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Adult stem cell – Wikipedia

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Adult stem cells are undifferentiated cells, found throughout the body after development, that multiply by cell division to replenish dying cells and regenerate damaged tissues. Also known as somatic stem cells (from Greek , meaning of the body), they can be found in juvenile as well as adult animals and humans, unlike embryonic stem cells.

Scientific interest in adult stem cells is centered on their ability to divide or self-renew indefinitely, and generate all the cell types of the organ from which they originate, potentially regenerating the entire organ from a few cells.[1] Unlike for embryonic stem cells, the use of human adult stem cells in research and therapy is not considered to be controversial, as they are derived from adult tissue samples rather than human embryos designated for scientific research. They have mainly been studied in humans and model organisms such as mice and rats.

A stem cell possesses two properties:

Hematopoietic stem cells are found in the bone marrow and umbilical cord blood and give rise to all the blood cell types.[3]

Mammary stem cells provide the source of cells for growth of the mammary gland during puberty and gestation and play an important role in carcinogenesis of the breast.[4] Mammary stem cells have been isolated from human and mouse tissue as well as from cell lines derived from the mammary gland. Single such cells can give rise to both the luminal and myoepithelial cell types of the gland, and have been shown to have the ability to regenerate the entire organ in mice.[4]

Intestinal stem cells divide continuously throughout life and use a complex genetic program to produce the cells lining the surface of the small and large intestines.[5] Intestinal stem cells reside near the base of the stem cell niche, called the crypts of Lieberkuhn. Intestinal stem cells are probably the source of most cancers of the small intestine and colon.[6]

Mesenchymal stem cells (MSCs) are of stromal origin and may differentiate into a variety of tissues. MSCs have been isolated from placenta, adipose tissue, lung, bone marrow and blood, Wharton's jelly from the umbilical cord,[7] and teeth (perivascular niche of dental pulp and periodontal ligament).[8] MSCs are attractive for clinical therapy due to their ability to differentiate, provide trophic support, and modulate innate immune response.[7] These cells have the ability to differentiate into various cell types such as osteoblasts, chondroblasts, adipocytes, neuroectodermal cells, and hepatocytes.[9] Bioactive mediators that favor local cell growth are also secreted by MSCs. Anti-inflammatory effects on the local microenvironment, which promote tissue healing, are also observed. The inflammatory response can be modulated by adipose-derived regenerative cells (ADRC) including mesenchymal stem cells and regulatory T-lymphocytes. The mesenchymal stem cells thus alter the outcome of the immune response by changing the cytokine secretion of dendritic and T-cell subsets. This results in a shift from a pro-inflammatory environment to an anti-inflammatory or tolerant cell environment.[10][11]

Endothelial stem cells are one of the three types of multipotent stem cells found in the bone marrow. They are a rare and controversial group with the ability to differentiate into endothelial cells, the cells that line blood vessels.

The existence of stem cells in the adult brain has been postulated following the discovery that the process of neurogenesis, the birth of new neurons, continues into adulthood in rats.[12] The presence of stem cells in the mature primate brain was first reported in 1967.[13] It has since been shown that new neurons are generated in adult mice, songbirds and primates, including humans. Normally, adult neurogenesis is restricted to two areas of the brain the subventricular zone, which lines the lateral ventricles, and the dentate gyrus of the hippocampal formation.[14] Although the generation of new neurons in the hippocampus is well established, the presence of true self-renewing stem cells there has been debated.[15] Under certain circumstances, such as following tissue damage in ischemia, neurogenesis can be induced in other brain regions, including the neocortex.

Neural stem cells are commonly cultured in vitro as so called neurospheres floating heterogeneous aggregates of cells, containing a large proportion of stem cells.[16] They can be propagated for extended periods of time and differentiated into both neuronal and glia cells, and therefore behave as stem cells. However, some recent studies suggest that this behaviour is induced by the culture conditions in progenitor cells, the progeny of stem cell division that normally undergo a strictly limited number of replication cycles in vivo.[17] Furthermore, neurosphere-derived cells do not behave as stem cells when transplanted back into the brain.[18]

Neural stem cells share many properties with haematopoietic stem cells (HSCs). Remarkably, when injected into the blood, neurosphere-derived cells differentiate into various cell types of the immune system.[19]

Olfactory adult stem cells have been successfully harvested from the human olfactory mucosa cells, which are found in the lining of the nose and are involved in the sense of smell.[20] If they are given the right chemical environment these cells have the same ability as embryonic stem cells to develop into many different cell types. Olfactory stem cells hold the potential for therapeutic applications and, in contrast to neural stem cells, can be harvested with ease without harm to the patient. This means they can be easily obtained from all individuals, including older patients who might be most in need of stem cell therapies.

Hair follicles contain two types of stem cells, one of which appears to represent a remnant of the stem cells of the embryonic neural crest. Similar cells have been found in the gastrointestinal tract, sciatic nerve, cardiac outflow tract and spinal and sympathetic ganglia. These cells can generate neurons, Schwann cells, myofibroblast, chondrocytes and melanocytes.[21][22]

Multipotent stem cells with a claimed equivalency to embryonic stem cells have been derived from spermatogonial progenitor cells found in the testicles of laboratory mice by scientists in Germany[23][24][25] and the United States,[26][27][28][29] and, a year later, researchers from Germany and the United Kingdom confirmed the same capability using cells from the testicles of humans.[30] The extracted stem cells are known as human adult germline stem cells (GSCs)[31]

Multipotent stem cells have also been derived from germ cells found in human testicles.[32]

To ensure self-renewal, stem cells undergo two types of cell division (see Stem cell division and differentiation diagram). Symmetric division gives rise to two identical daughter cells, both endowed with stem cell properties, whereas asymmetric division produces only one stem cell and a progenitor cell with limited self-renewal potential. Progenitors can go through several rounds of cell division before finally differentiating into a mature cell. It is believed that the molecular distinction between symmetric and asymmetric divisions lies in differential segregation of cell membrane proteins (such as receptors) between the daughter cells.

Discoveries in recent years have suggested that adult stem cells might have the ability to differentiate into cell types from different germ layers. For instance, neural stem cells from the brain, which are derived from ectoderm, can differentiate into ectoderm, mesoderm, and endoderm.[33] Stem cells from the bone marrow, which is derived from mesoderm, can differentiate into liver, lung, GI tract and skin, which are derived from endoderm and mesoderm.[34] This phenomenon is referred to as stem cell transdifferentiation or plasticity. It can be induced by modifying the growth medium when stem cells are cultured in vitro or transplanting them to an organ of the body different from the one they were originally isolated from. There is yet no consensus among biologists on the prevalence and physiological and therapeutic relevance of stem cell plasticity. More recent findings suggest that pluripotent stem cells may reside in blood and adult tissues in a dormant state.[35] These cells are referred to as "Blastomere Like Stem Cells"[36] and "very small embryonic like" "VSEL" stem cells, and display pluripotency in vitro.[35] As BLSC's and VSEL cells are present in virtually all adult tissues, including lung, brain, kidneys, muscles, and pancreas[37] Co-purification of BLSC's and VSEL cells with other populations of adult stem cells may explain the apparent pluripotency of adult stem cell populations. However, recent studies have shown that both human and murine VSEL cells lack stem cell characteristics and are not pluripotent.[38][39][40][41]

Stem cell function becomes impaired with age, and this contributes to progressive deterioration of tissue maintenance and repair.[42] A likely important cause of increasing stem cell dysfunction is age-dependent accumulation of DNA damage in both stem cells and the cells that comprise the stem cell environment.[42] (See also DNA damage theory of aging.)

Adult stem cells can, however, be artificially reverted to a state where they behave like embryonic stem cells (including the associated DNA repair mechanisms). This was done with mice as early as 2006[43] with future prospects to slow down human aging substantially. Such cells are one of the various classes of induced stem cells.

Adult stem cell research has been focused on uncovering the general molecular mechanisms that control their self-renewal and differentiation.

Adult stem cell treatments have been used for many years to successfully treat leukemia and related bone/blood cancers utilizing bone marrow transplants.[47] The use of adult stem cells in research and therapy is not considered as controversial as the use of embryonic stem cells, because the production of adult stem cells does not require the destruction of an embryo.

Early regenerative applications of adult stem cells has focused on intravenous delivery of blood progenitors known as Hematopetic Stem Cells (HSC's). CD34+ hematopoietic Stem Cells have been clinically applied to treat various diseases including spinal cord injury,[48] liver cirrhosis [49] and Peripheral Vascular disease.[50] Research has shown that CD34+ hematopoietic Stem Cells are relatively more numerous in men than in women of reproductive age group among spinal cord Injury victims.[51] Other early commercial applications have focused on Mesenchymal Stem Cells (MSCs). For both cell lines, direct injection or placement of cells into a site in need of repair may be the preferred method of treatment, as vascular delivery suffers from a "pulmonary first pass effect" where intravenous injected cells are sequestered in the lungs.[52] Clinical case reports in orthopedic applications have been published. Wakitani has published a small case series of nine defects in five knees involving surgical transplantation of mesenchymal stem cells with coverage of the treated chondral defects.[53] Centeno et al. have reported high field MRI evidence of increased cartilage and meniscus volume in individual human clinical subjects as well as a large n=227 safety study.[54][55][56][57] Many other stem cell based treatments are operating outside the US, with much controversy being reported regarding these treatments as some feel more regulation is needed as clinics tend to exaggerate claims of success and minimize or omit risks.[58]

The therapeutic potential of adult stem cells is the focus of much scientific research, due to their ability to be harvested from the parent body that is females during the delivery.[59][60][61] In common with embryonic stem cells, adult stem cells have the ability to differentiate into more than one cell type, but unlike the former they are often restricted to certain types or "lineages". The ability of a differentiated stem cell of one lineage to produce cells of a different lineage is called transdifferentiation. Some types of adult stem cells are more capable of transdifferentiation than others, but for many there is no evidence that such a transformation is possible. Consequently, adult stem therapies require a stem cell source of the specific lineage needed, and harvesting and/or culturing them up to the numbers required is a challenge.[62][63] Additionally, cues from the immediate environment (including how stiff or porous the surrounding structure/extracellular matrix is) can alter or enhance the fate and differentiation of the stem cells.[64]

Pluripotent stem cells, i.e. cells that can give rise to any fetal or adult cell type, can be found in a number of tissues, including umbilical cord blood.[65] Using genetic reprogramming, pluripotent stem cells equivalent to embryonic stem cells have been derived from human adult skin tissue.[66][67][68][69][70] Other adult stem cells are multipotent, meaning they are restricted in the types of cell they can become, and are generally referred to by their tissue origin (such as mesenchymal stem cell, adipose-derived stem cell, endothelial stem cell, etc.).[71][72] A great deal of adult stem cell research has focused on investigating their capacity to divide or self-renew indefinitely, and their potential for differentiation.[73] In mice, pluripotent stem cells can be directly generated from adult fibroblast cultures.[74]

In recent years, acceptance of the concept of adult stem cells has increased. There is now a hypothesis that stem cells reside in many adult tissues and that these unique reservoirs of cells not only are responsible for the normal reparative and regenerative processes but are also considered to be a prime target for genetic and epigenetic changes, culminating in many abnormal conditions including cancer.[75][76] (See cancer stem cell for more details.)

Adult stem cells express transporters of the ATP-binding cassette family that actively pump a diversity of organic molecules out of the cell.[77] Many pharmaceuticals are exported by these transporters conferring multidrug resistance onto the cell. This complicates the design of drugs, for instance neural stem cell targeted therapies for the treatment of clinical depression.

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StemCell Maxum Longevity Support | Make America Well

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A Natural formula designed to prevent premature aging. Feel better and look younger! Your cells lose function as you age. Adult stem cells rejuvenate old damaged tissues, but adult stem cells are also aging. Now you can do something about it. StemCell Maxum supports adult stem cells and their functions.

Scientific research is constantly finding new anti-aging discoveries. Biological aging does not need to be our destiny. People will eventually live long, healthy lives while maintaining younger characteristics. A lifetime that of centuries or longer will eventually be a reality. Maintaining the body of a 21 year old for a lifetime that could stretch to centuries or longer will be a reality. We are developing products and therapies to extend lifespan. Progress will continue indefinitely. Your best strategy is to use dietary supplements, exercise and a healthy diet and lifestyle to extend your lifespan.

StemCell Maxum is designed to prevent premature aging. This can help you feel better and look younger. Your cells lose function as you age. Adult stem cells rejuvenate damaged and old tissues, but adult stem cells are also aging. Now you can do something about it. StemCell Maxum supports adult stem cells and their functions.

Millions of people suffer from chronic disease conditions. We have hope that conditions afflicting mankind will eventually be remedied using stem cell regenerative medicine. Improve the effectiveness of your adult stem cells by using our StemCell -Longevity.

Ingredients in StemCell Maxum have been proven to support:

As a child, we rapidly recover from injury or illness because of the ability of our young regenerative stem cells to regenerate damaged tissues. As we age, our stem cells slowly lose their repairing capacity. This natural progression occurs slowly, but we start to notice the body changes especially after age 50. StemCell Maxum helps you regain your youthful regenerative potential.

Premature aging can be defeated by maximizing your longevity genes.

Users may expect a reduction in blood pressure, blood sugar, total cholesterol, LDL and triglycerides and an increase in HDL (good cholesterol) after a few months of taking StemCell Maxum.

All the organs and tissues of the body have adult stem cells for regenerating cells in case of injury or disease. As we age, adult stem cells gradually lose the ability to differentiate into functional tissue-specific cells. For example, cardiac muscle stem cells exist but elderly people have only one half the number of cardiac stem cells found in young people. Thus, adult stem cells become more dysfunctional as we age, causing progressively increased organ and tissue dysfunction.

An example of the aging role of adult stem cells is your skin continually losing dead cells, so that adult stem cells must continuously replenish the dying skin cells. With age, there are progressively fewer functional skin stem cells. Skin cell turnover slows, leading to thinner, dryer, less elastic skin that loses its youthful beauty. Hair thins and turns grey as functional hair follicle stem cells decline. Vision, hearing, smell, taste, and touch slowly decline with age, as the declining stem cell populations responsible for maintaining these functions are unable to fully rejuvenate.

Stimulating adult stem cell populations is not a simple task. If the proliferation of adult stem cells is over stimulated, then you may get overgrowth of tissues or a potential tumor. StemCell Maxum is a dietary supplement designed to improve the function of your existing stem cells. When an organ or tissue is damaged, it emits natural signals that new cells are needed to replace old or damaged cells. StemCell Maxum supports the adult stem cells that respond to provide new replacement cells.

Everyone can benefit from StemCell Maxum. Younger persons will enjoy the wellness endurance boost during sports or exercise. Older persons will notice increased energy, youthful appearance, wellness and better weight management.

Expected benefits of taking StemCell Maxum:

Caution: Normal blood glucose and/or blood pressure may result from taking StemCell Maxum. Please consult with your doctor and regularly monitor yourself if you are on medication for these disorders. StemCell Maxum is not recommended for pregnant or lactating individuals.

The statements above have not been reviewed by the FDA. StemCell Maxum is not meant as a preventive or treatment for any disease.

StemCell Maxum

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StemCell Maxum Longevity Support | Make America Well

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The Cost Of Stem Cell Therapy And Why It’s So Expensive …

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How much is stem cell therapy? As stated by CBC Canada,the cost of stem cell therapy is $5,000 to $8,000per stem cell treatment for patients. According to a Twitter poll by BioInformant, the cost can be even higher. Our May 2018 poll found that stem cell treatments can cost as much as $25,000 or more. This article explores the key factors that impact the cost of stem cell therapy, including the type of stem cells used within the protocol, the number of treatments required, and the site of theclinic. It also provides pricing quotes from stem cell clinics within the U.S. and worldwide.

In this article:

Stem cell therapy is the use of living cells as therapeutics to treat disease or injury. Read on to learn about the cost requirements of these procedures.

CBC Canadas pricing involves Cell Surgical Network (CSN) following its protocol to remove fat tissue and process it before re-injecting [adipose-derived stem cells] either directly or intravenously into the same patient. Unfortunately, the U.S. FDA and Department of Justice (DOJ) sent this network of stem cell treatment providers a permanent injunction notice in May 2018. Therefore, patients should not seek treatments from the group at this time.Although Cell Surgical Network (CSN) is based in California, it has a network of approximately 100 U.S. treatment centers. They also have three Canadian clinics located in Vancouver, Sudbury,andKamloops.

The controversy such as the one above stirs up questions about the safety of stem cell procedures. Anyone considering stem cell therapy from any tissue or source will benefit from understanding the possible consequences of stem cell therapy and the factors driving costs.

For the patient, a stem cell transplant involves multiple steps, including:

There are also real costs for the doctors who provide stem cell treatments. They have overhead costs, including:

There is also time and expertise required toperform the procedure and offer post-operative care. In some cases, the physician must pay licensing fees to access stem cell sourcing, processing, or delivery technologies.

Stem cell treatment has gained more and more traction over the last decade. It has been helped along by considerable advances in research. In 2017, the number of scientific publications about stem cells surpassed 300,000. The number of stem cell clinical trials has also surpassed4,600 worldwide.

However, stem cell therapy is still expensive. Among the cheapest and easiest options is to harvest adipose-derived stem cells (ADSCs) those that exist in adult fat layers and re-deliver them to the patient. Unlike harvesting from bone marrow or teeth, providers can feasibly remove fat, separate stem cells, then re-inject them into a patient the same day. This approach is typically less expensive than those that require more invasive procedures for harvesting. Because of its practicality in terms of cost, it has become a common approach to stem cell treatment.

Relatively easy harvesting stilldoesnt translate to inexpensive cost, although some are certainly more affordable than others. For orthopedic conditions, the costof stem cell therapy is typically lower, averaging between $5,000 and $8,000. Examples of these types of medical conditions include:

Note that these prices are typically out-of-pocket costs paid by the patientbecause most insurance companies will not cover them. They are considered experimental and unapproved by the FDA. This means patients needing stem cell treatment will need to use their own savings.

