cells do a fairly good job. But they could do better for some reason, the heart stops signaling for heart cells after only a week or so after the damage has occurred, leaving the repair job mostly undone. The partially repaired tissue becomes a burden to the heart, forcing it to work harder and less efficiently, leading to heart failure.

Initial research used a patients own stem cells, derived from the bone marrow, mainly because they were readily available and had worked in animal studies. Careful study revealed only a very modest benefit, so researchers have moved on to evaluate more promising approaches, including:

No matter what you may read, stem cell therapy for damaged hearts has yet to be proven fully safe and beneficial. It is important to know that many patients are not receiving the most current and optimal therapies available for their heart failure. If you have heart failure, and wondering about treatment options, an evaluation or a second opinion at a Center of Excellence can be worthwhile.

Randomized clinical trials evaluating these different approaches typically allow enrollment of only a few patients from each hospital, and hence what may be available at the Cleveland Clinic varies from time to time. To inquire about current trials, please call 866-289-6911 and speak to our Resource Nurses.

Cleveland Clinic is a large referral center for advanced heart disease and heart failure we offer a wide range of therapies including medications, devices and surgery. Patients will be evaluated for the treatments that best address their condition. Whether patients meet the criteria for stem cell therapy or not, they will be offered the most advanced array of treatment options.

Allogenic: from one person to another (for example: organ transplant)

Autogenic: use of one’s own tissue

Myoblasts: immature muscle cells, may be able to change into functioning heart muscle cells

Stem Cells: cells that have the ability to reproduce, generate new cells, and send signals to promote healing

Transgenic: Use of tissue from another species. (for example: some heart valves from porcine or bovine tissue)

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Stem Cell Therapy for Heart Disease – Cleveland Clinic

Heart Stem Cell Therapy | University of Utah Health Care

Keeping in tradition with the Us commitment to advance the fields of medicine and surgery, our physicians are focusing on regenerative medicine as the next frontier in treating cardiovascular disease. Researchers within the Cardiovascular Center estimate cell therapy will be FDA-approved within three years. The goal of this therapy is to give cells back to the heart in order for it to grow stronger, work harder, and function more like a younger heart. Currently, studies include the potentiality of injecting cardiac repair cells into patients hearts to improve function.

This is the first trial of its kind in the United States, providing heart patients who have limited or no other options with a viable treatment. Using some of the best imaging technology, researchers have been able to see improvements in patients within six months after injecting their own cells directly into the left ventricle of the heart during minimally invasive surgery.

To contact us, please use the contact number provided.

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Heart Stem Cell Therapy | University of Utah Health Care

Stem Cells Show Promise in Heart Failure Treatment

A new method for delivering stem cells to damaged heart muscle has shown early promise in treating severe heart failure, researchers report.

In a preliminary study, they found the tactic was safe and feasible for the 48 heart failure patients they treated. And after a year, the patients showed a modest improvement in the heart’s pumping ability, on average.

It’s not clear yet whether those improvements could be meaningful, said lead researcher Dr. Amit Patel, director of cardiovascular regenerative medicine at the University of Utah.

He said larger clinical trials are underway to see whether the approach could be an option for advanced heart failure.

Other experts stressed the bigger picture: Researchers have long studied stem cells as a potential therapy for heart failure — with limited success so far.

“There’s been a lot of promise, but not much of a clinical benefit yet,” said Dr. Lee Goldberg, who specializes in treating heart failure at the University of Pennsylvania.

Researchers are still sorting through complicated questions, including how to best get stem cells to damaged heart muscle, said Goldberg, who was not involved in the new study.

What’s “novel” in this research, he said, is the technique Patel’s team used to deliver stem cells to the heart. They took stem cells from patients’ bone marrow and infused them into the heart through a large vein called the coronary sinus.

Patel agreed that the technique is the advance.

“Most other techniques have infused stem cells through the arteries,” Patel explained. One obstacle, he said, is that people with heart failure generally have hardened, narrowed coronary arteries, and the infused stem cells “don’t always go to where they should.”

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Stem Cells Show Promise in Heart Failure Treatment

Cardiac Stem Cells (CSCs) | University of Maryland Medical …

For immediate release: September 10, 2012

Baltimore, MD –Researchers at the University of Maryland School of Medicine, who are exploring novel ways to treat serious heart problems in children, have conducted the first direct comparison of the regenerative abilities of neonatal and adult-derived human cardiac stem cells. Among their findings: cardiac stem cells (CSCs) from newborns have a three-fold ability to restore heart function to nearly normal levels compared with adult CSCs. Further, in animal models of heart attack, hearts treated with neonatal stem cells pumped stronger than those given adult cells. The study is published in the September 11, 2012, issue of Circulation.

The surprising finding is that the cells from neonates are extremely regenerative and perform better than adult stem cells, says the study’s senor author, Sunjay Kaushal, M.D., Ph.D., associate professor of surgery at the University of Maryland School of Medicine and director, pediatric cardiac surgery at the University of Maryland Medical Center. We are extremely excited and hopeful that this new cell-based therapy can play an important role in the treatment of children with congenital heart disease, many of whom don’t have other options.

Dr. Kaushal envisions cellular therapy as either a stand-alone therapy for children with heart failure or an adjunct to medical and surgical treatments. While surgery can provide structural relief for some patients with congenital heart disease and medicine can boost heart function up to two percent, he says cellular therapy may improve heart function even more dramatically. We’re looking at this type of therapy to improve heart function in children by 10, 12, or 15 percent. This will be a quantum leap in heart function improvement.