Although fat is a frequently utilized source for stem cells, it is also possible for physicians to utilize stem cells from bone marrow. Regenexx provides this service in the U.S. and Cayman Islands. With theRegenexxstem cell injection procedure, a small bone marrow sample is extracted through a needle, and blood is drawn from a vein in the arm. These samples are processed in a laboratory, and the cells it contains are injected into an area of the body that needs repair. On June 19, 2018, ACAP Health, a leading provider in innovative, clinical-based solutions partnered with Regenexx to reduce high-cost musculoskeletal surgeries.ACAP Health is a national leader in employer healthcare expense reduction. It is one of the first healthcare groups to partner with a stem cell treatment group to support insurance coverage to patients.

A recent Twitter poll conducted by BioInformant reported that, on average, patients can expect to spend $25,000 or more on stem cell therapies. According to the poll,

Most likely, those paying lower stem cell treatment costs under $5,000 were pursuing treatment for orthopedic or musculoskeletal conditions. In contrast, those paying higher treatment costs were likely getting treated for systemic or more complex conditions, such as diabetes, multiple sclerosis (MS), neurodegenerative diseases (such as Alzheimers disease or dementia), psoriatic arthritis, as well as the treatment for autism.

In the U.S., treatment protocols vary depending on the clinic and the treating physician. A one-time treatment that utilizes blood drawn from a patient can cost as little as $1,500. However, protocols that utilize a bone marrow or adipose (fat) tissue extraction can run as much as $15,000 $30,000. This is because bone marrow extraction is an invasive procedure that requires a penetrating bone and adipose tissue extraction requires a medical professional trained in liposuction.

For treatments that require a systemic or whole-body approach, the cost tends to be in the higher range, often averaging from $20,000 to $30,000. Examples of the diseases or conditions requiring this type of stem cell treatment include:

These higher costs reflect the complexity of treating these patients and the fact that multiple treatments are often required.

Founded by Dr. Neil Riordan, a globally recognized stem cell expert, theStem Cell Institutein Panama is one of the worlds most trusted adult stem cell therapy centers. Over the past 12 years, the center has performed more than10,000 procedures, making it a widely recognized destination for stem cell treatments.

Working in collaboration with universities and physicians worldwide, its stem cell treatment protocols utilize combinations of allogeneic human umbilical cord blood stem cells and autologous bone marrow stem cells to treat a wide variety of conditions.

A reader of BioInformant was recently treated for psoriatic arthritis at the Stem Cell Institute in Panama in early 2018. The price of his stem cell treatment was $22,000. With travel and lodging included, the total expenses were approximately $30,000.

Because of its proximity to the U.S., Mexico is increasingly becoming a destination for medical tourism.Before choosing a stem cell treatment provider in Mexico, ensure the clinic is fully authorized by COFEPRIS, the Mexican equivalent to the FDA.

One patient who recently shared stem cell treatment quotes with BioInformant found that the treatment for glycogen storage disease, a metabolic disorder that often onsets in infancy and continues into adulthood, would cost $23,900 throughGIOSTAR Mexico.

In contrast, the patient was quoted$33,000 throughCelltex, a U.S.-based company that treats patients in Cancun, Mexico.Celltex follows FDA regulations concerning the export of cells to Mexico and is compliant with the standards and procedures of COFEPRIS. Celltex also has an alliance with a certified hospital in Mexico, which is approved to receive cells and administer them to patients by a licensed physician.

In contrast, the patient was quoted $10,000 from Stem Cell Therapy of Las Vegas and Med Spa, an American clinic. This price difference may reflect regulatory restrictions that prevent U.S. providers from expanding cells. It may also reflect the therapeutic approach used by the clinic, as well as the quality of their expertise.

In Mexico, where certain types of stem cell expansion are allowed that are restricted within the U.S., treatment protocols vary depending on the clinic and the treating physician. A one-time treatment that utilizes peripheral blood from a patient can cost as little as $1,000. In contrast, protocols that utilize more invasive sources of stem cells can run as much as $15,000 $35,000. Examples of invasive procedures includebone marrow and adipose tissue extraction. In some cases, hospitalization may be required, which raises costs. The location of a stem cell facility can factor heavily into thecost of the procedure.

Not every cost associated with treatment gets billed to the patient at the time of the procedure. Hidden costs such as reactions to the treatment, graft-versus-host disease, or disability derived from the treatment can all result in more money to the patient, to insurance, or to the government.

For example, in the case of someone with cancer, it frequently isnt viable to harvest the patients own stem cells because they may contain cancerous cells that can reintroduce tumors to the body. Instead, the patient would receive stem cells by transplant. Treatments that involve cells from another person are called allogeneic treatments. The danger here is that the body may see those cells as invaders and attack them via the immune system, a condition known as graft-versus-host disease (GvHD). The body (host) and the introduced stem cells (graft) then battle rather than coexist.

Transplanted cells often face the risk of being rejected by their host; this article discusses the effect of plasma exchange on acute graft vs. host disease

Katie Bunde (@kbuns76) May 29, 2018

In addition to making the stem cell treatments less effective or ineffective, GvHD can be deadly. Roughly30 to 60 percent ofhematopoieticstem cell and bone marrow transplantationpatients sufferfrom it, and of those, 50 percent eventually die. The hospital costs associated with it are substantial.

Another hidden cost is the potential to disrupt a system that formerly functioned adequately. The best current example of this isthe case of Doris Tyler, who received bilateral stem cell injections in her eyes from Drs.RobertHalpernand JamieWalraven of Stem Cell Center of Georgia. According to her, while her vision was failing, it was still good enough to perform various tasks, and now it is not. That means the cost increases for her, as well as potential insurance or disability claims (though again, insurance is unlikely to cover the specific consequences of this action).

Because of tight regulations surrounding stem cell procedures performed in the United States, many stem cell treatment providers provide both on-shore (U.S.-based) and offshore (international) treatment options.Depending on where a treatment is received, patients may have to pay travel, lodging,and miscellaneous expenditures.

For example, Regenexx offers treatments at a wide range of U.S. facilities using non-expanded stem cells. However, it also offers a laboratory-expanded treatment option at a site in the Cayman Islands, which can administer higher cell doses to patients by expanding the cells in culture within a laboratory.

Similarly, Okyanos (pronounced Oh key AH nos) offers treatments to patients at its Florida location and provides more involved stem cell procedures at its offshore site inGrand Bahama. It was founded in 2011 and is a stem cell therapy provider specializing in treatments for congestive heart failure (CHF) and other chronic conditions. It is fully licensed under the Bahamas Stem Cell Therapy and Research Act and adheres to U.S. surgical center standards.

Similarly, Celltex is headquartered in Houston, Texas, but offers stem cell treatments in Cancun, Mexico. Celltex specializes in storing a patients mesenchymal stem cells (MSCs) for therapeutic use.

While no hard evidence yet points to stem cell clinics raising their rates as a result of lawsuits, that is a typical response in industries whose products or services the public perceives as a high risk.

An additional danger to stem cell treatment providers,points out Nature, is the reduction of bottom-line profits through former patients winning suits. If clinics have to pay out the money they earned and then some to individuals suing for damages, they may soon become faced with an unviable business model. That is a definite concern for those hoping to leverage these treatments now and in the future.

As with any other area of medicine, patient evaluations of stem cell providers and treatments run the gamut from extremely satisfied to desolately unhappy. Those like Doris Tyler who have lost their eyesight exist at the negative end of the spectrum. However, many others praise stem cell treatments for their power to heal diseases, boost immunity, fight cancer, and more.

For example, BioInformants Founder and President, Cade Hildreth, had a favorable experience with stem cell therapy. Cade had bone marrow-derived stem cells collected and then had them re-injected into the knee to treat a devastating orthopedic injury. Cade was able to reverse pain, swelling, and scarring to reclaim an elite athletic ability.

As of now, this much is clear. There exists enough interest in America and across the world that stem cell providers are continuing to offer a wide range of treatments. Stem cell treatments also offer the potential to reverse diseases that traditionally had to be chronically managed by drugs. Like most medical practices, stem cell treatments will require further testing to reveal merits and faults. Until then, the public will likely continue to pursue services when medical needs arise.

Although the cost of stem cell therapy is pricey, some patients choose to undergo the treatment because it is more economical than enduring the costs associated with chronic diseases.

Although most stem cell therapy providers do not provide FDA-approved procedures, the Food and Drug Administration (FDA) continues to encouragepatients to pursue approved therapies, even if there is a higher associated treatment cost.

Providers rarely post their prices for stem cell treatments in print or digital media because they want patients to understand the benefits of therapy before making a price decision. Additionally, the price of stem cell treatments varies by condition, the number of treatments required, and the complexity of the procedure, factors that can make it difficult for medical providers to provide cost estimates without a diagnostic visit for the patient. However, in many cases, it is not in the patients best interest to make treatment decisions based on the cost of stem cell therapy. The best way to know whether to pursue stem cell therapy is to explore patient outcomes by condition and compare the healing process to other surgical and non-surgical treatment options.

The cost of stem cell therapy is indeed expensive, especially because the procedures are rarely covered by health insurance. However, with the right knowledge and a clear understanding of the treatment process, the risk of undergoing stem cell therapy can be worth it, especially if it removes the requirement for a lifetime of prescription medication. Although stem cell therapy has associated risks, it has improved thousands of lives and will continue to play in a key role in the future of modern medicine.

Download this infographic for your reference:

Are you seeking a stem cell treatment? If so, we have partnered with GIOSTAR to help you acccess medical guidance and advice.

In alignment with what we believe at BioInformant, GIOSTARs goal is to offer cutting-edge, extensively researched stem cell therapy options designed to rejuvenate and improve a patients quality of life.

Click here to Schedule a Consultation or ask GIOSTAR a question.

If you found this blog valuable, subscribe to BioInformants stem cell industry updates.

As the first and only market research firm to specialize in the stem cell industry, BioInformant research is cited by The Wall Street Journal, Xconomy, AABB, and Vogue Magazine. Bringing you breaking news on an ongoing basis, we encourage you to join more than half a million loyal readers, including physicians, scientists, executives, and investors.

Do you think the cost of stem cell therapy is too much? Share your thoughts in the comments section below.

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Cost Of Stem Cell Therapy And Why Its So Expensive

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Stem Cell Therapy for ALS Patients

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Learn about what stem cells are, why they are important and how they are going to revolutionize healing and medical care in Canada.

Not all conditions are effectively treated by PRP injections or stem cell therapy, and with ongoing clinical trials its important to realize what stem cells can and cannot help with. Weve built a comprehensive list of the different types of conditions that stem cell therapy shows promise for, however if you dont find it listed wed recommend checking outDanish health website Regular maintenance of health is key to making sure long-term issues dont arise as we age, and part of that is a rich, balanced diet and careful supplementation.

Research on human embryos in general, and stem cell research in particular, has been the subject of public debate in Canada since the late 1980s. In 2002, the Canadian Institute of Health Research (CIHR) issued guidelines for research on human embryonic stem cell lines, which have been revised and reissued several times since 2005 (most recently in 2007). These guidelines regulate the allocation of state funds in the field of research on human embryonic stem cells and concern both the handling of existing stem cell lines and the establishment of new stem cell lines.

The guidelines specify a number of important conditions that must be fulfilled in order for research projects to be eligible for funding. These include, but are not limited to:

The Stem Cell Oversight Committee (SCOC) was set up to ensure that research projects comply with the provisions of the Directive and to address the complex ethical issues surrounding research projects. Any project applying for government funding in the field of stem cell research must first be positively evaluated by the SCOC.

In addition to the regulation of state funding, the Assisted Human Reproduction Act came into force in 2004, which broadly regulates the field of reproductive medicine. Unlike the guidelines of the CIHR, it is not merely a guideline for state funding of certain research activities, but a law that places certain activities under state control and generally prohibits others. Research on human embryos is one of the controlled activities of the Assisted Human Reproduction Act. According to 8 Para. 3, the approval according to 10 Para. 2 requires the consent of the donor after clarification of the intended use. The Assisted Human Reproduction Agency of Canada (AHRAC), established by law, is responsible for granting authorisations and monitoring research activities.

The extraction of ES cells also falls under this section and is therefore permitted in Canada. The use of in vitro embryos for research purposes, including the derivation of stem cells, is subject to the following conditions under the Assisted Human Reproduction Act:

The production of a human clone is prohibited according to 5 a Assisted Human Reproduction Act. This provision also includes so-called therapeutic cloning by nuclear transfer. According to 5 b, the creation of embryos for purposes other than the creation of a human being or the improvement of artificial reproduction procedures is also prohibited. The law does not apply to the handling of already established human embryonic stem cell lines.

The CBC news network and other media responded to Twitter posts and a YouTube live video about unapproved treatments that lately came up. Patients that suffer from chronic pain or disease could benefit from stem-cell therapies. Canadians who have been treated more open by their federal and other regulatory laws about unlicensed stem cell therapies are asking for the legalization or this procedure.

A new company now made it their mission to offer direct-to-customer opportunities for trainees and people in general which can mean a big advantage for a patient. Unproven stories about this training in marketing and science services are offering support for approved stem-cell professionals.

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Stem Cell Therapy for ALS Patients

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Spinal Cord Injury Center – Treatments, Research …

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Spinal Cord Injuries Are Not JustCaused by Trauma

When you think of spinal cord injury (SCI), traumatic events like a serious car accident may come to mind. While its true that car accidents are the leading cause of traumatic SCI, you may be surprised that non-traumatic diseasessuch as a spinal tumorcan also cause SCI.

SCI involves damage to the spinal cord that temporarily or permanently changes how it functions. SCI is divided into 2 categories: traumatic or non-traumatic. Even if the cause of SCI is non-traumatic, that doesnt lessen its impact or severitythe aftermath of SCI can have devastating effects on a persons life.Falls are the second most common cause of traumatic spinal cord injury. Photo Source: Spinal Cord Injury

Traumatic SCI occurs more often in men than womennearly 80% of cases affect men. People of all ages may experience SCI, but certain activities tend to affect different age groups more. For example, high-impact events like car accidents and sports injuries tend to occur more often in younger people. On the other hand, traumatic SCI caused by a fall is more common in adults over age 60.

Regardless of the cause, traumatic SCI occurs most frequently in the cervical spine (about 60% of cases involve the neck), followed by thoracic spine (32% involve the mid-back). Only 9% of cases occur in the lumbosacral spine, or low back and tailbone.

Understanding the Traumatic Spinal Cord Injury CascadeA traumatic SCI doesnt simply damage your spinal cord at the point of initial impact. In traumatic SCI, the primary injury (that is, the initial traumatic event that caused the SCI) may damage cells and dislocate your spinal vertebrae, which causes spinal cord compression. The primary injury also triggers a complex secondary injury cascade, which causes a series of biological changes that may occur weeks and months after the initial injury.

During the secondary injury cascade, the following processes occur:

This cascade changes the spinal cords structure and how it normally operates. Ultimately, this secondary injury cascade may interfere with the spinal cords ability to recover itself. This means a person with traumatic SCI may experience permanent nerve pain and dysfunction because of their injury.

Non-traumatic Spinal Cord InjuryTraumatic events arent the only causes of spinal cord damageSCI can also be caused by non-traumatic diseases in the spine. Spinal tumors are the leading cause of non-traumatic SCI, but infections and degenerative disc disease can also damage your spinal cord.

Though most people connect traumatic events to SCI, non-traumatic causes of SCI are a much more likely cause. To highlight just how common non-traumatic cases are versus their traumatic counterparts, consider the incidence of traumatic SCI in North America: 39 cases per million people. On the other hand, the incidence of non-traumatic SCI is 1,227 cases per million people for Canada alone (data for the rest of North America is not available).

A Healthy Research Outlook to Improve Spinal Cord Injury OutcomesOver the past 30 years, spine researchers have made great strides in developing successful protective and regenerative therapies to improve the health of the spinal cord and the survival rate of people with SCIbut the work is far from over. Current studies and clinical trials are examining innovative medical, surgical and cell-based treatments to further the medical communitys understanding of SCI, which will improve the quality of life and preserve a brighter future for people who experience these injuries.

Suggested Additional ReadingA special issue of the Global Spine Journal set forth guidelines for the Management of Degenerative Myelopathy and Acute Spinal Cord Injury, which is summarized on SpineUniverse in Summary of the Clinical Practice Guidelines for the Management of Degenerative Cervical Myelopathy and Traumatic Spinal Cord Injury.

Sources:Ahuja CS, Wilson JR, Nori S, et al. Traumatic spinal cord injury. Nature Reviews Disease Primers. 3, 17018. Accessed January 10, 2018.

Spinal Cord Injury. Facts and figures at a glance. National SCI Statistical Center (NSCI SC). 2017. Accessed January 10, 2018.

Updated on: 01/27/19

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Spinal Cord Injury Center - Treatments, Research ...

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Bone Marrow for Spine and Orthopaedic Stem Cell Treatment …

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Stem cells are the next frontier in the treatment of orthopaedic and spinal disorders, and the Cary Orthopaedics team is leading the way.

Using stem cells harvested from an adult patients own bone marrow,Dr. Sameer Mathurand Dr. Nael Shanti both board-certified orthopaedic spinal surgeons have developed a minimally invasive remedy for those suffering from degenerative disc disease, back pain and spinal arthritis. Applying a similar approach, Cary OrthosDr. Douglas Martini a fellowship-trained, board-certified orthopaedic surgeon specializing in sports medicine has crafted a pain-relief solution for patients living with osteoarthritis and soft tissue injuries.

Multiple research studies have shown a significant reduction in low back and joint pain and improved function after stem cell injections. While these treatments are new, 80% to 90% of patients are already reporting improvement in their symptoms after orthopaedic stem cell treatments.

Many patients suffering from degenerative disc diseases or low back pain are often not ideal candidates for surgery, and some who have chosen to undergo surgery have had unsatisfactory results. Therefore, the typical remedy for chronic orthopaedic conditions is extensive physical therapy combined with oral anti-inflammatory medications. The result: The majority of patients still had to live with pain.

Physicians at Cary Orthopaedics are utilizing orthopaedic stem cell treatment using the patients own bone marrow, the soft, spongy tissue found in the center of bones. Bone marrow in adults contains a rich reservoir of multipotent stem cells also known as Mesenchymal Precursor Cells (MPCs) that can be extracted from the patients pelvis or hip bone. Due to their unique, regenerative composition, these cells can become various types of tissues including soft tissue, bone or cartilage, which make them an excellent resource for repairing and rebuilding damaged tissue, accelerating the healing process and improving overall function.

Thanks to advancements in technology, the removal and harvesting process has become easier and less expensive. Since this is a minimally invasive procedure, it has fewer side effects compared to traditional surgery, and it causes minimal discomfort to the patient.

Bone marrow injections are a breakthrough for patients in pain. Dr. Martini, a sports medicine physician at Cary Orthopaedics, has been active in the sports medicine community, previously serving as team physician for the Carolina Hurricanes, numerous colleges, and local high schools. After 25 years of experience in sports medicine, he realizes the need for improved treatment options for the greying athlete. He has begun incorporating bone marrow aspirate concentrate (BAC) into the treatment of both acute and chronic soft tissue and joint-related injuries. I believe this will be equally helpful to the patient who needs to exercise for overall health benefits as it would be for those who need to stay at their peak athletic performance, says Dr. Martini.

We have found based on our research and experience that stem cell therapy can be very safe and effective when used with the appropriate patient population, said Kevin G. Morrison, PA-C, a member of Dr. Martinis team. All the feedback to this point has been quite positive, both on the process of having the procedure done as well as the early response. But ultimately long-term data will need to be compiled and critically examined.

Much of the previous research into stem cells has centered around placental stem cells, which can also adapt into other types of tissues. However, these have not performed well when put to the test for orthopaedic treatment. Bone marrow aspirate concentrate provides MPCs that can transform into osteocytes, chondrocytes and adipocytes, all of which are important in treating orthopedic conditions.

The latest research around mesenchymal stem cells, specifically bone marrow aspiration, is certainly promising. Dr. Martini will continue to collect more data and review patients responses.

Dr. Mathur has been an instrumental force in elevating the level of patient care at Cary Orthopaedic Spine Center since joining the practice in 2008. Dr. Mathur completed his medical school at the University of Pennsylvania and spinal reconstructive fellowship at the Rush University Medical Center in Chicago. He also taught at Dana Farber Cancer Institute in Boston. Over the last 10 years, in conjunction with the National Institutes of Health, he has conducted significant study of disc degeneration and analysis of the expression of genes that may damage the disc.

In the past decade, there have been several advancements in spinal surgery, but regenerative medicine is the next frontier, said Dr. Mathur. I see so many patients that have low back pain and leg pain from degenerative disc disease. For many, there is no good surgical treatment, and stem cell injections may be a viable option.

As an orthopaedic spine specialist, Dr. Mathur is not only an expert in spinal surgery but also in the diagnosis and treatment of a wide range of spinal problems. His depth of experience allows him to best determine whether a patient would benefit from physical therapy, stem cell injections or surgical intervention. When providing stem cell treatment, Dr. Mathur performs a single injection for all patients, whereas other clinics typically require multiple injections over several weeks.

There is currently extensive, ongoing research on the application of stem cell therapy and tissue regeneration, including an application for spinal cord injury and disc pathology, which is very exciting, said Dr. Shanti, who has dedicated a great deal of time researching the potential impact stem cell therapy can provide for his patients. Dr. Shanti believes stem cell therapy is the next great advancement in healthcare with an application for a wide spectrum of medical conditions.

Recently recognized as Top Orthopaedic Doctor by The Leading Physicians of the World for the outstanding patient care, Dr. Shantis in-depth experience and understanding of the spine allows him to guide his patients especially those with chronic back pain to the most appropriate path of treatment with the shared collaborative goal of pain relief. Dr. Shanti completed his spine surgery fellowship training at the prestigious New England Baptist Hospital, Tufts University program with an emphasis on minimally invasive spine surgery, and he has authored and presented multiple papers and textbooks on the advancement of minimally invasive spine surgery.

Orthopaedic stem cell treatment is an excellent solution for patients with degenerative disc disease and also those suffering from arthritis of the spine, bulging disc, low back pain, facet joint pain or disc with annular tears.

The stem cell injection is a same-day procedure that generally takes one hour to perform. The actual extraction of bone marrow takes up to 10 minutes. The bone marrow extraction site typically the back of the patients hip or pelvis bone is numbed using a mixture of local anesthetics. A suctioned syringe is attached to a long needle that reaches the posterior aspect of the hip. The patient may experience a minimal amount of discomfort during the extraction.

The sample is collected, transferred through a filter, and then placed into a centrifuge for spinning. The speed separates the stem cells and platelets from the bone marrow. This concentration of stem cells is then reintroduced into the degenerative or painful area under image guidance with fluoroscopy to confirm accurate placement.

The harvesting site will be numb for 1 to 2 hours after the procedure, so the patient will need to have transportation home. It is permissible to fly after the treatment, but this may cause increased pain or discomfort.

Stem cell therapy relies on the bodys own regenerative process to heal, which takes time. Patients have seen the benefits in two to three months after treatment; however, many have noticed improvements in symptoms sooner.

The recommended age range for the treatment is 20 to 70 years old. As the body ages, the quality and quantity of stem cells slowly decline. After age 70, patients may experience a sharper decline in stem cells, resulting in less beneficial outcomes.

If you think you might be a candidate for orthopaedic stem cell therapy treatment, contact Cary Orthopaedics to schedule a consultation.

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Become a Donor | The Bone Marrow Foundation

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Jack, diagnosed with Acute Myelogenous Leukemia (AML), and his donor Kristy

To become a donor it just takes a small vial of blood or swab of cheek cells to be typed as a bone marrow/stem cell donor. There are many patients who are desperately waiting to find a donor match. You may be able to save someones life. There are donor registry sites throughout the country.

You must be between the ages of 18 and 60 and in general good health. You should be committed to helping any patient. A simple blood test or cheek cell swab that is given through an authorized National Marrow Donor Program Donor Center or Recruitment Group is needed to obtain your HLA tissue type so it can be entered into the National Registry. You will have to complete a short health questionnaire and sign a form stating that you understand what it means to be listed in the Registry.

The cost for HLA tissue typing ranges from $45 to $96 depending on the Donor Center, the level of testing performed, and the laboratory that analyzes the test results. There may be funding available to offset this cost through the Donor Center. After the initial testing, all medical expenses are covered by the recipient or the recipients insurance. Please contact your local Donor Center for further information.

To find out more information and to become a donor:

Delete Blood Cancer |

The National Marrow Donor Program/Be The

The American Bone Marrow Donor

The Gift of

The Icla da Silva Foundation, Inc.Helping Children and Adults with Leukemia(866)

Every 15 minutes, someone in the United States is diagnosed with a medical condition (over 35,000 people a year) such as leukemia, anemias, myelodysplastic disorders and other life-threatening diseases that require treatment with bone marrow/stem cell transplants. Nearly 70 percent of these patients must rely on an unrelated donor to offer them this precious gift of life. Unfortunately, many patients who are in need of a bone marrow/stem cell transplant cannot find a suitable donor no relatives that match and no match among volunteer donors.

Fortunately, there is an alternative that has been researched and is now proving to be a good option for many of these patientsstem cells from a newborns placental and umbilical cord blood. A newborns umbilical cord and placenta contains stem cells that are the building blocks for mature blood and immune system cells. Umbilical cord blood is collected at the time of birth under controlled conditions, shipped to a blood bank where it is tested, typed and stored.

Two studies published in The New England Journal of Medicine, Volume 351:2276-285 and an editorial by Miguel A. Sanz, M.D., Ph.D. in the same issue, concluded that cord blood should be considered as an acceptable source of stem cells in the absence of a matched bone marrow donor. For many gravely ill patients (who do not have an available donor who is a match), the immediate availability of typed cord blood units is a compelling reason for its use. And for ethnic minorities, who may have unique combinations of HLA types, the chances of finding a donor match with cord blood is greater than from the existing bone marrow donor pool.

If you have a family history of certain diseases you might choose to save your babys cord blood with a private bank. Alternatively, you can donate the cord blood to a public bank. The Bone Marrow Foundation encourages you to direct any questions you have concerning the use and storage of cord blood to your physician or other appropriate health care professional. The following are further resources for more information on public and private banking:

Public Banking National Marrow Donor

National Cord Blood ProgramNew York Blood Center310 East 67th StreetNew York, NY 100211-866- 767-NCBP (6227)

Parents Guide to Cord Blood

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Human nervous system – The spinal cord |

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The spinal cord is an elongated cylindrical structure, about 45 cm (18 inches) long, that extends from the medulla oblongata to a level between the first and second lumbar vertebrae of the backbone. The terminal part of the spinal cord is called the conus medullaris. The spinal cord is composed of long tracts of myelinated nerve fibres (known as white matter) arranged around the periphery of a symmetrical butterfly-shaped cellular matrix of gray matter. The gray matter contains cell bodies, unmyelinated motor neuron fibres, and interneurons connecting either the two sides of the cord or the dorsal and ventral ganglia. Many interneurons have short axons distributed locally, but some have axons that extend for several spinal segments. Some interneurons may modulate or change the character of signals, while others play key roles in transmission and in patterned reflexes. The gray matter forms three pairs of horns throughout most of the spinal cord: (1) the dorsal horns, composed of sensory neurons, (2) the lateral horns, well defined in thoracic segments and composed of visceral neurons, and (3) the ventral horns, composed of motor neurons. The white matter forming the ascending and descending spinal tracts is grouped in three paired funiculi, or sectors: the dorsal or posterior funiculi, lying between the dorsal horns; the lateral funiculi, lying on each side of the spinal cord between the dorsal-root entry zones and the emergence of the ventral nerve roots; and the ventral funiculi, lying between the ventral median sulcus and each ventral-root zone.

Associated with local regions of the spinal cord and imposing on it an external segmentation are 31 pairs of spinal nerves, each of which receives and furnishes one dorsal and one ventral root. On this basis the spinal cord is divided into the following segments: 8 cervical (C), 12 thoracic (T), 5 lumbar (L), 5 sacral (S), and 1 coccygeal (Coc). Spinal nerve roots emerge via intervertebral foramina; lumbar and sacral spinal roots, descending for some distance within the subarachnoid space before reaching the appropriate foramina, produce a group of nerve roots at the conus medullaris known as the cauda equina. Two enlargements of the spinal cord are evident: (1) a cervical enlargement (C5 through T1), which provides innervation for the upper extremities, and (2) a lumbosacral enlargement (L1 through S2), which innervates the lower extremities. (The spinal nerves and the area that they innervate are described in the section The peripheral nervous system: Spinal nerves.)

The gray matter of the spinal cord is composed of nine distinct cellular layers, or laminae, traditionally indicated by Roman numerals. Laminae I to V, forming the dorsal horns, receive sensory input. Lamina VII forms the intermediate zone at the base of all horns. Lamina IX is composed of clusters of large alpha motor neurons, which innervate striated muscle, and small gamma motor neurons, which innervate contractile elements of the muscle spindle. Axons of both alpha and gamma motor neurons emerge via the ventral roots. Laminae VII and VIII have variable configurations, and lamina VI is present only in the cervical and lumbosacral enlargements. In addition, cells surrounding the central canal of the spinal cord form an area often referred to as lamina X.

All primary sensory neurons that enter the spinal cord originate in ganglia that are located in openings in the vertebral column called the intervertebral foramina. Peripheral processes of the nerve cells in these ganglia convey sensation from various receptors, and central processes of the same cells enter the spinal cord as bundles of nerve filaments. Fibres conveying specific forms of sensation follow separate pathways. Impulses involved with pain and noxious stimuli largely end in laminae I and II, while impulses associated with tactile sense end in lamina IV or on processes of cells in that lamina. Signals from stretch receptors (i.e., muscle spindles and tendon organs) end in parts of laminae V, VI, and VII; collaterals of these fibres associated with the stretch reflex project into lamina IX.

Virtually all parts of the spinal gray matter contain interneurons, which connect various cell groups. Many interneurons have short axons distributed locally, but some have axons that extend for several spinal segments. Some interneurons may modulate or change the character of signals, while others play key roles in transmission and in patterned reflexes.

Sensory tracts ascending in the white matter of the spinal cord arise either from cells of spinal ganglia or from intrinsic neurons within the gray matter that receive primary sensory input.

The largest ascending tracts, the fasciculi gracilis and cuneatus, arise from spinal ganglion cells and ascend in the dorsal funiculus to the medulla oblongata. The fasciculus gracilis receives fibres from ganglia below thoracic 6, while spinal ganglia from higher segments of the spinal cord project fibres into the fasciculus cuneatus. The fasciculi terminate upon the nuclei gracilis and cuneatus, large nuclear masses in the medulla. Cells of these nuclei give rise to fibres that cross completely and form the medial lemniscus; the medial lemniscus in turn projects to the ventrobasal nuclear complex of the thalamus. By this pathway, the medial lemniscal system conveys signals associated with tactile, pressure, and kinesthetic (or positional) sense to sensory areas of the cerebral cortex.

Fibres concerned with pain, thermal sense, and light touch enter the lateral-root entry zone and then ascend or descend near the periphery of the spinal cord before entering superficial laminae of the dorsal hornlargely parts of laminae I, IV, and V. Cells in these laminae then give rise to fibres of the two spinothalamic tracts. Those fibres crossing in the ventral white commissure (ventral to the central canal) form the lateral spinothalamic tract, which, ascending in the ventral part of the lateral funiculus, conveys signals related to pain and thermal sense. The anterior spinothalamic tract arises from fibres that cross the midline in the same fashion but ascend more anteriorly in the spinal cord; these fibres convey impulses related to light touch. At medullary levels the two spinothalamic tracts merge and cannot be distinguished as separate entities. Many of the fibres, or collaterals, of the spinothalamic tracts terminate upon cell groups in the reticular formation, while the principal tracts convey sensory impulses to relay nuclei in the thalamus.

Impulses from stretch receptors are carried by fibres that synapse upon cells in deep laminae of the dorsal horn or in lamina VII. The posterior spinocerebellar tract arises from the dorsal nucleus of Clarke and ascends peripherally in the dorsal part of the lateral funiculus. The anterior spinocerebellar tract ascends on the ventral margin of the lateral funiculus. Both tracts transmit signals to portions of the anterior lobe of the cerebellum and are involved in mechanisms that automatically regulate muscle tone without reaching consciousness.

Tracts descending to the spinal cord are involved with voluntary motor function, muscle tone, reflexes and equilibrium, visceral innervation, and modulation of ascending sensory signals. The largest, the corticospinal tract, originates in broad regions of the cerebral cortex. Smaller descending tracts, which include the rubrospinal tract, the vestibulospinal tract, and the reticulospinal tract, originate in nuclei in the midbrain, pons, and medulla oblongata. Most of these brainstem nuclei themselves receive input from the cerebral cortex, the cerebellar cortex, deep nuclei of the cerebellum, or some combination of these.

In addition, autonomic tracts, which descend from various nuclei in the brainstem to preganglionic sympathetic and parasympathetic neurons in the spinal cord, constitute a vital link between the centres that regulate visceral functions and the nerve cells that actually effect changes.

The corticospinal tract originates from pyramid-shaped cells in the premotor, primary motor, and primary sensory cortex and is involved in skilled voluntary activity. Containing about one million fibres, it forms a significant part of the posterior limb of the internal capsule and is a major constituent of the crus cerebri in the midbrain. As the fibres emerge from the pons, they form compact bundles on the ventral surface of the medulla, known as the medullary pyramids. In the lower medulla about 90 percent of the fibres of the corticospinal tract decussate and descend in the dorsolateral funiculus of the spinal cord. Of the fibres that do not cross in the medulla, approximately 8 percent cross in cervical spinal segments. As the tract descends, fibres and collaterals branch off at all segmental levels, synapsing upon interneurons in lamina VII and upon motor neurons in lamina IX. Approximately 50 percent of the corticospinal fibres terminate within cervical segments.

At birth, few of the fibres of the corticospinal tract are myelinated; myelination takes place during the first year after birth, along with the acquisition of motor skills. Because the tract passes through, or close to, nearly every major division of the neuraxis, it is vulnerable to vascular and other kinds of lesions. A relatively small lesion in the posterior limb of the internal capsule, for example, may result in contralateral hemiparesis, which is characterized by weakness, spasticity, greatly increased deep tendon reflexes, and certain abnormal reflexes.

The rubrospinal tract arises from cells in the caudal part of the red nucleus, an encapsulated cell group in the midbrain tegmentum. Fibres of this tract decussate at midbrain levels, descend in the lateral funiculus of the spinal cord (overlapping ventral parts of the corticospinal tract), enter the spinal gray matter, and terminate on interneurons in lamina VII. Through these crossed rubrospinal projections, the red nucleus exerts a facilitating influence on flexor alpha motor neurons and a reciprocal inhibiting influence on extensor alpha motor neurons. Because cells of the red nucleus receive input from the motor cortex (via corticorubral projections) and from globose and emboliform nuclei of the cerebellum (via the superior cerebellar peduncle), the rubrospinal tract effectively brings flexor muscle tone under the control of these two regions of the brain.

The vestibulospinal tract originates from cells of the lateral vestibular nucleus, which lies in the floor of the fourth ventricle. Fibres of this tract descend the length of the spinal cord in the ventral and lateral funiculi without crossing, enter laminae VIII and IX of the anterior horn, and terminate upon both alpha and gamma motor neurons, which innervate ordinary muscle fibres and fibres of the muscle spindle (see below Functions of the human nervous system: Movement). Cells of the lateral vestibular nucleus receive facilitating impulses from labyrinthine receptors in the utricle of the inner ear and from fastigial nuclei in the cerebellum. In addition, inhibitory influences upon these cells are conveyed by direct projections from Purkinje cells in the anterior lobe of the cerebellum. Thus, the vestibulospinal tract mediates the influences of the vestibular end organ and the cerebellum upon extensor muscle tone.

A smaller number of vestibular projections, originating from the medial and inferior vestibular nuclei, descend ipsilaterally in the medial longitudinal fasciculus only to cervical levels. These fibres exert excitatory and inhibitory effects upon cervical motor neurons.