Heart failure in children, as in adults, has been on the rise in the past decade and the prognosis for patients hospitalized with heart failure remains poor. In contrast to adults, Dr. Kaushal says heart failure in children is typically the result of a constellation of problems: reduced cardiac blood flow; weakening and enlargement of the heart; and various congenital malformations. Recent research has shown that several types of cardiac stem cells can help the heart repair itself, essentially reversing the theory that a broken heart cannot be mended.

Stem cells are unspecialized cells that can become tissue- or organ-specific cells with a particular function. In a process called differentiation, cardiac stem cells may develop into rhythmically contracting muscle cells, smooth muscle cells or endothelial cells. Stem cells in the heart may also secrete growth factors conducive to forming heart muscle and keeping the muscle from dying.

To conduct the study, researchers obtained a small amount of heart tissue during normal cardiac surgery from 43 neonates and 13 adults. The cells were expanded in a growth medium yielding millions of cells. The researchers developed a consistent way to isolate and grow neonatal stem cells from as little as 20 milligrams of heart tissue. Adult and neonate stem cell activity was observed both in the laboratory and in animal models. In addition, the animal models were compared to controls that were not given the stem cells.

Dr. Kaushal says it is not clear why the neonatal stem cells performed so well. One explanation hinges on sheer numbers: there are many more stem cells in a baby’s heart than in the adult heart. Another explanation: neonate-derived cells release more growth factors that trigger blood vessel development and/or preservation than adult cells.

This research provides an important link in our quest to understand how stem cells function and how they can best be applied to cure disease and correct medical deficiencies, says E. Albert Reece, M.D., Ph.D., M.B.A., vice president for medical affairs, University of Maryland; the John Z. and Akiko K. Bowers Distinguished Professor; and dean, University of Maryland School of Medicine. Sometimes simple science is the best science. In this case, a basic, comparative study has revealed in stark terms the powerful regenerative qualities of neonatal cardiac stem cells, heretofore unknown.

Insights gained through this research may provide new treatment options for a life-threatening congenital heart syndrome called hypoplastic left heart syndrome (HLHS). Dr. Kaushal and his team will soon begin the first clinical trial in the United States to determine whether the damage to hearts of babies with HLHS can be reversed with stem cell therapy. HLHS limits the heart’s ability to pump blood from the left side of the heart to the body. Current treatment options include either a heart transplant or a series of reconstructive surgical procedures. Nevertheless, only 50-60 percent of children who have had those procedures survive to age five.

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Cardiac Stem Cells (CSCs) | University of Maryland Medical …

Cardiovascular Stem Cell Therapy

Stem Cell Clinical Research & Deployment Cardiovascular & Pulmonary Conditions

The Manhattan Regenerative Medicine Medical Group is proud to be part of the only Institutional Review Board (IRB)-based stem cell treatment network in the United States that utilizes fat-transfer surgical technology. The Manhattan Regenerative Medicine Medical Group offers IRB approved protocols and investigational use ofAdult Autologous Adipose-derived Stem Cells (ADSCs) for clinical research and deployment for numerous Cardiovascular and Pulmonary disorders, inclusive of:

Cardiovascular conditions include medical problems involving the heart and vascular system (the arterial and venous blood vessels). The most common cardiovascular condition is atherosclerotic coronary artery disease (ASCVD), which especially affects the coronary arteries and is the leading cause of heart attacks and death worldwide; and Congestive Heart Failure (CHF).

Other common cardiovascular conditions involve the cardiac muscle (CHF), cardiac valves, and heart rhythm. Many patients are typically treated with a multitude of medications; many patients require surgical interventions such as coronary angioplasty, coronary artery bypass, or other surgeries. Often patients, despite maximum therapy with medications and surgery, continue to suffer pain, discomfort, disability and have marked restrictions in their normal daily living activities.

The Manhattan Regenerative Medicine Medical Group is proud to be part of the only Institutional Review Board (IRB)-based stem cell treatment network in the United States that utilizes fat-transfer surgical technology. We have an array of ongoing IRB-approved protocols, andwe provide care for patients with a wide variety of disorders that may be treated with adult stem cell-based regenerative therapy.

The Manhattan Regenerative Medicine Medical Group offers IRB approved protocols and investigational use of Autologous Adult Adipose Derived Stem Cells (ADSCs) for clinical research and deployment for numerous cardiovascular conditions. These ADSCs cells are derived from fat an exceptionally abundant source of stem cells that has been removed during our mini-liposuction office procedure. The source of the regenerative stem cells actually comes from stromal vascular fraction (SVF) a protein rich segment from processed adipose tissue. SVF contains a mononuclear cell line (predominantly autologous mesenchymal stem cells), macrophage cells, endothelial cells, red blood cells, and important growth factors that facilitate the stem cell process and promote their activity. Our technology allows us to isolate high numbers of viable cells that we can deploy during the same surgical setting.

The SVF and stem cells are then deployed back into the patients body via injection or IV infusion on an outpatient basis; the total procedure takes less than two hours; and only local anesthesia is used. Not all cardiovascular problems respond to stem cell therapy, and each patient must be assessed individually to determine the potential for optimal results from this regenerative medicine process.

The Manhattan Regenerative Medicine Medical Group is committed not only to providing a high degree of quality care for our patients with cardiovascular problems but we are also highly committed to clinical stem cell research and the advancement of regenerative medicine. At the Miami Stem Cell Treatment Center we exploit anti-inflammatory, immuno-modulatory and regenerative properties of adult stem cells to mitigate cardiovascular conditions which are otherwise lethal to our bodies.

Myocardial infarction (heart attack) is responsible for significant cardiac muscle destruction and impairment due to ischemia (lack of blood flow). This can lead to further or recurrent restriction of blood flow thereby causing re-current infarct and pain on exertion (or even rest) known as chronic angina. Chronic angina causes restriction of daily activities of everyday living and is plagued with chest pain, chest pressure, and depression. This problem is caused most commonly by coronary artery disease which is very common in the United States and associated with significant morbidity and mortality.

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Cardiovascular Stem Cell Therapy

Stem Cells for Heart Cell Therapies – National Center for …


Myocardial infarctioninduced heart failure is a prevailing cause of death in the United States and most developed countries. The cardiac tissue has extremely limited regenerative potential, and heart transplantation for reconstituting the function of damaged heart is severely hindered mainly due to the scarcity of donor organs. To that end, stem cells with their extensive proliferative capacity and their ability to differentiate toward functional cardiomyocytes may serve as a renewable cellular source for repairing the damaged myocardium. Here, we review recent studies regarding the cardiogenic potential of adult progenitor cells and embryonic stem cells. Although large strides have been made toward the engineering of cardiac tissues using stem cells, important issues remain to be addressed to enable the translation of such technologies to the clinical setting.

Heart disease is a significant cause of morbidity and mortality worldwide. In the United States, heart failure is ranked number one as a cause of death, affecting over 5 million people and with more than 500,000 new cases diagnosed each year.1 The health care expenditures associated with heart failure were $26.7 billion in 2004 and are estimated to $33.2 billion in 2007. Although significant progress has been made in mechanical devices and pharmacological interventions, more than half of the patients with heart failure die within 5 years of initial diagnosis. Wide application of heart transplantation is severely hindered by the limited availability of donor organs. To this end, cardiac cell therapy may be an appealing alternative to current treatments for heart failure.

Recent investigations focusing on engineering cells and tissues to repair or regenerate damaged hearts in animal models and in clinical trials have yielded promising results. Considering the limited regenerative capacity of the heart muscle, renewable sources of cardiomyocytes are highly sought. Cells suitable for myocardial engineering should be nonimmunogenic, should be easy to expand to large quantities, and should differentiate into mature, fully functional cardiomyocytes capable of integrating to the host tissue. Adult progenitor cells (APCs) and embryonic stem cells (ESCs) have extensive proliferative potential and can adopt different cell fates, including that of heart cells. The recent advances in the fields of stem cell biology and heart tissue engineering have intensified efforts toward the development of regenerative cardiac therapies. In this article, we review findings pertaining to the cardiogenic potential of major APC populations and of ESCs (). We also discuss significant challenges in the way of realizing stem cellbased therapies aiming to reconstitute the normal function of heart.

Potential sources of stem/progenitor cells for cardiac repair. ESCs derived from the inner cell mass of a blastocyst can be manipulated ex vivo to differentiate toward heart cells. APCs residing in various tissues such as the BM and skeletal muscle may …

Bone marrow (BM) is a heterogeneous tissue comprising of multiple cell types, including minute fractions of mesenchymal stem cells (MSCs; 0.0010.01% of total cells2) and hematopoietic stem cells (HSCs; 0.71.5cells/108 nucleated marrow cells3). The heterogeneity of BM makes challenging the identification of a subpopulation of cells capable of cardiogenesis, and studies of BM celltocardiac cell transdifferentiation should be examined through this prism.

The notion that BM-derived cells may contribute to the regeneration of the heart was first illustrated when dystrophic (mdx) female mice received BM cells from male wild-type mice.4 More than 2 months after the transplantation, tissues of the recipient mice were histologically examined for the presence of Y-chromosome+ donor cells. Besides the skeletal muscle, donor cells were identified in the cardiac region, suggesting that circulating BM cells contribute to the regeneration of cardiomyocytes.

Further supporting evidence was provided by Jackson et al.5 in studies using a side population (SP) of cells characterized by their intrinsic capacity to efflux Hoechst 33342 dye through the ATP-binding Bcrp1/ABCG2 transporter. The cells were isolated from the BM fraction of HSCs of Rosa26 mice constitutively expressing the -galactosidase reporter gene (LacZ). After SP cells were injected into mice with coronary occlusioninduced ischemia, cells coexpressing LacZ and cardiac -actinin were identified around the infarct region with a frequency of 0.02%. Endothelial engraftment was more prevalent (3.3%). The observed improvement in myocardial function may thus be attributed to the potential of BM cells to give rise to a rather endothelial progeny. This may be a parallel to cardiovascular progenitors from differentiating ESCs giving rise to cardiomyocytes, and endothelial and vascular smooth muscle lineages.6,7

Orlic et al.8 also reported the regeneration of infarcted myocardium after transplantation of lineage-negative (LIN)/C-KIT+ BM cells from transgenic mice constitutively expressing enhanced green fluorescent protein (eGFP). Cells were injected in the contracting wall close to the infarct area. Nine days after transplantation, an impressive 68% of the infarct was occupied by newly formed myocardium with eGFP+ cells displaying cardiomyocyte markers such as troponin, MEF2, NKX2.5, cardiac myosin, GATA-4, and -sarcomeric actin. Similar outcomes were reported by the same group9 when mouse C-KIT+ (but not screened for LIN) BM cells were transplanted.