The reticulospinal tracts arise from relatively large but restricted regions of the reticular formation of the pons and medulla oblongatathe same cells that project ascending processes to intralaminar thalamic nuclei and are important in the maintenance of alertness and the conscious state. The pontine reticulospinal tract arises from groups of cells in the pontine reticular formation, descends ipsilaterally as the largest component of the medial longitudinal fasciculus, and terminates among cells in laminae VII and VIII. Fibres of this tract exert facilitating influences upon voluntary movements, muscle tone, and a variety of spinal reflexes. The medullary reticulospinal tract, originating from reticular neurons on both sides of the median raphe, descends in the ventral part of the lateral funiculus and terminates at all spinal levels upon cells in laminae VII and IX. The medullary reticulospinal tract inhibits the same motor activities that are facilitated by the pontine reticulospinal tract. Both tracts receive input from regions of the motor cortex.

Descending fibres involved with visceral and autonomic activities emanate from groups of cells at various levels of the brainstem. For example, hypothalamic nuclei project to visceral nuclei in both the medulla oblongata and the spinal cord; in the spinal cord these projections terminate upon cells of the intermediolateral cell column in thoracic, lumbar, and sacral segments. Preganglionic parasympathetic neurons originating in the oculomotor nuclear complex in the midbrain project not only to the ciliary ganglion but also directly to spinal levels. Some of these fibres reach lumbar segments of the spinal cord, most of them terminating in parts of laminae I and V. Pigmented cells in the isthmus, an area of the rostral pons, form a blackish-blue region known as the locus ceruleus; these cells distribute the neurotransmitter norepinephrine to the brain and spinal cord. Fibres from the locus ceruleus descend to spinal levels without crossing and are distributed to terminals in the anterior horn, the intermediate zone, and the dorsal horn. Other noradrenergic cell groups in the pons, near the motor nucleus of the facial nerve, project uncrossed noradrenergic fibres that terminate in the intermediolateral cell column (that is, lamina VII of the lateral horn). Postganglionic sympathetic neurons associated with this system have direct effects upon the cardiovascular system. Cells in the nucleus of the solitary tract project crossed fibres to the phrenic nerve nucleus (in cervical segments three through five), the intermediate zone, and the anterior horn at thoracic levels; these innervate respiratory muscles.

Human nervous system - The spinal cord |

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Current Strategies and Challenges for Purification of …

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Theranostics 2017; 7(7):2067-2077. doi:10.7150/thno.19427


Kiwon Ban1, Seongho Bae2, Young-sup Yoon2, 3

1. Department of Biomedical Sciences, City University of Hong Kong, Hong Kong;2. Department of Medicine, Division of Cardiology, Emory University, Atlanta, Georgia, USA;3. Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea.

This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license ( See for full terms and conditions.

Cardiomyocytes (CMs) derived from human pluripotent stem cells (hPSCs) are considered a most promising option for cell-based cardiac repair. Hence, various protocols have been developed for differentiating hPSCs into CMs. Despite remarkable improvement in the generation of hPSC-CMs, without purification, these protocols can only generate mixed cell populations including undifferentiated hPSCs or non-CMs, which may elicit adverse outcomes. Therefore, one of the major challenges for clinical use of hPSC-CMs is the development of efficient isolation techniques that allow enrichment of hPSC-CMs. In this review, we will discuss diverse strategies that have been developed to enrich hPSC-CMs. We will describe major characteristics of individual hPSC-CM purification methods including their scientific principles, advantages, limitations, and needed improvements. Development of a comprehensive system which can enrich hPSC-CMs will be ultimately useful for cell therapy for diseased hearts, human cardiac disease modeling, cardiac toxicity screening, and cardiac tissue engineering.

Keywords: Cardiomyocytes, hPSCs

Heart failure is the leading cause of death worldwide [1]. Approximately 6 million people suffer from heart failure in the United States every year [1]. Despite this high incidence, existing surgical and pharmacological interventions for treating heart failure are limited because these approaches only delay the progression of the disease; they cannot directly repair the damaged hearts [2]. In the case of large myocardial infarction (MI), patients progress to heart failure and die within short time from the onset of symptoms [3].

The adult human heart has minimal regenerative capacity, because during mammalian development, the proliferative capacity of cardiomyocytes (CMs) progressively diminishes and becomes terminally differentiated shortly after birth [4].Therefore, once CMs are damaged, they are rarely restored [5]. When MI occurs, the infarcted area is easily converted to non-contractile scar tissue due to loss of CMs and replacement by fibrosis [6]. Development of a fibroblastic scar initiates a series of events that lead to adverse remodeling, hypertrophy, and eventual heart failure [2, 3, 7].

While heart transplantation is considered the most viable option for treating advanced heart failure, the number of available donor hearts is always less than needed [6]. Therefore, more realistic therapeutic options have been required [2]. Accordingly, over the past two decades, cell-based cardiac repair has been intensively pursued [2, 7]. Several different cell types have been tested and varied outcomes were obtained. Indeed, the key factor for successful cell-based cardiac repair is to find the optimal cell type that can restore normal heart function. Naturally, CMs have been considered the best cell type to repair a damaged heart [8]. In fact, many scientists hypothesized that implanted CMs would survive in damaged hearts and form junctions with host CMs and synchronously contract with the host myocardium [9]. In fact, animal studies with primary fetal or neonatal CMs demonstrated that transplanted CMs could survive in infarcted hearts [9-11]. These primary CMs reduced scar size, increased wall thickness, and improved cardiac contractile function with signs of electro-mechanical integration [9-11]. These studies strongly suggest that CMs can be a promising source to repair the heart. However, the short supply and ethical concerns disallow using primary human CMs. In a patient with ischemic cardiomyopathy, about 40-50% of the CMs are lost in 40 to 60 grams of heart tissue [7]. Even if we seek to regenerate a fairly small portion of the damaged myocardium, a large number of human primary CMs would be required, which is impossible.

Accordingly, CMs differentiated from human pluripotent stem cells (hPSCs) including both embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) have emerged as a promising option for candidate CMs for cell therapy [12, 13]. hPSCs have many advantages as a source for CMs. First, hPSCs have obvious cardiomyogenic potential. hPSC derived-CMs (hPSC-CMs) possess a clear cardiac phenotype, displaying spontaneous contraction, cardiac excitation-contraction (EC) coupling, and expression of cardiac transcription factors, cardiac ion channels, and cardiac structural proteins [14, 15]. Second, undifferentiated hPSCs and their differentiated cardiac progeny display significant proliferation capacity, allowing generation of a large number of hPSC-CMs. Lastly, many pre-clinical studies demonstrated that implantation of hPSC-CMs can repair injured hearts and improve cardiac function [16-19]. Histologically, implanted hPSC-CMs are engrafted, aligned and coupled with the host CMs in a synchronized manner [16-19].

In the last two decades, various protocols for differentiating hPSCs into CMs have been developed to improve the efficiency, purity and clinical compatibility [20] [18]. The reported differentiation methods include, but are not limited to: differentiation via embryoid body (EB) formation [20], co-culture with END-2 cells [18], and monolayer culture [15, 21, 22]. The EB-mediated CM differentiation protocol is one of the most widely employed methods due to its simple procedure and low cost. However, it often becomes labor-intensive to produce scalable EBs for further differentiation, which makes it difficult for therapeutic applications. EB-mediated differentiation also produces inconsistent results, showing beating CMs from 5% to 70% of EBs. Recently, researchers developed monolayer methods to complement the problems of EB-based methods [15, 21, 22]. In one representative protocol, hPSCs are cultured at a high density (up to 80%) and treated with a high concentration of Activin A (100 ng/ml) for 1 day and BMP4 (10 ng/ml) for 4 days followed by continuous culture on regular RPMI media with B27 [15]. This protocol induces spontaneous beating at approximately 12 days and produces approximately 40% CMs after 3 weeks. These hPSC-CMs can be further cultured in RPMI-B27 medium for another 2-3 weeks without significant cell damage [15]. However, these protocols use media with proprietary formulations, which complicates clinical application. As shown, most monolayer-based methods employ B27, which is a complex mix of 21 components. Some of the components of B27, including bovine serum albumin (BSA), are animal-derived products, and the effects of B27 components on differentiation, maturation or subtype specification processes are poorly defined. In 2014, Burridge and his colleagues developed an advanced protocol that is defined, cost-effective and efficient [22]. By subtracting one component from B27 at a time and proceeding with cardiac differentiation, the researchers reported that BSA and L-ascorbic acid 2-phosphate are essential components in cardiac differentiation. Subsequently, by replacing BSA with rice-derived recombinant human albumin, the chemically defined medium with 3 components (CDM3) was produced. The application of a GSK-inhibitor, CHIR99021, for the first 2 days followed by 2 days of the Wnt-inhibitor Wnt-59 to cells is an optimal culture condition in CDM3 resulting in similar levels of live-cell yields and CM differentiation [22].

Despite remarkable improvement in the generation of hPSC-CMs, obtaining pure populations of hPSC-CMs still remains challenging. Currently available methods can only generate a mixture of cells which include not only CMs but other cell types. This is one of the most critical barriers for applications of hPSC-CMs in regenerative therapy, drug discovery, and disease investigation. For Instance, cardiac transplantation of non-pure hPSC-CMs mixed with undifferentiated hPSCs or other cell types may produce tumors or unwanted cell types in hearts [23-28]. Accordingly, a pure or enriched population of hPSC-CMs would be required, particularly for cardiac cell therapy. Enriched hPSC-CMs would also be more beneficial for myocardial repair due to improved electric and mechanical properties [29]. A pure, homogeneous population of hPSC-CMs would pose less arrhythmic risk and have enhanced contractile performance, and would be more useful in disease modeling as they better reflect native CM physiology. Finally, purified hPSC-CMs would better serve for testing drug efficacy and toxicity. Therefore, many researchers have tried to develop methods to purify CMs from cardiomyogenically differentiated hPSCs.

There are three important topics that are not addressed in this review. First is the beneficial role of other cell types such as endothelial cells and fibroblasts in the integration, survival, and function of CMs [30-32]. We did not discuss this issue because it would need a separate review due to the volume of material. While the roles of such cells are important, the value of having purified hPSC-CMs is not diminished. Although cell mixtures or tissue engineered products can be used, unless purified CMs are employed, they would form tumors or other cells/tissues when implanted in vivo. Our point here is that even if cardiomyocytes are mixed with non-CMs, all cells should be clearly defined and purified as well. If the mixture is made in a non-purified or non-defined manner (for example, an unsophisticated top-down approach), there would be undefined cells that are neither CMs, ECs, nor fibroblasts and these unidentified cells will make aberrant tissues or tumors. Second, we did not deal with maturation of hPSC-CMs because of its broad scope and depth [33, 34]. Third is direct reprogramming or conversion of somatic cells into CMs. There has been another advancement in the generation of CMs by directly reprogramming or converting somatic cells into CM-like cells by introducing a combination of cardiac transcription factors (TFs) or muscle-specific microRNAs (miRNAs) both in vitro and in vivo [35-41]. These cells are referred to as induced CMs (iCMs) or cardiac-like myocytes (iCLMs). While this is an important advancement, we did not cover this topic either due to its size. Accordingly, this review will focus on the various strategies for purifying or enriching hPSC-CMs reported to date (Figure 1).

Early on, researchers isolated hPSC-CMs manually under microscopy by mechanically separating out the beating areas from myogenically differentiating hPSC cultures [18, 20, 42]. This method usually generates 5-70% hPSC-CMs. Although generally crude, it can enrich even higher percentages of CMs with further culture. This manual isolation method has the advantage of being easy, but while it can be useful for small-scale research, it is very labor intensive and not scalable, precluding large scale research or clinical application.

Currently available strategies for enriching cardiomyocytes derived from human pluripotent stem cells.

Xu et el. reported that hPSC-CMs, due to their physical and structural properties, can be enriched by Percoll density gradient centrifugation [43]. Percoll was first formulated by Pertoft et al [44] and it was originally developed for the isolation of cells, organelles, or viruses by density centrifugation. The Percoll-based method has several advantages. The procedure for Percoll-based separation is very simple and easy, it is inexpensive, and its low viscosity allows more rapid sedimentation and lower centrifugal forces compared to a sucrose density gradient. Lastly, it can be prepared and kept for a long time in an isotonic solution to maintain osmolarity. Although Percoll separation has resulted in major improvements in hPSC-CM isolation procedures, it has clear limitations with regard to purity and scalability. Previous studies found that Percoll separation is only able to enrich 40 -70% of hPSC-CMs. It is also not compatible with large-scale enrichment of hPSC-CMs.

Another traditional method for purifying hPSC-CMs is based on the expression of a drug resistant gene or a fluorescent reporter gene such as eGFP or DsRed, which is driven by a cardiac specific promoter in genetically modified hPSC lines [45, 46]. Here, enrichment of hPSC-CMs can be achieved by either drug treatment to eliminate cells that do not express the drug resistant gene or with FACS to isolate fluorescent cells [47, 48].

Briefly, enrichment of PSC-CMs by genetically based selection was first reported by Klug et al [49]. The authors generated murine ES cell lines via permanent gene transfection of the aminoglycoside phosphotransferase gene driven by the MHC (MYH7) promoter. With this approach, highly purified murine ESC-CMs up to 99% were achieved. Next, several studies reported the use of various CM-specific promoters to enrich ESC-CMs such as Mhc (Myh6), Myh7, Ncx (Sodium Calcium exchanger) and Mlc2v (Myl2) [46, 50, 51]. In the case of hESCs, MHC/EGFP hESCs were generated by permanent transfection of the EGFP-tagged MHC promoter [52]. Similarly, an NKX2.5/eGFP hESC line was generated to enrich GFP positive CMs [53]. However, since MHC and NKX2.5 are expressed in general CMs, the resulting CMs contain a mixture of the three subtypes of CMs, nodal-, atrial-, and ventricular-like CMs. To enrich only ventricular-like CMs, Huber et al. generated MLC2v/GFP ESCs to be able to isolate MLC2v/GFP positive ventricular-like cells by FACS [52] [54-57]. In addition, the cGATA6 gene was used to purify nodal-like hESC-CMs [58]. Future studies should focus on testing new types of cardiac specific promoters and devising advanced selection procedures to improve this strategy.

While fluorescence-based cell sorting is more widely used, the drug selection method may be a better approach to enrich high purity of hPSC-CMs during differentiation/culture as it does not require FACS. The advantage is its capability for high-purity cell enrichment due to specific gene-based cell sorting. These highly pure cells can allow more precise mechanistic studies and disease modeling. Despite its many advantages, the primary weakness of genetic selection is genetic manipulation, which disallows its use for therapeutic application. Insertion of reporter genes into the host genome requires viral or nonviral transfection/transduction methods, which can induce mutagenesis and tumor formation [50, 59-61].

Practically, antibody-based cell enrichment is the best method for cell purification to date. When cell type-specific surface proteins or marker proteins are known, one can tag cells with antibodies against the proteins and sort the target cells by FACS or magnetic-activated cell sorting (MACS). The main advantage is its specificity and sensitivity, and its utility is well demonstrated in research and even in clinical therapy with hematopoietic cells [62]. Another advantage is that multiple surface markers can be used at the same time to isolate target cells when one marker is not sufficient. However, no studies have reported surface markers that are specific for CMs, even after many years. Recently, though, several researchers demonstrated that certain proteins can be useful for isolating hPSC-CMs.

In earlier studies, KDR (FLK1 or VEGFR2) and PDGFR- were used to isolate cardiac progenitor cells [63]. However, since these markers are also expressed on hematopoietic cells, endothelial cells, and smooth muscle cells, they could not enrich only hPSC-CMs. Next, two independent studies reported two surface proteins, SIRPA [64] and VCAM-1 [65], which it was claimed could specifically identify hPSC-CMs. Dubois et al. screened a panel of 370 known antibodies against CMs differentiated from hESCs and identified SIRPA as a specific surface protein expressed on hPSC-CMs [64]. FACS with anti-SIRPA antibody enabled the purification of CMs and cardiac precursors from cardiomyogenically differentiating hPSC cultures, producing cardiac troponin T (TNNT2, also known as cTNT)-positive cells, which are generally considered hPSC-CMs, with up to 98% purity. In addition, a study performed by Elliot and colleagues identified another cell surface marker, VCAM1 [53]. In this study, the authors used NKX2.5/eGFP hESCs to generate hPSC-CMs, allowing the cells to be sorted by their NKX2.5 expression. NKX2.5 is a well-known cardiac transcription factor and a specific marker for cardiac progenitor cells [66, 67]. To identify CM-specific surface proteins, the authors performed expression profiling analyses and found that expression levels of both VCAM1 and SIRPA were significantly upregulated in NKX2.5/eGFP+ cells. Flow cytometry results showed that both proteins were expressed on the cell surface of NKX2.5/eGFP+ cells. Differentiation day 14 NKX2.5/eGFP+ cells expressed VCAM1 (71 %) or SIRPA (85%) or both VCAM1 and SIRPA (37%). When the FACS-sorted SIRPA-VCAM1-, SIRPA+ or SIRPA+VCAM1+ cells were further cultured, only SIRPA+ or SIRPA+VCAM1+ cells showed NKX2.5/eGFP+ contracting portion. Of note, NKX2.5/eGFP and SIRPA positive cells showed higher expression of smooth muscle cell and endothelial cell markers indicating that cells sorted solely based on SIRPA expression may not be of pure cardiac lineage. Hence, the authors concluded that a more purified population of hPSC-CMs could be isolated by sorting with both cell surface markers. Despite significant improvements, it appears that these surface markers are not exclusively specific for CMs as these antibodies also mark other cell types including smooth muscle cells and endothelial cells. Furthermore, they are also known to be expressed in the brain and the lung, which raises concerns whether these surface proteins can be used as sole markers for the purification of hPSC-CMs compatible for clinical applications.