Although these findings led to the conclusion that BM cells can repopulate a damaged heart, work by other investigators has casted doubt on this assertion. Balsam et al.10 noted that mice with infarcts receiving BM LIN/C-KIT+, C-KIT-enriched or THY1.1low/LIN/stem cell antigen-1 (SCA-1+) cells exhibited improved ventricular function. However, donor cells expressed granulocyte but not heart cell markers 1 month after injection. In another study,11 HSCs carrying a nuclear-localized LacZ gene flanked by the cardiac -myosin heavy chain promoter were delivered into the periinfarct zone of mice 5h after coronary artery occlusion. One to 4 weeks later, LacZ+ cells were absent in heart tissue sections from 117 mice that received HSCs. Similarly, no eGFP+ cells were detected in the infarcted hearts of mice infused with BM cells constitutively expressing eGFP. Finally, Nygren et al.12 in similar transplantation experiments observed only blood cells (mainly leukocytes) originating from BM HSCs in the infarcted myocardium without evidence of transdifferentiation of donor cells to cardiomyocytes.

Continued here:
Stem Cells for Heart Cell Therapies – National Center for …

cardiovascular disease :: Cardiac stem cells |

Cardiac stem cells, which have the ability to differentiate (specialize) into mature heart cells and therefore could be used to repair damaged or diseased heart tissue, have garnered significant interest in the development of treatments for heart disease and cardiac defects. Cardiac stem cells can be derived from mature cardiomyocytes through the process of dedifferentiation, in which mature heart cells are stimulated to revert to a stem cell state. The stem cells can then be stimulated to redifferentiate into myocytes or endothelial cells. This approach enables millions of cardiac stem cells to be produced in the laboratory.

In 2009 a team of doctors at Cedars-Sinai Heart Institute in Los Angeles, California, reported the first attempted use of cardiac stem cell transplantation to repair damaged heart tissue. The team removed a small section of tissue from the heart of a patient who had suffered a heart attack, and the tissue was cultured in a laboratory. Cells that had been stimulated to dedifferentiate were then used to produce millions of cardiac stem cells, which were later reinfused directly into the heart of the patient through a catheter in a coronary artery. A similar approach was used in a subsequent clinical trial reported in 2011; this trial involved 14 patients suffering from heart failure who were scheduled to undergo cardiac bypass surgery. More than three months after treatment, there was slight but detectable improvement over cardiac bypass surgery alone in left ventricle ejection fraction (the percentage of the left ventricular volume of blood that is ejected from the heart with each ventricular contraction).

Stem cells derived from bone marrow, the collection of which is considerably less invasive than heart surgery, are also of interest in the development of regenerative heart therapies. The collection and reinfusion into the heart of bone marrow-derived stem cells within hours of a heart attack may limit the amount of damage incurred by the muscle.

There are many types of arterial diseases. Some are generalized and affect arteries throughout the body, though often there is variation in the degree they are affected. Others are localized. These diseases are frequently divided into those that result in arterial occlusion (blockage) and those that are nonocclusive in their manifestations.

Atherosclerosis, the most common form of arteriosclerosis, is a disease found in large and medium-sized arteries. It is characterized by the deposition of fatty substances, such as cholesterol, in the innermost layer of the artery (the intima). As the fat deposits become larger, inflammatory white blood cells called macrophages try to remove the lipid deposition from the wall of the artery. However, lipid-filled macrophages, called foam cells, grow increasingly inefficient at lipid removal and undergo cell death, accumulating at the site of lipid deposition. As these focal lipid deposits grow larger, they become known as atherosclerotic plaques and may be of variable distribution and thickness. Under most conditions the incorporation of cholesterol-rich lipoproteins is the predominant factor in determining whether or not plaques progressively develop. The endothelial injury that results (or that may occur independently) leads to the involvement of two cell types that circulate in the bloodplatelets and monocytes (a type of white blood cell). Platelets adhere to areas of endothelial injury and to themselves. They trap fibrinogen, a plasma protein, leading to the development of platelet-fibrinogen thrombi. Platelets deposit pro-inflammatory factors, called chemokines, on the vessel walls. Observations of infants and young children suggest that atherosclerosis can begin at an early age as streaks of fat deposition (fatty streaks).

Atherosclerotic lesions are frequently found in the aorta and in large aortic branches. They are also prevalent in the coronary arteries, where they cause coronary artery disease. The distribution of lesions is concentrated in points where arterial flow gives rise to abnormal shear stress or turbulence, such as at branch points in vessels. In general the distribution in most arteries tends to be closer to the origin of the vessel, with lesions found less frequently in more distal sites. Hemodynamic forces are particularly important in the system of coronary arteries, where there are unique pressure relationships. The flow of blood through the coronary system into the heart muscle takes place during the phase of ventricular relaxation (diastole) and virtually not at all during the phase of ventricular contraction (systole). During systole the external pressure on coronary arterioles is such that blood cannot flow forward. The external pressure exerted by the contracting myocardium on coronary arteries also influences the distribution of atheromatous obstructive lesions.