More recently, Protze et al. reported successful differentiation and enrichment of sinoatrial node-like pacemaker cells (SANLPCs) from differentiating hPSCs by using cell surface markers and an NKX2-5-reporter hPSC line [68]. They found that BMP signaling specified cardiac mesoderm toward the SANLPC fate and retinoic acid signaling enhanced the pacemaker phenotype. Furthermore, they showed that later inhibition of the FGF pathway, the TFG pathway, and the WNT pathway shifted cell fate into SANLPCs, and final cell sorting for SIRPA-positive and CD90-negative cells resulted in enrichment of SANLPCs up to ~83%. These SIRPA+CD90- cells showed the molecular, cellular and electrophysiological characteristics of SANLPCs [68]. While this study makes important progress in enriching SANLPCs by modulating signaling pathways, no specific surface markers for SANLPCs were identified and the yield was still short of what is usually expected for cells purified via FACS.

Hattori et al. developed a highly efficient non-genetic method for purifying hPSC-derived CMs, in which they employed a red fluorescent dye, tetramethylrhodamine methyl ester perchlorate (TMRM), that can label active mitochondria. Since CMs contain a large number of mitochondria, CMs from mice and marmosets (monkey) could be strongly stained with TMRM [69]. They further found that primary CMs from several different types of animals and CMs derived from both mESCs and hESCs were successfully purified by FACS up to 99% based on the TMRM signals. In addition to its efficiency for CM enrichment, TMRM did not affect cell viability and disappeared completely from the cells within 24 hrs. Importantly, injected hPSC-CMs purified in this way did not form teratoma in the heart tissues. However, since TMRM only functions in CMs with high mitochondrial density, this method cannot purify entire populations of hPSC-CMs [64]. While originally TMRM was claimed to be able to isolate mature hPSC-CMs, mounting evidence indicates that hPSC-CMs are similar to immature human CMs at embryonic or fetal stages. Therefore, both the exact phenotype of the cells isolated by TMRM and its utility are rather questionable [33, 34]. Two subsequent studies demonstrated that TMRM failed to accurately distinguish hPSC-CMs due to the insufficient amounts of mitochondria [64].

Employing the unique metabolic properties of CMs, Tohyama et al. developed an elegant purification method to enrich PSC-CMs [70]. This approach is based on the remarkable biochemical differences in lactate and glucose metabolism between CMs and non-CMs, including undifferentiated cells. Mammalian cells use glucose as their main energy source [71]. However, CMs are capable of energy production from different sources such as lactate or fatty acids [71]. A comparative transcriptome analysis was performed to detect metabolism-related genes which have different expression patterns between newborn mouse CMs and undifferentiated mouse ESCs. These results showed that CMs expressed genes encoding tricarboxylic acid (TCA) cycle enzymes more than genes related to lipid and amino acid synthesis and the pentose phosphate cycle compared to undifferentiated ESCs. To further prove this observation, they compared the metabolites of these pathways using fluxome analysis between CMs and other cell types such as ESCs, hepatocytes and skeletal muscle cells, and found that CMs have lower levels of metabolites related to lipid and amino acid synthesis and pentose phosphate. Subsequently, authors cultured newborn rat CMs and mouse ESCs in media with lactate, forcing the cells to use the TCA cycle instead of glucose, and they observed that CMs were the only cells to survive this condition for even 96 hrs. They further found that when PSC derivatives were cultured in lactate-supplemented and glucose-depleted culture medium, only CMs survived. Their yield of CM population was up to 99% and no tumors were formed when these CMs were transplanted into hearts. This lactate-based method has many advantages: its simple procedures, ease of application, no use of FACS for cell sorting, and relatively low cost. More recently, this method was applied to large-scale CM aggregates to ensure scalability. As a follow-up study, the same group recently reported a more refined lactate-based enrichment method which further depletes glutamine in addition to glucose [72]. The authors found that glutamine is essential for the survival of hPSCs since hPSCs are highly dependent on glycolysis for energy production rather than oxidative phosphorylation. The use of glutamine- and glucose-depleted lactate-containing media resulted in more highly purified hPSC-CMs with less than 0.001% of residual PSCs [72]. One concern of this lactate-based enrichment method is the health of the purified hPSC-CMs, because physiological and functional characteristics of hPSC-CMs cultured in glucose- and glutamine-depleted media for a long time may have functional impairment since CMs with mature mitochondria were not able to survive without glucose and glutamine, although they were able to use lactate to synthesize pyruvate and glutamate [72]. In addition, this lactate-based strategy can only be applied to hPSC- CMs, but not other hPSC derived cells such as neuron or -cells.

Our group also recently reported a new method to isolate hPSC-CMs by directly labelling cardiac specific mRNAs using nano-sized probes called molecular beacons (MBs) [29, 73, 74]. Designed to detect intracellular mRNA targets, MBs are dual-labeled antisense oligonucleotide (ODN) nano-scale probes with a DNA or RNA backbone, a Cy3 fluorophore at the 5' end, and a Black Hole quencher 2 (BHQ2) at the 3' end [75, 76]. They form a stem-loop (hairpin) structure in the absence of a complementary target, quenching the fluorescence of the reporter. Hybridization with the target mRNA opens the hairpin and physically separates the reporter from the quencher, allowing a fluorescence signal to be emitted upon excitation. The MB-based method can be applied to the purification of any cell type that has known specific gene(s) [77].

In one study [29], we designed five MBs targeting unique sites in TNNT2 or MYH6/7 mRNA in both mouse and human. To determine the most efficient transfection method to deliver MBs into living cells, various methods were tested and nucleofection was found to have the highest efficiency. Next, we tested the sensitivity and specificity of MBs using an immortalized mouse CM cell line, HL-1, and other cell types. Finally, we narrowed it down to one MB, MHC-MB, which showed >98% sensitivity and > 95% specificity. This MHC-MB was applied to cardiomyogenically differentiated mouse and human PSCs and FACS sorting was performed. The resultant MHC-MB-positive cells expressed cardiac proteins at ~97% when measured by flow cytometry. These sorted cells also demonstrated spontaneous contraction and all the molecular and electrophysiological signatures of human CMs. Importantly, when these purified CMs were injected into the mouse infarcted myocardium, they were well integrated into the myocardium without forming any tumors, and they improved cardiac function.

In a subsequent study [74], we refined a method to enrich ventricular CMs from differentiating PSCs (vCMs) by targeting a transcription factor which is not robustly expressed in cells. Since vCMs are the main source for generating cardiac contractile forces and the most frequently damaged in the heart, there has been great demand to develop a method that can obtain a pure population of vCMs for cardiac repair. Despite this critical unmet need, no studies have demonstrated the feasibility of isolating ventricular CMs without permanently altering their genome. Accordingly, we first designed MBs targeting the Iroquois homeobox protein 4 (Irx4) mRNA, a vCM specific transcription factor [78, 79]. After testing sensitivity and specificity, one IRX4-MB was selected and applied to myogenically differentiated mPSCs. The FACS-sorted IRX4-MB-positive cells exhibited vCM-like action potentials in more than 98% of cells when measured by several electrophysiological analyses including patch clamp and Ca2+ transient analyses. Furthermore, these cells maintained spontaneous contraction and expression of vCM-specific proteins.

The MB-based cell purification method is theoretically the most broadly applicable technology among the purification methods because it can isolate any target cells expressing any specific gene. Thus, the MB-based sorting technique can be applied to the isolation of other cell types such as neural-lineage cells or islet cells, which are critical elements in regenerative medicine but do not have specific surface proteins identified to date. In addition, theoretically, this technology may have the highest efficiency when MBs are designed to have the maximum sensitivity and specificity for the cells of interest, but not others. These characteristics are particularly important for cell therapy. Despite these advantages, the delivery method of MB into the cells needs to be improved. So far, nucleofection is the best delivery method, but caused some cell damage with

Recently, Miki and colleagues reported a novel method for purifying cells of interest based on endogenous miRNA activity [80]. Miki et al. employed several synthetic mRNA switches (= miRNA switch), which consist of synthetic mRNA sequences that include a recognition sequence for miRNA and an open reading frame that codes a desired gene, such as a regulatory protein that emits fluorescence or promotes cell death. If the miRNA recognition sequence binds to miRNA expressed in the desired cells, the expression of the regulatory protein is suppressed, thus distinguishing the cell type from others that do not contain the miRNA and express the protein.

Briefly, the authors first identified 109 miRNA candidates differentially expressed in distinct stages of hPSC-CMs (differentiation day 8 and 20). Next, they found that 14 miRNAs were co-expressed in hPSC-CMs at day 8 and day 20 and generated synthetic mRNAs that recognize these 14 miRNA, called miRNA switches. Among those miRNA switches, miR-1-, miR-208a-, and miR-499a-5p-switches successfully enriched hPSC-CMs with purity of sorted cells up to 96% determined by TNNT2 intracellular flow cytometry. Particularly, hPSC-CMs enriched by the miR-1-switch showed substantially higher expression of several cardiac specific genes/proteins and lower expression of non-CM genes/proteins compared with control cells. Patch clamp confirmed that these purified hPSC-CMs possessed both ventricular-like and atrial-like action potentials.

One of the major advantages of this technology is its wider applicability to other cell types. miRNA switches have the flexibility to design the open reading frame in the mRNA sequence such that any desired transgene can be incorporated into the miRNA switches to regulate the cell phenotype based on miRNA activity. The authors tested this possibility by incorporating BIM sequence, an apoptosis inducer, into the cardiac specific miR-1- and miR-208a switches and tested whether they could selectively induce apoptosis in non-CMs. They found that miR-1- and miR-208a-Bim-switches successfully enriched cTNT-positive hPSC-CMs without cell sorting. Enriched hPSC-CMs by 208a-Bim-switch were injected into the hearts of mice with acute MI and they engrafted, survived, expressed both cTNT and CX43, and formed gap junctions with the host myocardium. No teratoma was detected. In addition, other miRNA switches such as miR-126-, miR-122-5p-, and miR-375-switches targeting endothelial cells, hepatocytes, and -cells, respectively, successfully enriched these cell types differentiated from hPSCs. However, identification of specific miRNAs expressed only in the specific cell type of interest and verification of their specificity in target cells will be key issues for continuing to use this miRNA-based cell enrichment method.

Recent advances in biomedical engineering have contributed to developing systems that can isolate target cells using physicochemical properties of the cells. Microfluidic systems have been intensively applied for cell separation due to recent improvements in miniaturizing a cell culture system [81-83]. These advances made possible the design of automated microfluidic devices with cellular microenvironments and controlled fluid flows that save time and cost in experiments. Thus, there have been an increasing number of studies seeking to apply the microfluidic system for cell separation. Among the first, Singh et al. tested the possibility of using a microfluidic system for the separation of hPSC [84] by preparative detachment of hPSCs from differentiating cultures based on differences in the adhesion properties of different cell types. Distinct streams of buffer that generated varying levels of shear stress further allowed selective enrichment of hPSC colonies from mixed populations of adherent non-hPSCs, achieving up to 95% purity. Of note, this strategy produced hPSC survival rates almost two times higher than FACS, reaching 80%.

Subsequently, for hPSC-CMs purification, Xin et al. developed a microfluidic system with integrated ridge-like flow derivations and fishnet-like microcolumns for the enrichment of hiPSC-CMs [85]. This device is composed of a 250 mm-long microfluidic channel, which has two integrated parallel microcolumns with surfaces functionalized with anti-human TRA-1 antibody for undifferentiated hiPSC trapping. Aided by the ridge-like surface patterns on the upper wall of the channel, micro-streams are generated so that the cell suspension of mixed undifferentiated hiPSCs and hiPSC-CMs are forced to cross the functionalized fishnet-like microcolumns, resulting in trapping of undifferentiated hiPSCs due to the interaction between the hiPSCs and the columns, and the untrapped hiPSC-CMs are eventually separated. By modulating flow and coating with anti-human TRA-1 antibody, they were able to enrich CMs to more than 80% purity with 70% viability. While this study demonstrated that a microfluidic device could be used for purifying hPSC-CMs, it was not realistic because the authors used a mixture of only undifferentiated hiPSCs and hiPSC-CMs. In real cardiomyogenically differentiated hiPSCs, undifferentiated hiPSCs are rare and many intermediate stage cells or other cell types are present, so the idea that this simple device can select only hiPSC-CMs from a complex mixture is uncertain.

Overall, the advantages of microfluidic system based cell isolation include fast speed, improved cell viability and low cost owing to the automated microfluidic devices that can control cellular microenvironments and fluid flows [86-88]. However, microfluidic-based cell purification methods have limitations in terms of low purity and scalability [89-92]. In fact, there have been only a few studies demonstrating the feasibility that microfluidic device-based cell separation could achieve higher than 80% purity of target cells. Furthermore, currently available microfluidic devices allow only separation of a small number of cells ( 95% purity.

Having available a large quantity of a homogeneous population of cells of interest is an important factor in advancing biomedical research and clinical medicine, and is especially true for hPSC-CMs. While remarkable progress has been made in the methods for differentiating hPSCs into CMs, technologies to enrich hPSC-CMs, particularly those which are clinically applicable, have been emerging only over the last few years. Contamination with other cell types and even the heterogeneous nature of hPSC-CMs significantly hinder their use for several future applications such as cardiac drug toxicology screening, human cardiac disease modeling, and cell-based cardiac repair. For instance, cardiac drug-screening assays require pure populations of hPSC-CMs, so that the observed signals can be attributed to effects on human CMs. Studies of human cardiac diseases can also be more adequately interpreted with purified populations of patient derived hiPSC-CMs. Clinical applications with hPSC-CMs will need to be free of other PSC derivatives to minimize the risk of teratoma formation and other adverse outcomes.

Summary of representative methods for hPSC-CM purification

Schematic pictures of microfluidic device for enriching hiPSC-CMs. (A) The part of the device designed for trapping undifferentiated hiPSCs. (B) (Left) Illustration of the overall microfluidic device assembled with peristaltic pump, cell suspension reservoirs, and a serpentine channel. (Right) Magnified image showing a channel combining microcolumns and ridge-like flow derivation structures. Modified from Li et al. On chip purification of hiPSC-derived cardiomyocytes using a fishnet-like microstructure. Biofabrication. 2016 Sep 8;8(3): 035017

Therefore, development of reproducible, effective, non-mutagenic, scalable, and economical technologies for purifying hPSC-CMs, independent of hPSC lines or differentiation protocols, is a fundamental requirement for the success of hPSC-CM applications. Fortunately, new technologies based on the biological specificity of CMs such as MITO-tracker, molecular beacons, lactate-enriched-glucose depleted-media, and microRNA switches have been developed. In addition, technologies based on engineering principles have recently yielded a promising platform using microfluidic technology. While due to the short history of this field, more studies are needed to verify the utility of these technologies, the growing attention toward this research is a welcome move.

Another important question raised recently is how to non-genetically purify chamber-specific subtypes of CMs such as ventricular-like, atrial-like and nodal-like hPSC-CMs. So far, only a few studies have addressed this potential with human PSCs. We also showed that a molecular beacon-based strategy could enrich ventricular CMs differentiated from PSCs [74]. Another study demonstrated generation of SA-node like pacemaker cells by using a stepwise treatment of various morphogens and small molecules followed by cell sorting with several sub-specific surface markers. However, the yield of both studies was relatively low (

In summary, technological advances in the purification of hPSC-CMs have opened an avenue for realistic application of hPSC-CMs. Although initial success was achieved for purification of CMs from differentiating hPSC cultures, questions such as scalability, clinical compatibility, and cellular damage remain to be answered and isolation of human subtype CMs has yet to be demonstrated. While there are other challenges such as maturity, in vivo integration, and arrhythmogenecity, this development of purification technology represents major progress in the field and will provide unprecedented opportunities for cell-based therapy, disease modeling, drug discovery, and precision medicine. Furthermore, the availability of chamber-specific CMs with single cell analyses will facilitate more sophisticated investigation of human cardiac development and cardiac pathophysiology.

This work was supported by the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (MSIP) (No 2015M3A9C6031514), the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI15C2782, HI16C2211) and grants from NHLBI (R01HL127759, R01HL129511), NIDDK (DP3-DK108245). This work was also supported by a CityU Start-up Grant (No 7200492), a CityU Research Project (No 9610355), and a Georgia Immuno Engineering Consortium through funding from Georgia Institute of Technology, Emory University, and the Georgia Research Alliance.

The authors have declared that no competing interest exists.

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15. Laflamme MA, Chen KY, Naumova AV, Muskheli V, Fugate JA, Dupras SK. et al. Cardiomyocytes derived from human embryonic stem cells in pro-survival factors enhance function of infarcted rat hearts. Nat Biotechnol. 2007;25:1015-24

16. Yuasa S, Itabashi Y, Koshimizu U, Tanaka T, Sugimura K, Kinoshita M. et al. Transient inhibition of BMP signaling by Noggin induces cardiomyocyte differentiation of mouse embryonic stem cells. Nat Biotechnol. 2005;23:607-11

17. Nemir M, Croquelois A, Pedrazzini T, Radtke F. Induction of cardiogenesis in embryonic stem cells via downregulation of Notch1 signaling. Circ Res. 2006;98:1471-8

18. Mummery C, Ward-van Oostwaard D, Doevendans P, Spijker R, van den Brink S, Hassink R. et al. Differentiation of human embryonic stem cells to cardiomyocytes: role of coculture with visceral endoderm-like cells. Circulation. 2003;107:2733-40

19. Passier R, Oostwaard DW, Snapper J, Kloots J, Hassink RJ, Kuijk E. et al. Increased cardiomyocyte differentiation from human embryonic stem cells in serum-free cultures. Stem Cells. 2005;23:772-80

20. Kehat I, Kenyagin-Karsenti D, Snir M, Segev H, Amit M, Gepstein A. et al. Human embryonic stem cells can differentiate into myocytes with structural and functional properties of cardiomyocytes. J Clin Invest. 2001;108:407-14

21. Yang L, Soonpaa MH, Adler ED, Roepke TK, Kattman SJ, Kennedy M. et al. Human cardiovascular progenitor cells develop from a KDR+ embryonic-stem-cell-derived population. Nature. 2008;453:524-8

22. Burridge PW, Matsa E, Shukla P, Lin ZC, Churko JM, Ebert AD. et al. Chemically defined generation of human cardiomyocytes. Nat Methods. 2014;11:855-60

23. Kehat I, Kenyagin-Karsenti D, Snir M, Segev H, Amit M, Gepstein A. et al. Human embryonic stem cells can differentiate into myocytes with structural and functional properties of cardiomyocytes. J Clin Invest. 2001;108:407-14

24. Zhang J, Wilson GF, Soerens AG, Koonce CH, Yu J, Palecek SP. et al. Functional cardiomyocytes derived from human induced pluripotent stem cells. Circ Res. 2009;104:e30-41

25. Nussbaum J, Minami E, Laflamme MA, Virag JAI, Ware CB, Masino A. et al. Transplantation of undifferentiated murine embryonic stem cells in the heart: teratoma formation and immune response. FASEB J. 2007;21:1345-57

26. Lee AS, Tang C, Rao MS, Weissman IL, Wu JC. Tumorigenicity as a clinical hurdle for pluripotent stem cell therapies. Nat Med. 2013;19:998-1004

27. Masuda S, Miyagawa S, Fukushima S, Sougawa N, Ito E, Takeda M. et al. Emerging innovation towards safety in the clinical application of ESCs and iPSCs. Nat Rev Cardiol. 2014;11:553-4

28. Masuda S, Miyagawa S, Fukushima S, Sougawa N, Okimoto K, Tada C. et al. Eliminating residual iPS cells for safety in clinical application. Protein Cell. 2015;6:469-71

29. Ban K, Wile B, Kim S, Park H-J, Byun J, Cho K-W. et al. Purification of cardiomyocytes from differentiating pluripotent stem cells using molecular beacons that target cardiomyocyte-specific mRNA. Circulation. 2013;128:1897-909

30. Masumoto H, Ikuno T, Takeda M, Fukushima H, Marui A, Katayama S. et al. Human iPS cell-engineered cardiac tissue sheets with cardiomyocytes and vascular cells for cardiac regeneration. Sci Rep. 2014;4:6716

31. Kensah G, Roa Lara A, Dahlmann J, Zweigerdt R, Schwanke K, Hegermann J. et al. Murine and human pluripotent stem cell-derived cardiac bodies form contractile myocardial tissue in vitro. Eur Heart J. 2013;34:1134-46

32. Thavandiran N, Dubois N, Mikryukov A, Mass S, Beca B, Simmons CA. et al. Design and formulation of functional pluripotent stem cell-derived cardiac microtissues. Proc Natl Acad Sci U S A. 2013;110:E4698-E707

33. Yang X, Pabon L, Murry CE. Engineering adolescence: maturation of human pluripotent stem cell-derived cardiomyocytes. Circ Res. 2014;114:511-23

34. Robertson C, Tran DD, George SC. Concise review: maturation phases of human pluripotent stem cell-derived cardiomyocytes. Stem Cells. 2013;31:829-37

35. Ieda M, Fu JD, Delgado-Olguin P, Vedantham V, Hayashi Y, Bruneau BG. et al. Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors. Cell. 2010;142:375-86

36. Qian L, Huang Y, Spencer CI, Foley A, Vedantham V, Liu L. et al. In vivo reprogramming of murine cardiac fibroblasts into induced cardiomyocytes. Nature. 2012;485:593-8

37. Jayawardena TM, Egemnazarov B, Finch EA, Zhang L, Payne JA, Pandya K. et al. MicroRNA-mediated in vitro and in vivo direct reprogramming of cardiac fibroblasts to cardiomyocytes. Circ Res. 2012;110:1465-73

38. Song K, Nam YJ, Luo X, Qi X, Tan W, Huang GN. et al. Heart repair by reprogramming non-myocytes with cardiac transcription factors. Nature. 2012;485:599-604

39. Nam YJ, Song K, Luo X, Daniel E, Lambeth K, West K. et al. Reprogramming of human fibroblasts toward a cardiac fate. Proc Natl Acad Sci U S A. 2013;110:5588-93

40. Jayawardena TM, Finch EA, Zhang L, Zhang H, Hodgkinson CP, Pratt RE. et al. MicroRNA induced cardiac reprogramming in vivo: Evidence for mature cardiac myocytes and improved cardiac function. Circ Res. 2015;116:418-24

41. Wada R, Muraoka N, Inagawa K, Yamakawa H, Miyamoto K, Sadahiro T. et al. Induction of human cardiomyocyte-like cells from fibroblasts by defined factors. Proc Natl Acad Sci U S A. 2013;110:12667-72

42. Caspi O, Huber I, Kehat I, Habib M, Arbel G, Gepstein A. et al. Transplantation of human embryonic stem cell-derived cardiomyocytes improves myocardial performance in infarcted rat hearts. J Am Coll Cardiol. 2007;50:1884-93

43. Xu C, Police S, Rao N, Carpenter MK. Characterization and enrichment of cardiomyocytes derived from human embryonic stem cells. Circ Res. 2002;91:501-8

44. Pertoft H, Laurent TC, Ls T, Kgedal L. Density gradients prepared from colloidal silica particles coated by polyvinylpyrrolidone (Percoll). Anal Biochem. 1978;88:271-82

45. Doevendans PA, Becker KD, An RH, Kass RS. The utility of fluorescentin vivoreporter genes in molecular cardiology. Biochem Biophys Res Commun. 1996;222:352-8

46. Ritner C, Wong SSY, King FW, Mihardja SS, Liszewski W, Erle DJ. et al. An engineered cardiac reporter cell line identifies human embryonic stem cell-derived myocardial precursors. PLoS One. 2011;6:e16004

47. Ma J, Guo L, Fiene SJ, Anson BD, Thomson JA, Kamp TJ. et al. High purity human-induced pluripotent stem cell-derived cardiomyocytes: electrophysiological properties of action potentials and ionic currents. Am J Physiol Heart Circ Physiol. 2011;301:H2006-H17

48. Xu XQ, Zweigerdt R, Soo SY, Ngoh ZX, Tham SC, Wang ST. et al. Highly enriched cardiomyocytes from human embryonic stem cells. Cytotherapy. 2008;10:376-89

49. Klug MG, Soonpaa MH, Koh GY, Field LJ. Genetically selected cardiomyocytes from differentiating embronic stem cells form stable intracardiac grafts. J Clin Invest. 1996;98:216-24

50. Anderson D, Self T, Mellor IR, Goh G, Hill SJ, Denning C. Transgenic enrichment of cardiomyocytes from human embryonic stem cells. Mol Ther. 2007;15:2027-36

51. Fu J-D, Jiang P, Rushing S, Liu J, Chiamvimonvat N, Li RA. Na+/Ca2+ exchanger is a determinant of excitation-contraction coupling in human embryonic stem cell-derived ventricular cardiomyocytes. Stem Cells Dev. 2009;19:773-82

52. Huber I, Itzhaki I, Caspi O, Arbel G, Tzukerman M, Gepstein A. et al. Identification and selection of cardiomyocytes during human embryonic stem cell differentiation. FASEB J. 2007;21:2551-63

53. Elliott DA, Braam SR, Koutsis K, Ng ES, Jenny R, Lagerqvist EL. et al. NKX2-5(eGFP/w) hESCs for isolation of human cardiac progenitors and cardiomyocytes. Nat Methods. 2011;8:1037-40

54. Bizy A, Guerrero-Serna G, Hu B, Ponce-Balbuena D, Willis BC, Zarzoso M. et al. Myosin light chain 2-based selection of human iPSC-derived early ventricular cardiac myocytes. Stem Cell Res. 2013;11:1335-47

55. Lee MY, Sun B, Schliffke S, Yue Z, Ye M, Paavola J. et al. Derivation of functional ventricular cardiomyocytes using endogenous promoter sequence from murine embryonic stem cells. Stem Cell Res. 2012;8:49-57

56. MLLER M, FLEISCHMANN BK, SELBERT S, JI GJ, ENDL E, MIDDELER G. et al. Selection of ventricular-like cardiomyocytes from ES cells in vitro. FASEB J. 2000;14:2540-8

57. Zhang Q, Jiang J, Han P, Yuan Q, Zhang J, Zhang X. et al. Direct differentiation of atrial and ventricular myocytes from human embryonic stem cells by alternating retinoid signals. Cell Res. 2011;21:579-87

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Bone Marrow & Stem Cell Transplant | Weill Cornell Medicine

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Bone Marrow & Stem Cell Transplant

The Bone Marrow and Stem Cell Transplant Program at Weill Cornell Medicine was established with the mission of providing the best care and most innovative research in a compassionate and comfortable environment.

We take a multidisciplinary approach to care for patients with cancer and blood diseases who need stem cell transplants, providing world-class clinical care in collaboration with experts in leukemia, lymphoma, myeloma and other blood disorders. Based at NewYork-Presbyterian/Weill Cornell Medical Center, one of the top ten general hospitals in the nation, the expertise of our consulting team is unsurpassed.

Our patients and families cope with life-threatening illness; as such, sensitivity and compassion are a priority for our team. We view each patient as an individual, and our approach ensures that each treatment regimen is narrowly tailored to meet the unique, changing needs of our patients and their families before, during and after transplant.

As New Yorks premier healthcare institution, Weill Cornell Medicine is at the forefront of scientific research and clinical trials, enabling us to provide a full range of diagnostic and treatment protocols, including the latest breakthroughs in medicine.

Our Team

Our team of internationally-recognized bone marrow transplant and stem cell surgery specialists is known for advanced work and published research in:

Treating patients with aggressive leukemia and myelodysplastic syndromes

Bridge protocols for patients with refractory lymphoma and leukemia

Novel strategies to mobilize stem cells and improve transplantation for patients with multiple myeloma, leukemia and lymphoma

Transplants for solid tumors, severe auto-immune disorders, and AIDS


We pride ourselves on exceptional outcomes and offer patients the most advanced diagnostic methods and treatment therapies to improve quality of life, including:

Umbilical cord blood transplant

Outpatient transplant

Autologous stem cell transplant; uses stem cells extracted from the bone marrow or peripheral blood of the patients own blood

Allogeneic stem cell transplant; uses stem cells extracted from the bone marrow or peripheral blood of a matching donor

Hematopoietic stem cell transplant; used to treat certain cancers of the blood/bone marrow, including leukemia and myeloma

Matched unrelated donor stem cell transplantation through the National Donor Matching Program

Non-ablative "mini" transplants

Haplo-Cord Transplant, allowing us to find donors for all patients, regardless of age or ethnic background

Bendamustine, a therapy that is well-tolerated and has excellent response rates in patients with myeloma

Novel forms of transplant, offering hope and success to older patients with leukemia

Clinical Trials

Clinical trials are important to improve outcomes and offer new treatment options. At Weill Cornell Medicine, we conduct more studies in blood cancers than any of our regional peers, allowing us to provide our patients with access to many multi-phase clinical trials. As active members of the international cancer research community, our oncologists also collaborate with other research centers to offer patients the most promising treatments available.

Second Opinions

In concert with your referring physician, we are always available to offer a second opinion in the form of a consultation with one of our specialists.

Why Choose Us?

Our collaborative approach means our patients receive supportive, comprehensive care and the most cutting-edge stem cell therapy and treatments. This enables patients to receive the best possible transplant outcomes. Additionally, we offer more allogeneic stem cell transplants for older adults than any other center in New York City and the entire tri-state area.

For more information or to schedule an appointment, call us at 212-746-2119 or 212-746-2646.

Located in New York City, Weill Cornell Medical College is ranked among the nations best by U.S. News & World Report year after year.

Bone Marrow & Stem Cell Transplant | Weill Cornell Medicine

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Spinal Neurons Grown From Stem Cells For First Time | News …

By admin

Modern medicine has still not managed to crack the problem of spinal cord injuries that result in significant paralysis or loss of functional status.

There are numerous factors that influence the inability to restore movement or autonomous bodily control to these patients. A prominent example of these is the inability to cultivate new neurons that make up and power the spinal cord.

However, some researchers have claimed that they have successfully induced generic human stem cells to differentiate into stem cells that apply more specifically to the spine.

Why We Cant Repair a Spine (Yet)

Strategies involving the implantation of any kind of donor cell to regenerate or recreate damaged spinal tissue have not shown much success. Furthermore, some medical researchers also believe that such forays into regenerative medicine are not feasible, in terms of costs and resources, at this point. Therefore, this area of cell-based therapy is still very much at the development stage.

The goals of many current projects in this area revolve around the restoration of the motor function in subjects (mostly rodents in animal models). This requires the full re-generation and reinstatement of the corticospinal tract (CST), an important spinal region that communicates with the relevant cortices in the brain.

A limited number of reports claim to have achieved this. However, this leaves the rest of the spine un-addressed, which may have a residual effect on movement and other functions.

New Direction in Cell-Based Therapy for Spinal Injuries

In the past, CST-based trials used grafts of multipotent cells, which were progenitor cells rather than true stem cells.

However, a newer study has documented a technique in which human pluripotent stem cells were used, which could differentiate into all the cells a spinal section needs, and not just the CST ones.

Reportedly, these neural stem cells further diversified into different types of neurons. Therefore, it can be concluded that neural stem cells may be capable of more complete regeneration of missing or damaged spinal tissue in living subjects.

The researchers behind the apparent breakthrough claimed that their cells were capable of doing this in an appropriate model. However, the research was conducted by causing the stem cells to grow a customized spinal graft, which was then transplanted using the model.

A transverse spinal section showing some functions of various spinal region. (Source: Public Domain)

The scientists claimed that these grafts integrated well with the sections of pre-existing spinal tissue upstream and downstream of the graft location. These consisted of various intra-, supra- and cortico-spinal networks of neural connections, which allowed peripheral nervous functions, including movement, under normal circumstances.

In addition, it is necessary for these networks to distinguish between the dorsal (or backward-facing) and ventral portions of the spine. This is because these regions send different signals to the brain in different directions in the average healthy spine. The researchers asserted that their spinal grafts were indeed capable of these distinctions.

The scientists behind this project reported that their models subjects gained increased functional status as a result of receiving one of these grafts. However, it can be assumed that these assertions are getting slightly ahead of their time, in terms of being approved as a real-world treatment.

The researchers also noted that their new spinal stem cells and the neurons that they differentiate into can be used as an excellent in vitro model for the neurobiology of the spine. In addition, the cells may also now be used to test other novel potential treatments for spinal disorders.


The scientists behind this project collaborated across the departments of neurosciences and psychiatry & neurology at the University of California (Los Angeles), as well as the San Diego Veterans Administrations Healthcare System. The team published their findings in an August 2018 issue of Nature Methods.

The researchers also hope that future work on this model could lead to the application of their cells to next-generation regenerative medicine that focuses on the spine and how to repair it after injury or damage.

Therefore, we may be able to look forward to a time, in which improved medicine could restore paraplegic patients to the health and autonomy that they may cherish.

Top Image: The spine is an important component of the human nervous system. (Source: Pixabay)


H. Kumamaru, et al. (2018) Generation and post-injury integration of human spinal cord neural stem cells. Nature Methods.

S. A. Goldman. (2016) Stem and Progenitor Cell-Based Therapy of the Central Nervous System: Hopes, Hype, and Wishful Thinking. Cell Stem Cell. 18:(2). pp.174-188.

K. Kadoya, et al. (2016) Spinal cord reconstitution with homologous neural grafts enables robust corticospinal regeneration. Nat Med. 22:(5). pp.479-487.

Deirdre ODonnell

Spinal Neurons Grown From Stem Cells For First Time | News ...

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What is VetStem Regenerative Medicine? | Why Use Adipose …

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VetStem Technology: Summary

VetStem Regenerative Cell Therapy is based on a clinical technology licensed from Artecel Inc. Original patents are from the University of Pittsburgh and Duke University.

Adipose-derived regenerative cells are:

VetStem Regenerative Cell (VSRC) therapy delivers a functionally diverse cell population able to communicate with other cells in their local environment. Until recently, differentiation was thought to be the primary function of regenerative cells. However, the functions of regenerative cells are now known to be much more diverse and are implicated in a highly integrated and complex network. VSRC therapy should be viewed as a complex, yet balanced, approach to a therapeutic goal. Unlike traditional medicine, in which one drug targets one receptor, Regenerative Medicine, including VSRC therapy, can be applied in a wide variety of traumatic and developmental diseases. Regenerative cell functions include:

In general, in vitro studies demonstrate that MSCs limit inflammatory responses and promote anti-inflammatory pathways.

Multiple studies demonstrate that MSCs secrete bioactive levels of cytokines and growth factors that support angiogenesis, tissue remodeling, differentiation, and antiapoptotic events.25,28 MSCs secrete a number of angiogenesis-related cytokines such as:28

Adipose-derived MSC studies demonstrate a diverse plasticity, including differentiation into adipo-, osteo-, chondro-, myo-, cardiomyo-, endothelial, hepato-, neuro-, epithelial, and hematopoietic lineages, similar to that described for bone marrow derived MSCs.22 These data are supported by in vivo experiments and functional studies that demonstrated the regenerative capacity of adipose-derived MSCs to repair damaged or diseased tissue via transplant engraftment and differentiation.6,9,30

Homing (chemotaxis) is an event by which a cell migrates from one area of the body to a distant site where it may be needed for a given physiological event. Homing is an important function of MSCs and other progenitor cells and one mechanism by which intravenous or parenteral administration of MSCs permits an auto-transplanted therapeutic cell to effectively target a specific area of pathology.

Adipose-derived regenerative cells contain endothelial progenitor cells and MSCs that assist in angiogenesis and neovascularization by the secretion of cytokines, such as hepatic growth factor (HGF), vascular endothelial growth factor (VEGF), placental growth factor (PGF), transforming growth factor (TGF), fibroblast growth factor (FGF-2), and angiopoietin.25

Apoptosis is defined as a programmed cell death or cell suicide, an event that is genetically controlled.35 Under normal conditions, apoptosis determines the lifespan and coordinated removal of cells. Unlike during necrosis, apoptotic cells are typically intact during their removal (phagocytosis).