Excerpt from:
cardiovascular disease :: Cardiac stem cells |

cardiovascular disease :: Cardiac stem cells |

Cardiac stem cells, which have the ability to differentiate (specialize) into mature heart cells and therefore could be used to repair damaged or diseased heart tissue, have garnered significant interest in the development of treatments for heart disease and cardiac defects. Cardiac stem cells can be derived from mature cardiomyocytes through the process of dedifferentiation, in which mature heart cells are stimulated to revert to a stem cell state. The stem cells can then be stimulated to redifferentiate into myocytes or endothelial cells. This approach enables millions of cardiac stem cells to be produced in the laboratory.

In 2009 a team of doctors at Cedars-Sinai Heart Institute in Los Angeles, California, reported the first attempted use of cardiac stem cell transplantation to repair damaged heart tissue. The team removed a small section of tissue from the heart of a patient who had suffered a heart attack, and the tissue was cultured in a laboratory. Cells that had been stimulated to dedifferentiate were then used to produce millions of cardiac stem cells, which were later reinfused directly into the heart of the patient through a catheter in a coronary artery. A similar approach was used in a subsequent clinical trial reported in 2011; this trial involved 14 patients suffering from heart failure who were scheduled to undergo cardiac bypass surgery. More than three months after treatment, there was slight but detectable improvement over cardiac bypass surgery alone in left ventricle ejection fraction (the percentage of the left ventricular volume of blood that is ejected from the heart with each ventricular contraction).

Stem cells derived from bone marrow, the collection of which is considerably less invasive than heart surgery, are also of interest in the development of regenerative heart therapies. The collection and reinfusion into the heart of bone marrow-derived stem cells within hours of a heart attack may limit the amount of damage incurred by the muscle.

There are many types of arterial diseases. Some are generalized and affect arteries throughout the body, though often there is variation in the degree they are affected. Others are localized. These diseases are frequently divided into those that result in arterial occlusion (blockage) and those that are nonocclusive in their manifestations.

Atherosclerosis, the most common form of arteriosclerosis, is a disease found in large and medium-sized arteries. It is characterized by the deposition of fatty substances, such as cholesterol, in the innermost layer of the artery (the intima). As the fat deposits become larger, inflammatory white blood cells called macrophages try to remove the lipid deposition from the wall of the artery. However, lipid-filled macrophages, called foam cells, grow increasingly inefficient at lipid removal and undergo cell death, accumulating at the site of lipid deposition. As these focal lipid deposits grow larger, they become known as atherosclerotic plaques and may be of variable distribution and thickness. Under most conditions the incorporation of cholesterol-rich lipoproteins is the predominant factor in determining whether or not plaques progressively develop. The endothelial injury that results (or that may occur independently) leads to the involvement of two cell types that circulate in the bloodplatelets and monocytes (a type of white blood cell). Platelets adhere to areas of endothelial injury and to themselves. They trap fibrinogen, a plasma protein, leading to the development of platelet-fibrinogen thrombi. Platelets deposit pro-inflammatory factors, called chemokines, on the vessel walls. Observations of infants and young children suggest that atherosclerosis can begin at an early age as streaks of fat deposition (fatty streaks).

Atherosclerotic lesions are frequently found in the aorta and in large aortic branches. They are also prevalent in the coronary arteries, where they cause coronary artery disease. The distribution of lesions is concentrated in points where arterial flow gives rise to abnormal shear stress or turbulence, such as at branch points in vessels. In general the distribution in most arteries tends to be closer to the origin of the vessel, with lesions found less frequently in more distal sites. Hemodynamic forces are particularly important in the system of coronary arteries, where there are unique pressure relationships. The flow of blood through the coronary system into the heart muscle takes place during the phase of ventricular relaxation (diastole) and virtually not at all during the phase of ventricular contraction (systole). During systole the external pressure on coronary arterioles is such that blood cannot flow forward. The external pressure exerted by the contracting myocardium on coronary arteries also influences the distribution of atheromatous obstructive lesions.

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cardiovascular disease :: Cardiac stem cells |

Stem Cell Research at Johns Hopkins Medicine: Repairing …

By the time Bill Beatty made it to the Emergency Department in Howard County, he was already several hours into a major heart attack. His physicians performed a series of emergency treatments that included an intra-aortic balloon pump, but the 57-year-old engineers blood pressure remained dangerously low. The cardiologist called for a helicopter to transfer him to Johns Hopkins.

It was fortuitous timing: Beatty was an ideal candidate for a clinical trial and soon received an infusion of stem cells derived from his own heart tissue, making him the second patient in the world to undergo the procedure.

Of all the attempts to harness the promise of stem cell therapy, few have garnered more hope than the bid to repair damaged hearts. Previous trials with other stem cells have shown conflicting results. But this new trial, conducted jointly with cardiologist Eduardo Marbn at Cedars-Sinai Medical Center in Los Angeles, is the first time stem cells come from the patients own heart.

Cardiologist Jeffrey Brinker, M.D., a member of the Hopkins team, thinks the new protocol could be a game-changer. That’s based partly on recent animal studies in which scientists at both institutions isolated stem cells from the injured animals hearts and infused them back into the hearts of those same animals. The stem cells formed new heart muscle and blood vessel cells. In fact, says Brinker, the new cells have a pre-determined cardiac fate. Even in the culture dish, he says, theyre a beating mass of cells.

Whats more, according to Gary Gerstenblith, M.D., J.D., the animals in these studies showed a significant decrease in relative infarct size, shrinking by about 25 percent. Based on those and earlier findings, investigators were cleared by the FDA and Hopkins Institutional Review Board to move forward with a human trial.