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Stem cell-filled implant restores some spinal cord …

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Stem cell-filled implants helped repair spinal cord damage in animals, according to a study led by UC San Diego scientists. If all goes well, the implants with neural stem cells could be ready for testing in human patients in a few years.

Rats with completely severed spinal cords regained some voluntary motion after getting the implants, said the study, published Monday in the journal Nature Medicine. The study is online at

They were able to move the joints of their lower legs, said study co-author Dr. Mark Tuszynski. They couldn't support their weight very well, but they could move the legs around the joints. If one were to project what this means to humans, it might mean that the legs are still weak, but that with an assist they would be able to control them.

The next step is to repeat the procedure in monkeys, said Tuszynski, director of the Translational Neuroscience Institute at UC San Diego School of Medicine.

If successful, it would fulfill one of the biggest hopes for stem cell therapy.

Repairing spinal cord injuries has long been a major goal of the states stem cell program, the California Institute for Regenerative Medicine, or CIRM. The agency was formed in 2004 with the passage of Prop. 71. The late actor Christopher Reeve figured prominently in the campaign for Prop. 71.

While there have been encouraging reports of individual spinal cord injury patients benefiting from stem cell-based therapy, no such treatment has been approved as safe and effective. So scientists at UCSD and elsewhere are trying to make a treatment that can be reliably replicated.

Another study with neural stem cells without the implant has shown benefit in monkeys after spinal cord injury, Tuszynski said. This work is closer to the clinical stage.

The rat implants were constructed by 3D bioprinting of a biologically compatible hydrogel, which is mostly made up of water. These 2-millimeter-wide implants contain tiny channels that guide growth of neural stem cells, also called neural progenitor cells. The cells matured into neurons and reconnected severed nerves, Tuszynski said.

Besides guiding growth, the implants allowed blood vessels to grow, nourishing the newly formed cells. This process, called vascularization, has been hard to achieve in growing new tissue. But with the biologically compatible implants, vascularization occurred spontaneously.

The implants also protected the neural stem cells from the inflammatory damage associated with a fresh injury.

This is a nice marriage of the technology of bioengineering and 3D printing with stem cell biology to treat a really important human disease that needs better therapy, Tuszynski said.

Implants can be quickly custom-made for human spinal cord injuries, according to the study. Researchers bioprinted implants of 4 centimeters within 10 minutes. These were made according to MRI scans of real human spinal cord injuries.

Two other UCSD study authors, Shaochen Chen and Wei Zhu, have co-founded a San Diego startup, Allegro 3D, to commercialize the rapid bioprinting technology. Allegro is doing this independently of the spinal cord injury research.

We will be talking to people to find a partner, said Chen, a founding co-director of the Biomaterials and Tissue Engineering Center at UC San Diego. It takes money, time and effort, so it won't be done in a university setting.

The neural stem cells are produced from a lineage of human embryonic stem cells. This lineage was one of the original certified while George W. Bush was president.

The researchers treat the cells with their own cocktail of growth chemicals that coax them into becoming spinal cord neural stem cells, which cant become any other kind of cell besides types of spinal cord cells.

When these cells are placed at the injury site, with or without the implant, the stem cells complete development.

Importantly, these cells grow axons, the long fibers that carry nerve signals, Tuszynski said. They extend out of the implant and into the spinal cord below the injury. They relay signals that cross synapses, the tiny gaps between nerve cells.

Because the cells arent from the patient, the body may tend to reject them. So patients receiving these cells will need immunosuppressive therapy, he said.

Newer classes of immune-suppressing drugs now available are safer and better tolerated than earlier ones, Tusyznski said.

We think patients would stay on them for awhile, he said.

The research was funded by the National Institutes of Health; the California Institute for Regenerative Medicine; and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation.

UCSD also hosts ongoing stem cell-based clinical trials for spinal cord injuries and other diseases. More information can be found at the Sanford Stem Cell Clinical Center, reachable at

Related reading

3D printed implant promotes nerve cell growth to treat spinal cord injury

Biomimetic 3D-printed scaffolds for spinal cord injury repair

Allegro 3D

Stem cell-based spinal cord therapy expanded to more patients

Stem cells have become keys to unlock how life develops

UCSD finds possible treatment for paralysis

Genetic analysis conducted on one Neanderthal woman who lived 52,000 years ago was published Oct. 5 in a report in the journal Science. (October 6, 2017)

Genetic analysis conducted on one Neanderthal woman who lived 52,000 years ago was published Oct. 5 in a report in the journal Science. (October 6, 2017)

At 9:52 a.m. Pacific, OSIRIS-REx (short for Origins, Spectral Interpretation, Resource Identification, and Security-Regolith Explorer) hits its closest point to Earth, 11,000 miles above Antarctica. (Sept. 22, 2017)

At 9:52 a.m. Pacific, OSIRIS-REx (short for Origins, Spectral Interpretation, Resource Identification, and Security-Regolith Explorer) hits its closest point to Earth, 11,000 miles above Antarctica. (Sept. 22, 2017)

The Food and Drug Administration has launched a crackdown on clinics hawking stem cell treatments for a range of ailments. (September 1, 2017) (Sign up for our free video newsletter here

The Food and Drug Administration has launched a crackdown on clinics hawking stem cell treatments for a range of ailments. (September 1, 2017) (Sign up for our free video newsletter here

Researchers used eggs from healthy females and the sperm of a man who carried a gene mutation that causes inherited hypertrophic cardiomyopathy. (Aug. 3, 2017)(Sign up for our free video newsletter here

Researchers used eggs from healthy females and the sperm of a man who carried a gene mutation that causes inherited hypertrophic cardiomyopathy. (Aug. 3, 2017)(Sign up for our free video newsletter here

Research published July 27 suggested that transcranial magnetic stimulation could prove useful in distinguishing Alzheimers disease from frontotemporal dementia. (July 27, 2017)(Sign up for our free video newsletter here

Research published July 27 suggested that transcranial magnetic stimulation could prove useful in distinguishing Alzheimers disease from frontotemporal dementia. (July 27, 2017)(Sign up for our free video newsletter here

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Stem Cell Treatment Cardiovascular Disease, Heart Disease …

By admin

Cardiovascular disease, also called heart disease, is a broad medical term used to describe a group of conditions that affect the blood vessels or the heart. It is the most common cause of death worldwide.1

Conditions of cardiovascular disease include:

The Stem Cells Transplant Institutein Costa Rica, uses adult autologous stem cells for the treatment of cardiovascular disease (heart disease). The symptoms of cardiovascular disease will depend on the specific type of heart disease.

Treatment at the Stem Cells Transplant Institute could help improve the symptoms of cardiovascular disease such as:

Heart disease and cardiovascular disease are often used interchangeably. These terms refer to a group of conditions that affect the blood vessels and heart. Valvular heart disease affects how the valves pump blood flow in and out of the heart. Cardiomyopathy affects the contractions of the heart muscle. Heart arrhythmias are disturbances in the electrical conduction making the heart beat irregular. Coronary artery disease is the most common cause of cardiovascular disease and stem cell therapy may be an effective treatment.

Coronary artery disease is caused by atherosclerosis, the buildup of plaque, causing a narrowing or blocking the blood vessels in the coronary arteries. Coronary artery disease is the leading cause of cardiovascular disease. Atherosclerosis can lead to chest pain, heart attack or stroke.

Coronary arteries carry oxygen rich blood to the heart. Plaque is caused by the presence of cholesterol, calcium, fat, and other substances in the blood. When plaque builds up in the blood vessels it narrows the arteries causing them to harden and weaken, reducing the amount of oxygen rich blood to the heart. As a result, the heart cannot pump blood effectively to the rest of the body potentially leading to heart failure and ultimately death.

If the plaque building up in the coronary arteries breaks, a blood clot forms around the plaque. If the clot cuts off the blood flow to the heart muscle completely, the heart muscle is unable to get the necessary oxygen and nutrients causing a part of the heart muscle to die. The result is a heart attack or myocardial infarction,

Coronary artery disease, high blood pressure or a previous heart attack can lead to the onset of heart failure. Heart failure is a chronic, progressive disease typically caused by another heart condition resulting in the heart muscle losing its ability to supply the rest of body with enough blood and oxygen.

Atherosclerosis can also cause peripheral artery disease. Peripheral arterial disease occurs when the narrowed peripheral arteries cannot send enough blood flow to the extremities, usually the legs. The most common symptoms of peripheral artery disease are; cramping, pain, and/or tiredness in the leg or hip muscles during exertion. The most severe symptom of peripheral artery disease is critical limb ischemia, pain at rest due to reduced blood flow to the limb.

Approximately 85% of strokes are ischemic strokes. Atherosclerosis is the most common cause of ischemic stroke. If the arteries become too narrow due to plaque buildup, the blood cells may collect and form a clot. A larger clot can block the artery where it is formed (thrombotic stroke) while a smaller clot may travel until it reaches an artery closer to the brain (embolic stroke). When the arteries to your brain become narrow or blocked, the required blood flow is reduced resulting in stroke. Other causes of ischemic stroke are clots due to an irregular heartbeat or heart attack.

Stem cell therapy at the Stem Cells Transplant Institute may be a good alternative for patients seeking a safe, non-surgical treatment for cardiovascular disease.

Notably, adult stem and progenitor cells including.mesenchymal stem cells have progressed into clinical trials and have shown positive benefits.5

Stem cell transplantation uses healthy cells to promote the repair of damaged cells and regeneration of healthy and functional cells to repair injured tissue.1 The therapeutic effect of stem cell transplantation in patients with cardiovascular disease may be due to the paracrine effect. The theory is transplanted stem cells repair damaged tissue by releasing factors that promote regeneration of healthy stem cells, reduce inflammation, promote the growth of new blood vessels, inhibit cell death, and reduce hypertrophy.1

The results of initial research using mesenchymal stem cell transplantation:

Heart Failure

Adipose derived stem cells improve left ventricular function, promote angiogenesis, lower fibrosis, and decrease inflammation. Several months following treatment, stem cells continue to migrate to the heart muscle regenerating and renewing healthy heart function. Stem cell therapy cannot help all patients with cardiovascular disease but for many patients stem cell therapy combined with lifestyle modification may be a safe, effective, non-surgical alternative treatment.

Lifestyle changes that can help improve cardiovascular disease include:

The Stem Cells Transplant Institute uses autologous mesenchymal stem cells for the treatment of cardiovascular disease. Autologous means the stem cells are collected from the recipient so the risk of rejection is virtually eliminated. Mesenchymal stem cells are one type of adult stem cells that are found in a variety of tissues including; adipose tissue, lung, bone marrow, and blood. Mesenchymal stem cells have several advantages over other types of stem cells; ability to migrate to sites of tissue injury, strong immunosuppressive effect, and better safety after infusion.2,3 Mesenchymal stem cells are a promising treatment for cardiovascular disease. Treatment at the Stem Cells Transplant Institute may improve the symptoms and long-term complications of cardiovascular disease.

A team of stem cell experts developed an FDA approved method and protocol for harvesting and isolating adipose derived stem cells for autologous reimplantation. The collection and use of adult stem cells does not require the destruction of embryos and for this reason, more U.S. federal funding is being spent on stem cell research.

The stem cells are administered intravenously.

Costa Rica has one of the best healthcare systems in world and is ranked among the highest for medical tourism. Using the most advanced technologies, the team of experts at The Stem Cells Transplant Institute believes in the potential of stem cell therapy for the treatment of cardiovascular disease. We are committed to providing personalized service and the highest quality of care to every patient. Contact us to see if stem cell therapy may be a treatment option for you.

1.Sun R.Advances in stem cell therapy for cardiovascular disease (Review). National Journal of Mol. Med. 38: 23-29, 2016. 2 Hare JM, Fishman JE, Gerstenblith G, DiFede Velazquez DL, Zambrano JP, Suncion VY, Tracy M, Ghersin E, Johnston PV, Brinker JA, et al: Comparison of allogeneic vs autologous bone marrow-derived mesenchymal stem cells delivered by transendocardial injection in patients with ischemic cardiomyopathy: the POSEIDON randomized trial. JAMA 308: 2369-2379, 2012.3 Miyahara Y, Nagaya N, Kataoka M, Yanagawa B, Tanaka K, Hao H, Ishino K, Ishida H, Shimizu T, Kangawa K, et al: Monolayered mesenchymal stem cells repair scarred myocardium after myocardial infarction. Nat Med 12: 459-465, 2006. 4 Mazo M, Planat-Bnard V, Abizanda G, Pelacho B, Lobon B, Gavira JJ, Peuelas I, Cemborain A, Pnicaud L, Laharrague P, et al: Transplantation of adipose derived stromal cells is associated with functional improvement in a rat model of chronic myocardial infarction. Eur J Heart Fail 10: 454-462, 2008. 5 Stem cell-based therapies to promote angiogenesis in ischemic cardiovascular disease Luqia Hou,1,2 Am J Physiol Heart Circ Physiol 310: H455H465, 2016. 6 Kinnaird T, Stabile E, Burnett MS, Lee CW, Barr S, Fuchs S, Epstein SE. Marrow-derived stromal cells express genes encoding a broad spectrum of arteriogenic cytokines and promote in vitro and in vivo arteriogenesis through paracrine mechanisms. Circ Res 94: 678685, 2004. 7 Kinnaird T, Stabile E, Burnett MS, Shou M, Lee CW, Barr S, Fuchs S, Epstein SE. Local delivery of marrow-derived stromal cells augments collateral perfusion through paracrine mechanisms. Circulation 109: 15431549, 2004.

8 Hare JM, Fishman JE, Gerstenblith G, DiFede Velazquez DL, Zambrano JP, Suncion VY, Tracy M, Ghersin E, Johnston PV, Brinker JA, Breton E, Davis-Sproul J, Schulman IH, Byrnes J, Mendizabal AM, Lowery MH, Rouy D, Altman P, Wong Po Foo C, Ruiz P, Amador A, Da Silva J, McNiece IK, Heldman AW, George R, Lardo A. Comparison of allogeneic vs autologous bone marrowderived mesenchymal stem cells delivered by transendocardial injection in patients with ischemic cardiomyopathy: the POSEIDON randomized trial. JAMA 308: 23692379, 2012.

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FUJIFILM Cellular Dynamics to Establish New Production …

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- Accelerating the practical application of treatments that apply iPS cells towards the early industrialization of regenerative medicine- Making the high quality and highly efficient production of iPS cells a reality

January 4, 2019FUJIFILM Cellular Dynamics, Inc.

FUJIFILM Cellular Dynamics, Inc. (FCDI), a US subsidiary of FUJIFILM Corporation (President: Kenji Sukeno) and a leader in the development and manufacture of human induced pluripotent stem (iPS) cells and tissue-specific cells differentiated from iPS cells, will establish a new cGMP-compliant* production facility with an investment of about 21 million US dollars in order to enhance its production of iPS cells for cell therapy. The facility is scheduled to begin operations during fiscal year ending March 2020.FCDI will use the iPS cells produced at this facility to accelerate development of its regenerative medicine products. In addition, by also conducting contract development and manufacturing of iPS cells and iPS cell-derived differentiated cells, it will expand its business and scale to the industrial stage.

Regenerative medicine is drawing interest as a solution for unmet medical needs. There are high expectations for the practical application of treatments that utilize iPS cells, as these cells possess totipotency and the capacity for infinite reproduction, making it possible to produce a large volume of diverse cells. To fulfill the promise of cell therapy, sophisticated techniques and know-how are required to culture, induce differentiation in, and control the quality of cells.

FCDI will be establishing a new production facility equipped with cell culture facilities appropriate for the production of a large volume of cells, as well as culture facilities appropriate for small-scale, diverse production, and a system capable of highly precise cell quality analyses. By also harnessing world-class technologies for the initialization and induction of differentiation in iPS cells and Fujifilm's advanced engineering technology and image analysis technology, the facility will be capable of efficiently producing high-quality iPS cells.Going forward, FCDI will use the high-quality iPS cells produced at this facility to accelerate the development of regenerative medicine products in the areas of age-related macular degeneration, retinitis pigmentosa, Parkinson's disease, heart diseases, and cancer. FCDI will also contribute to the realization and spread of treatments that utilize iPS cells by widely conducting the contract development and manufacturing of iPS cells and iPS cell-derived differentiated cells.

Currently, FCDI provides iPS cells and iPS cell-derived differentiated cells to public institutions, major pharmaceutical companies, and academia including the California Institute for Regenerative Medicine** and the National Heart, Lung, and Blood Institute*** while accelerating the development of its regenerative medicine products. FCDI will continue to harness its accumulated data, technologies, and know-how related to iPS cells, working together with academic institutions and corporations around the world and utilize the technologies and know-how of Fujifilm group companies including Fujifilm, Japan Tissue Engineering Co., Ltd., FUJIFILM Wako Pure Chemical Corporation, and Irvine Scientific Sales Company, Inc. to further expand its iPS cell-based business and contribute to the elevation of regenerative medicine business to the industrial stage.

Overview of the New Facility

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Bone marrow suppression – Wikipedia

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Bone marrow suppressionSynonymMyelotoxicity, myelosuppression

Bone marrow suppression also known as myelotoxicity or myelosuppression, is the decrease in production of cells responsible for providing immunity (leukocytes), carrying oxygen (erythrocytes), and/or those responsible for normal blood clotting (thrombocytes).[1] Bone marrow suppression is a serious side effect of chemotherapy and certain drugs affecting the immune system such as azathioprine.[2] The risk is especially high in cytotoxic chemotherapy for leukemia.

Nonsteroidal anti-inflammatory drugs (NSAIDs), in some rare instances, may also cause bone marrow suppression. The decrease in blood cell counts does not occur right at the start of chemotherapy because the drugs do not destroy the cells already in the bloodstream (these are not dividing rapidly). Instead, the drugs affect new blood cells that are being made by the bone marrow.[3] When myelosuppression is severe, it is called myeloablation.[4]

Many other drugs including common antibiotics may cause bone marrow suppression. Unlike chemotherapy the effects may not be due to direct destruction of stem cells but the results may be equally serious. The treatment may mirror that of chemotherapy-induced myelosuppression or may be to change to an alternate drug or to temporarily suspend treatment.