In Beattys case, Hopkins heart failure chief Stuart Russell, M.D., extracted a small sample of heart tissue and shipped it to Cedars Sinai, where stem cells were isolated, cultured and expanded to large numbers. Hopkins cardiologist Peter Johnston, M.D., says cardiac tissue is robust in its ability to generate stem cells, typically yielding several million transplantable cells within two months.

When ready, the cells were returned to Baltimore and infused back into Beatty through a balloon catheter placed in his damaged artery, ensuring target-specific delivery. Then the watching and waiting began. For the Hopkins team, Beattys infarct size will be tracked by imaging chief Joao Lima, M.D., M.B.A.,and his associates using MRI scans.

Now back home and still struggling with episodes of compromised stamina and shortness of breath, Beatty says his Hopkins cardiologists were fairly cautious in their prognosis, but hell be happy for any improvement.

Nurse coordinator Elayne Breton says Beatty is scheduled for follow-up visits at six months and 12 months, when they hope to find an improvement in his hearts function. But at least one member of the Hopkins team was willing acknowledge a certain optimism. The excitement here, says Brinker, is huge.

The trial is expected to be completed within one to two years.

Originally posted here:
Stem Cell Research at Johns Hopkins Medicine: Repairing …

Stem cell technology could lead to ailing heart mending …

Tsai et al./Stem Cell Reports 2015

Weill Cornell investigators have discovered how to generate large numbers of rare cells in the network that pushes the heart’s chambers to consistently contract. In this image, investigators stained these cells, generated from embryonic stem cells, to reveal cell-specific genes (green and red, indicated by arrows). The blue represents stained cell nuclei.

For the first time, scientists can efficiently generate large numbers of rare cells in the network that pushes the heart’s chambers to consistently contract. The technique, published May 28 in Stem Cell Reports, could be a first step toward using a person’s own cells to repair an irregular heartbeat known as cardiac arrhythmia.

This study, while done using mouse cells, will now allow us to develop human heart cells and test their function in repairing damaged hearts, said the study’s senior author, Dr. Todd Evans, vice chair for research and the Peter I. Pressman Professor in the Department of Surgery at Weill Cornell Medical College.

The human heart beats billions of times during a lifetime, so it’s not surprising that development of irregular heartbeats can lead to a variety of cardiac diseases, Evans says. But treatments for these disorders are costly, and often ineffective.

The government pays more than $3 billion each year for cardiac arrhythmia-related diseases. Despite this enormous expense, the treatments we have available are inadequate, Evans said. For example, artificial pacemakers are often used, but these can fail, and are particularly challenging therapies for children.

One solution is to coax a patient’s own cells to generate the specific kinds of cells in the cardiac conduction system (CCS) that maintain a regular heartbeat.

We can imagine someday using these cells, for example, to create patches that can replace defective conduction fibers. Of course this is still a long way off, as we would need to study how to coax them into integrating properly with the rest of the CCS, Evans said. But previously, we did not even have the capacity to generate the cells, and now we can do so in a manner that is scalable, so that such preclinical research is now feasible.

Evans worked with Dr. Shuibing Chen, an expert in stem cell and chemical biology, and Dr. Su-Yi Tsai, a postdoctoral fellow and the study’s lead investigator. Other key contributors were from the laboratory of Dr. Glenn Fishman, who specializes in cardiac physiology at New York University.

Their first goal was to increase the efficiency of coaxing mouse embryonic stem cells to become CCS cells. They created mouse stem cells that can express a CCS marker gene that can be quantified. This allows them to measure how many embryonic cells morph into CCS cells.

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Stem cell technology could lead to ailing heart mending …

6. Mending a Broken Heart: Stem Cells and Cardiac Repair …

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.

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6. Mending a Broken Heart: Stem Cells and Cardiac Repair …

Bone-Derived Stem Cells Repair the Heart After Myocardial …

Rationale: Autologous bone marrowderived or cardiac-derived stem cell therapy for heart disease has demonstrated safety and efficacy in clinical trials, but functional improvements have been limited. Finding the optimal stem cell type best suited for cardiac regeneration is the key toward improving clinical outcomes.

Objective: To determine the mechanism by which novel bone-derived stem cells support the injured heart.

Methods and Results: Cortical bonederived stem cells (CBSCs) and cardiac-derived stem cells were isolated from enhanced green fluorescent protein (EGFP+) transgenic mice and were shown to express c-kit and Sca-1 as well as 8 paracrine factors involved in cardioprotection, angiogenesis, and stem cell function. Wild-type C57BL/6 mice underwent sham operation (n=21) or myocardial infarction with injection of CBSCs (n=67), cardiac-derived stem cells (n=36), or saline (n=60). Cardiac function was monitored using echocardiography. Only 2/8 paracrine factors were detected in EGFP+ CBSCs in vivo (basic fibroblast growth factor and vascular endothelial growth factor), and this expression was associated with increased neovascularization of the infarct border zone. CBSC therapy improved survival, cardiac function, regional strain, attenuated remodeling, and decreased infarct size relative to cardiac-derived stem cells or saline-treated myocardial infarction controls. By 6 weeks, EGFP+ cardiomyocytes, vascular smooth muscle, and endothelial cells could be identified in CBSC-treated, but not in cardiac-derived stem cellstreated, animals. EGFP+ CBSC-derived isolated myocytes were smaller and more frequently mononucleated, but were functionally indistinguishable from EGFP myocytes.

Conclusions: CBSCs improve survival, cardiac function, and attenuate remodeling through the following 2 mechanisms: (1) secretion of proangiogenic factors that stimulate endogenous neovascularization, and (2) differentiation into functional adult myocytes and vascular cells.

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Bone-Derived Stem Cells Repair the Heart After Myocardial …

Heart Disease – Stemaid : Embryonic Stem-cells

Clara’s Story

Clara had a severe heart attack in 2004. Before contacting us she had received adult stem cells from a company in Thailand – a process requiring at least a one week stay.

When she contacted Stemaid, she had just had an echocardiogram showing that her overall left ventricular ejection fraction was estimated to be 30 to 35%. She opted to receive one injection of 5 million Embryonic Stem Cells by Stemaid in November 2010. She arrived at 1pm and was done by 3pm the same day.

We received the following email from her in April 2011: I had an EKO last week and rate is 44%, up from the 33/35% it was before I received Stemaid’s stem cells! . Are the stem cells still available and still as good?

The heart contains a small amount of stem cells, the cardiac stem cells, that are produced when there is a need for production of more heart cells or for an active replacement of damaged ones. These cardiac cells are produced in high quantity for about one week following an infarction, actively repairing the damaged areas of the heart.

However this high production stops after a week and the repair stops as well.

Initial studies showed that by introducing embryonic stem cells, the heart starts to repair again within minutes of their injection. More recent studies showed that the injection of embryonic stem cells actually triggers the production of cardiac stem cells for one week. Another week of active repair is offered each time that one receives embryonic stem cells.

If you have suffered from an infarction, we suggest a minimum of 3 injections of esc over the course of 3 weeks to get significant repair.

Some of the patients who have received Stemaid Embryonic Stem-Cells have agreed to be mentioned on our website so that we may illustrate the benefits of them.

Heart Disease – Stemaid : Embryonic Stem-cells

Stem cell therapy : When will it help the heart? | The Why …

Stem cells: When will they heal the heart?

Its been 15 years since a University of Wisconsin-Madison researcher isolated embryonic stem cells the do-anything cells that appear in early development. Its been six years since adult human cells were transformed into the related induced pluripotent stem cells.


Some day, stem cell therapy could restore cells, save hearts, and avoid the need for some heart transplants, such as this one. This heart is ready for its new home.

And yet the early hope to grow spare parts turning stem cells into specialized cells for repairing a failing brain, pancreas or heart, remains mostly promise rather than reality.

Researchers have since found how to transform stem cells into a wide variety of body cells, including heart muscle cells, or cardiomyocytes. But the holy Grail tissue supplementation or replacement remains tantalizingly out of reach.

Last week, Why Files attended a symposium on treating cardiovascular disease with stem cells, at the BioPharmaceutical Technology Center Institute near Madison, Wis. We found the picture unexpectedly complicated: as multiple kinds of stem cells are grown and delivered in a bewildering variety of ways to treat a catalog of conditions.

So far, stem cells have not been approved to treat any heart disease in the United States.

Still, the need remains clear. Disorders of the heart and blood vessels, which deliver oxygen and nutrients to the body, continue to kill. Today, one of every 2.6 Americans will die of some cause related to their heart, writes Columbia University Medical Center.

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Stem cell therapy : When will it help the heart? | The Why …

9. Can Stem Cells Repair a Damaged Heart? [Stem Cell …

Heart attacks and congestive heart failure remain among the Nation’s most prominent health challenges despite many breakthroughs in cardiovascular medicine. In fact, despite successful approaches to prevent or limit cardiovascular disease, the restoration of function to the damaged heart remains a formidable challenge. Recent research is providing early evidence that adult and embryonic stem cells may be able to replace damaged heart muscle cells and establish new blood vessels to supply them. Discussed here are some of the recent discoveries that feature stem cell replacement and muscle regeneration strategies for repairing the damaged heart.

For those suffering from common, but deadly, heart diseases, stem cell biology represents a new medical frontier. Researchers are working toward using stem cells to replace damaged heart cells and literally restore cardiac function.

Today in the United States, congestive heart failurethe ineffective pumping of the heart caused by the loss or dysfunction of heart muscle cellsafflicts 4.8 million people, with 400,000 new cases each year. One of the major contributors to the development of this condition is a heart attack, known medically as a myocardial infarction, which occurs in nearly 1.1 million Americans each year. It is easy to recognize that impairments of the heart and circulatory system represent a major cause of death and disability in the United States [5].

What leads to these devastating effects? The destruction of heart muscle cells, known as cardiomyocytes, can be the result of hypertension, chronic insufficiency in the blood supply to the heart muscle caused by coronary artery disease, or a heart attack, the sudden closing of a blood vessel supplying oxygen to the heart. Despite advances in surgical procedures, mechanical assistance devices, drug therapy, and organ transplantation, more than half of patients with congestive heart failure die within five years of initial diagnosis. Research has shown that therapies such as clot-busting medications can reestablish blood flow to the damaged regions of the heart and limit the death of cardiomyocytes. Researchers are now exploring ways to save additional lives by using replacement cells for dead or impaired cells so that the weakened heart muscle can regain its pumping power.

How might stem cells play a part in repairing the heart? To answer this question, researchers are building their knowledge base about how stem cells are directed to become specialized cells. One important type of cell that can be developed is the cardiomyocyte, the heart muscle cell that contracts to eject the blood out of the heart’s main pumping chamber (the ventricle). Two other cell types are important to a properly functioning heart are the vascular endothelial cell, which forms the inner lining of new blood vessels, and the smooth muscle cell, which forms the wall of blood vessels. The heart has a large demand for blood flow, and these specialized cells are important for developing a new network of arteries to bring nutrients and oxygen to the cardiomyocytes after a heart has been damaged. The potential capability of both embryonic and adult stem cells to develop into these cells types in the damaged heart is now being explored as part of a strategy to restore heart function to people who have had heart attacks or have congestive heart failure. It is important that work with stem cells is not confused with recent reports that human cardiac myocytes may undergo cell division after myocardial infarction [1]. This work suggests that injured heart cells can shift from a quiescent state into active cell division. This is not different from the ability of a host of other cells in the body that begin to divide after injury. There is still no evidence that there are true stem cells in the heart which can proliferate and differentiate.

Researchers now know that under highly specific growth conditions in laboratory culture dishes, stem cells can be coaxed into developing as new cardiomyocytes and vascular endothelial cells. Scientists are interested in exploiting this ability to provide replacement tissue for the damaged heart. This approach has immense advantages over heart transplant, particularly in light of the paucity of donor hearts available to meet current transplantation needs.

What is the evidence that such an approach to restoring cardiac function might work? In the research laboratory, investigators often use a mouse or rat model of a heart attack to study new therapies (see Figure 9.1. Rodent Model of Myocardial Infarction). To create a heart attack in a mouse or rat, a ligature is placed around a major blood vessel serving the heart muscle, thereby depriving the cardiomyocytes of their oxygen and nutrient supplies. During the past year, researchers using such models have made several key discoveries that kindled interest in the application of adult stem cells to heart muscle repair in animal models of heart disease.

Figure 9.1. Rodent Model of Myocardial Infarction.

( 2001 Terese Winslow, Lydia Kibiuk)

Recently, Orlic and colleagues [9] reported on an experimental application of hematopoietic stem cells for the regeneration of the tissues in the heart. In this study, a heart attack was induced in mice by tying off a major blood vessel, the left main coronary artery. Through the identification of unique cellular surface markers, the investigators then isolated a select group of adult primitive bone marrow cells with a high capacity to develop into cells of multiple types. When injected into the damaged wall of the ventricle, these cells led to the formation of new cardiomyocytes, vascular endothelium, and smooth muscle cells, thus generating de novo myocardium, including coronary arteries, arterioles, and capillaries. The newly formed myocardium occupied 68 percent of the damaged portion of the ventricle nine days after the bone marrow cells were transplanted, in effect replacing the dead myocardium with living, functioning tissue. The researchers found that mice that received the transplanted cells survived in greater numbers than mice with heart attacks that did not receive the mouse stem cells. Follow-up experiments are now being conducted to extend the posttransplantation analysis time to determine the longer-range effects of such therapy [8]. The partial repair of the damaged heart muscle suggests that the transplanted mouse hematopoietic stem cells responded to signals in the environment near the injured myocardium. The
cells migrated to the damaged region of the ventricle, where they multiplied and became “specialized” cells that appeared to be cardiomyocytes.

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9. Can Stem Cells Repair a Damaged Heart? [Stem Cell …

Repairing the heart with stem cells – Harvard Health

Could this experimental treatment reverse damage caused by a heart attack?

The heart muscle relies on a steady flow of oxygen-rich blood to nourish it and keep it pumping. During a heart attack, that blood flow is interrupted by a blockage in an artery. Without blood, the area of heart fed by the affected artery begins to die and scar tissue forms in the area. Over time, this damage can lead to heart failure, especially when one heart attack comes after another.

Though the heart is a tough organ, the damaged portions become unable to pump blood as efficiently as they once could. People who have had a heart attack therefore may face a lifetime of maintenance therapymedications and other treatments aimed at preventing another heart attack and helping the heart work more efficiently.

A new treatment using stem cellswhich have the potential to grow into a variety of heart cell typescould potentially repair and regenerate damaged heart tissue. In a study published last February in The Lancet, researchers treated 17 heart attack patients with an infusion of stem cells taken from their own hearts. A year after the procedure, the amount of scar tissue had shrunk by about 50%.

These results sound dramatic, but are they an indication that we’re getting close to perfecting this therapy? “This is a field where, depending on which investigator you ask, you can get incredibly different answers,” says Dr. Richard Lee, professor of medicine at Harvard Medical School and a leading expert on stem cell therapy.

“The field is young. Some studies show only modest or no improvement in heart function, but others have shown dramatically improved function,” he says. “We’re waiting to see if other doctors can also achieve really good results in other patients.”

Studies are producing such varied outcomes in part because researchers are taking different approaches to harvesting and using stem cells. Some stem cells are taken from the bone marrow of donors, others from the patient’s own heart. It’s not clear which approach is the most promising.

Several different types of approaches are being used to repair damaged heart muscle with stem cells. The stem cells, which are often taken from bone marrow, may be inserted into the heart using a catheter. Once in place, stem cells help regenerate damaged heart tissue.

Like any other therapy, injecting stem cells into the heart can fail or cause side effects. If the stem cells are taken from an unrelated donor, the body’s immune system may reject them. And if the injected cells can’t communicate with the heart’s finely tuned electrical system, they may produce dangerous heart rhythms (arrhythmias). So far, side effects haven’t been a major issue, though, and that has encouraged investigators to push onward.

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Repairing the heart with stem cells – Harvard Health