Because the bone marrow is the manufacturing center of blood cells, the suppression of bone marrow activity causes a deficiency of blood cells. This condition can rapidly lead to life-threatening infection, as the body cannot produce leukocytes in response to invading bacteria and viruses, as well as leading to anaemia due to a lack of red blood cells and spontaneous severe bleeding due to deficiency of platelets.

Parvovirus B19 inhibits erythropoiesis by lytically infecting RBC precursors in the bone marrow and is associated with a number of different diseases ranging from benign to severe. In immunocompromised patients, B19 infection may persist for months, leading to chronic anemia with B19 viremia due to chronic marrow suppression.[5]

Bone marrow suppression due to azathioprine can be treated by changing to another medication such as mycophenolate mofetil (for organ transplants) or other disease-modifying drugs in rheumatoid arthritis or Crohn's disease.

Bone marrow suppression due to anti-cancer chemotherapy is much harder to treat and often involves hospital admission, strict infection control, and aggressive use of intravenous antibiotics at the first sign of infection.[citation needed]

G-CSF is used clinically (see Neutropenia) but tests in mice suggest it may lead to bone loss.[6][7]

GM-CSF has been compared to G-CSF as a treatment of chemotherapy-induced myelosuppression/Neutropenia.[8]

In developing new chemotherapeutics, the efficacy of the drug against the disease is often balanced against the likely level of myelotoxicity the drug will cause. In-vitro colony forming cell (CFC) assays using normal human bone marrow grown in appropriate semi-solid media such as ColonyGEL have been shown to be useful in predicting the level of clinical myelotoxicity a certain compound might cause if administered to humans.[9] These predictive in-vitro assays reveal effects the administered compounds have on the bone marrow progenitor cells that produce the various mature cells in the blood and can be used to test the effects of single drugs or the effects of drugs administered in combination with others.

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Spinal Cord Injury Explained – Mad Spaz Club

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Injury to the spinal cord can be caused by acute (sudden) or chronic (developing) trauma as well as medical conditions. Frequent causes of chronic compression injuries are herniated disks and primary or secondary tumors. Compromised blood perfusion, the delivery of nutritive arterial blood to capillary bed, as in anterior spinal cord syndrome can also be severely detrimental to spinal cord function. However the most damaging Spinal Cord Injury is one of acute trauma resulting in permanent paralysis.

Traumatic spinal cord injury have been classified into five categories by the American Spinal Injury Association and the International Spinal Cord Injury Classification System:

Spinal cord injury where no motor or sensory function remains in the sacral segments S4-S5.

Spinal cord injury sensory but not motor function remains below the neurological level and includes the sacral segments S4-S5. Typically a transient phase and if the person recovers any motor function below the neurological level, theyare considered motor incomplete and classified C or D.

Spinal cord injury where motor function remains below the neurological level and more than half of key muscles below the neurological level have a muscle grade of less than 3, which indicates active movement with full range of motion against gravity.

Spinal cord injury where motor function exists below the neurological level and at least half of the key muscles below the neurological level have a muscle grade of 3 or more.

Where motor and sensory scores are normal. It is possible to have spinal cord injury and neurological deficits with completely normal motor and sensory scores.

The annual incidence rate of spinal cord injury varies from country to country, ranging from 15 to 71 per million (/m). In 2008 the incidence of spinal cord injury in the United Kingdom around 13 /m, Australia 14 /m, Canadi 35 /m, China 65 /m and the United States 35 /m per year. This suggests around 40 per million or 52,000 spinal injuries occur every year globally.

Of the 12,000 new cases of paraplegia and quadriplegia that occur in the United States each year 4,000 patients die before reaching hospital. Causes of acute spinal cord injury include motor vehicle accidents, work-related accidents, recreational accidents, falls and violence (shootings and stab wounds).

Paralysis occurs our times as often in males as females where about 60% of victims are under 30 years of age and 5% under 13 years of age (the pediatric age group). Falls from a height greater than their own is the largest cause of spinal trauma amongst the pediatric age group. A long-term outcome study of patients aged 25 to 34 who had suffered acute traumatic SCI before the pediatric age showed an employment rate of 54% while the employment rate in the general population for the same age group was 84%.

Limitation or complete loss of the capability to achieve economic independence following SCI combined with additional medical costs causes severe economic hardship for many living with paralysis and their immediate family. Further limitations to living a full social life are architectural barriers, buildings only accessible by stairs and a lack of ramps on sidewalks for example.

Increased awareness through education has played a key role in resolving these barriers and those created by negative or overprotective attitudes of healthy, non-injured people toward persons with spinal cord injury. When persons with spinal cord injury cannot fully participate society suffers. Not only are ethical standards, artistic and financial contributions to society lost, huge expenses for specialised lifelong care are incurred.

80% of SCI occur in people under the age of 30. The average life-time cost of thoracic paraplegia is $1.25 million and high level cervical quadriplegia such as those on ventilators $25 million USD. In 1990 the cost for acute and long term care of surviving spinal cord injury victims was estimated at $4 billion in the United States alone.

Road traffic accidents 45%

Domestic and industrial accidents 34%

Sporting injuries 15%

Self harm and criminal assault 6%

The first known description of acute spinal cord trauma and resulting neurological deficits was in the Edwin Smith papyrus which is believed to be more than 3,500 years old. In this ancient Egyptian document Smith accurately described the clinical symptoms and traumatic effects of quadriplegia (tetraplegia) anailment not to be treated. An indication of the feelings helplessness medical practitioners suffered at the time, a doctors value measured by the extent of cure achieved.

No strategies ensuring longterm survival for patients with spinal cord injury existed. A view which prevailed well into the early 1900s. In the First World War the mortality rate for those with a spinal cord injury was 95%, mainly attributed to urinary sepsis and complications from pressure sores. Less than 1% survived for more than twenty years.

During World War II the number of casualties from spinal cord injuries both military and civilian increased dramatically in Europe. Specialized hospital units known as peripheral nerve centers developed between the wars in Germany and the United States demonstrating the advantages of concentrating special needs patients under specialized care. Great importance was placed on the unique opportunities offered by these specialized units. Gaining new insight in the natural course of the disease and further development of new therapeutic strategies.

Building on those experiences, specialized spinal cord injury units started opening throughout England in the 1940s. Mortality rates from a spinal cord injury were recorded at 35% in the 1960s. Today nearly every capital city operates an acute care spinal unit.

Dr. Ludwig Guttmann and his colleagues at the Spinal Cord Unit of Stoke Mandeville Hospital developed new treatment approaches including frequent repositioning of paralyzed patients to avoid developing bedsores, a potential source of sepsis and intermittent sterile catheterization to prevent urinary sepsis. The success in patient survival was dramatic enough to require development of completely new strategies for social reintegration of patients with spinal cord injury. Adapted workplaces and wheelchair accessible housing championed in the 1940s and 1950s by the English Red Cross has today become an integral component in the framework of social politics in most industrialized countries. Respiratory complications are now the leading cause of death in patients admitted with SCI. Secondary are heart disease, septicemia (blood poisoning), pulmonary emboli (blood clot in lungs), suicide, and unintentional injuries.

Dr. Guttmann and his colleagues viewed physical rehabilitation as the basis of social reintegration both physically and psychologically. Supporting the idea of athletic competition in disciplines adequate and adapted to the physical capacity of their patients. Starting with two teams a competition in 1948 paralleling the Olympic Games in England, the idea of competitive sports for the paralyzed developed rapidly.

In 1960 the first Paralympic Games were held in Rome. The Paralympic games were held in the same year as the Olympic Games for the able-bodied using the same facilities, a tradition that has been followed ever since. The idea of competitive sports was extended to include people with a multitude of physical handicaps other than spinal cord injury emerging as the Paralympics we know today.

In many countries initiatives have risen at communal and national levels with the intent to decrease the incidence of spinal cord trauma and offer support and advice to both those with spinal cord injuries and their families. Many generously offer financial support for scientific and clinical research.

The prevention oriented Think First initiative, Canadian-based CORD and Wheels in Motion, the Christopher Reeve Paralysis Foundation, the U.K. Spinal Cord Trust, and the Paralyzed Veterans of America all maintain informative web sites with valuable information on the subject of spinal cord injury.

Although the overall incidence of SCI has not noticeably decreased the severity of injuries has deceased overall. Fewer now suffer complete injuries and survival rates have increased. This is mostly attributed to improvements in prehospital care including widespread instruction of first aid principles as well as the introduction of spinal cord immobilization and administration of advanced medicines during rescue and transport. Increased public awareness of risk factors leading to head trauma and spinal cord injury, the introduction of mandatory use of safety belts and installation of air bags in modern vehicles has also served to decrease trauma severity.

Until recently research suggested once spinal cord trauma had occurred nothing could be done to alter the natural course of developing pathology, that damage to the central nervous system was permanent and repair impossible. At the beginning of the twenty-first century this belief came to change in the minds of scientists, clinicians, patients and their families. Research laboratories around the world adopted two new approaches:

1. Prevention of secondary injury and repair of manifest damage. The term secondary injury describes the observation that central nervous system structures that survived the primary mechanical trauma die at a later point in time due to deterioration of the milieu (nerve ending sheath) at the site of injury.

2. The amount and severity of secondary injury damage can be significantly larger than that of the primary injury. Researchers focused on identification of substances and therapeutic methods that help minimize secondary injury effects. In the field of cell biology, isolation and manipulation of specific cell types is being undertaken in effort to induce certain cell types, including stem cells and olfactory ensheathing cells to help repair damaged central nervous system structures.

Clinical research continues to improve outcomes for those with a spinal cord injury, such as stimulators for bladder control, orthopedic correctional procedures and physical mobilization. Integration of biomedical research like pattern generators, mechanics and kinetics of movement with the latest developments in computer science and engineering has given rise to neuronal networks. Neuroprostheses are being developed which enable paraplegics to move about and walk.

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Clinical trial of stem cell therapy for traumatic spinal …

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Mayo Clinic is enrolling patients in a phase 1 clinical trial of adipose stem cell treatment for spinal cord injury caused by trauma. The researchers already have approval from the Food and Drug Administration for subsequent phase 2A and 2B randomized control crossover trials.

Participants in the phase 1 clinical trial must have experienced a trauma-related spinal cord injury from two weeks to one year prior to enrollment. They will receive intrathecal injections of adipose-derived mesenchymal stem cells. No surgery or implantable medical device is required.

"That is the most encouraging part of this study," says Mohamad Bydon, M.D., a consultant in Neurosurgery specializing in spinal surgery at Mayo Clinic in Rochester, Minnesota, and the study's director. "Intrathecal injection is a well-tolerated and common procedure. Stem cells can be delivered with an implantable device, but that would require surgery for implantation and additional surgeries to maintain the device. If intrathecal treatment is successful, it could impact patients' lives without having them undergo additional surgery or maintain permanently implantable devices for the rest of their lives."

To qualify for the trial, patients must have a spinal cord injury of grade A or B on the American Spinal Injury Association (ASIA) Impairment Scale. After evaluation at Mayo Clinic, eligible patients who enroll will have adipose tissue extracted from their abdomens or thighs. The tissue will be processed in the Human Cellular Therapies Laboratories, which are co-directed by Allan B. Dietz, Ph.D., to isolate and expand stem cells.

Four to six weeks after the tissue extraction, patients will return to Mayo Clinic for intrathecal injection of the stem cells. The trial participants will then be evaluated periodically for 96 weeks.

Mayo Clinic has already demonstrated the safety of intrathecal autologous adipose-derived stem cells for neurodegenerative disease. In a previous phase 1 clinical trial, with results published in the Nov. 22, 2016, issue of Neurology, Mayo Clinic researchers found that therapy was safe for people with amyotrophic lateral sclerosis (ALS). The therapy, developed in the Regenerative Neurobiology Laboratory under the direction of Anthony J. Windebank, M.D., is moving into phase 2 clinical trials.

Dr. Windebank is also involved in the new clinical trial for people with traumatic spinal cord injuries. "We have demonstrated that stem cell therapy is safe in people with ALS. That allows us to study this novel therapy in a different population of patients," he says. "Spinal cord injury is devastating, and it generally affects people in their 20s or 30s. We hope eventually that this novel therapy will reduce inflammation and also promote some regeneration of nerve fibers in the spinal cord to improve function."

Mayo Clinic's extensive experience with stem cell research provides important guidance for the new trial. "We know from prior studies that stem cell treatment can be effective in aiding with regeneration after spinal cord injury, but many questions remain unanswered," Dr. Bydon says. "Timing of treatment, frequency of treatment, mode of delivery, and number and type of stem cells are all open questions. Our hope is that this study can help answer some of these questions."

In addition to experience, Mayo Clinic brings to this clinical trial the strength of its multidisciplinary focus. The principal investigator, Wenchun Qu, M.D., M.S., Ph.D., is a consultant in Physical Medicine and Rehabilitation at Mayo Clinic's Minnesota campus, as is another of the trial's investigators, Ronald K. Reeves, M.D. Dr. Dietz, the study's sponsor, is a transfusion medicine specialist. Also involved is Nicolas N. Madigan, M.B., B.Ch., BAO, Ph.D., a consultant in Neurology at Mayo Clinic's Minnesota campus.

The study team is in discussions with U.S. military medical centers to enroll patients, and discussing additional collaboration with international sites, potentially in Israel or Europe, for future phases of the study.

"At Mayo Clinic, we have a high-volume, patient-centered multidisciplinary practice," Dr. Bydon says. "That allows us to do the most rigorous scientific trial that is in the best interests of our patients."

Mayo Clinic. Adipose Stem Cells for Traumatic Spinal Cord Injury (CELLTOP).

Staff NP, et al. Safety of intrathecal autologous adipose-derived mesenchymal stromal cells in patients with ALS. Neurology. 2016;87:2230.

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Stem Cell Therapy for Spinal Cord Injury- Treatment for …

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Stem Cell Therapy for Spinal Cord Injury-Spinal cord injury is one of the progressively degenerating, crippling disorders attributing towards the dislocation of bones and vertebrae; which is a general result of trauma and/or injury.

The accidental injury generally damages connecting nerves internally; in order to halt the back and forth communication between brain and rest of the body parts. This communication gap is the primary cause of partial or complete loss of movement, paralysis as well as numbness. Apparently, many times it has also been evident that spinal cord may get affected not because of the injury but because of different types of nerve infection; which if ignored for a longer time, may allow unusual bleeding in between the spaces around the spinal cord. Some of the common forms of these notable infections are spinal stenosis, spina bifida, etc.

A person with a potential threat to severe spinal cord damage should be hospitalized for an intensive care unit immediately. Stabilization of blood pressure, lung function, and prevention of further damage to the spinal cord; should be emphasized with immediate effect. Other injuries are as well to be looked at; for an accidental damage.

Experts may prescribe some routine tests, in order to detect the extent of injuries. These tests can be

Classification of SCI is generally based on the extent of pain and loss of movement, associated with the damage. Moreover, when the damage is associated with neuronal loss, nerve locations and anumber of nerves that have been damaged can as well be referred to classify spinal cord injury.

The recovery period for patients suffering from spinal cord injury is dependent upon the level of injury, muscular strength and the type of injury; but in general, the notable recovery period can be anytime between 4-6 months.

Through conventionally demonstrated medicines, it is generally impossible to completely cure spinal cord damage or paralytic aftereffects of injury. In fact, the anti-inflammatory medicines that have been prescribed conventionally can affect other vital organs of the body, due to continuous hormonal modifications. Although with the advent of stem cells through the science of regenerative medicine has proven to be very helpful in offering a definite cure for SCI and other orthopedic related illnesses. The potential ability of these stem cells to be differentiated into neurons has been well studied and confirmed through different scientific literature and the same hypothesis can be applied to treat and restore back the functional attributes of damaged spinal cord.

Thus, stem cells and their regenerative powers can potentially work to solve the internal mysteries of spinal cord injury; but the extent of recovery and therapeutic outcome are still the challenges that are being faced by the medical fraternities.

For further queries regardingstem cell therapy for spinal cord injury, feel free to connect us at+91-96543 21400 or You can also connect us through Advancells Enquiry.

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Cardiac Regeneration, Stem Cells | Research | Baylor …

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Theme Leaders

James Martin, M.D. Ph.D.Professor, Molecular PhysiologyResearch Interest - Hippo, Wnt, Bmp signaling in development, regeneration, heart disease

Todd Rosengart, M.D., F.A.C.S.Chair/Professor, SurgeryResearch Interest - Cardiac regeneration, cardiac gene therapy, angiogenesis

Members of Theme Six are developing stem cell and cellular reprogramming strategies to treat cardiovascular diseases such as infarction in situ. The goal is to use viral vectors to induce transdifferentiation of cardiac fibroblasts and myofibroblasts into functionalcardiomyocytes in situ in a patients heart. We are modeling and developing the processes in rats, pigs, and in human cardiac fibroblasts. The hope is to have options available for clinical trials within 3-5 years.

Members of Theme Six are involved in research aimed at improving heart function after different types of injury and in particular the devastating loss of heart muscle after myocardial infarction. One current approach is to investigate gene pathways, many of which are important in heart development, that enhance the ability of cardiac muscle to respond to injury. Recent exciting findings have shown that manipulations of specific genetic pathways, such as the Hippo pathway, enhance heart repair. Current investigations in this area include uncovering the molecular mechanisms underlying improved heart repair in order to develop novel therapies.

Another exciting approach involves in vivo reprogramming of cardiac fibroblasts into cardiac muscle as a way to enhance heart function after ischemic injury. This novel method was inspired by the observation by Yamanaka that fibroblasts can be reprogrammed to pluripotent cells in cultured cells. Important recent work has shown that providing a cocktail of factors to cardiac fibroblasts results in conversion of those fibroblasts into cardiac muscle. Current efforts are directed at improving the efficiency of in vivo reprogramming with the goal of using this approach in therapy, recognizing that use of this strategy in human cells will likely be more challenging than in rodent and other non-human strains. The combination of angiogenic pretreatment of scar with this strategy appears to be critical to its success.

Sadek HA, Martin JF, Takeuchi JK, Leor J, Nei Y, Giacca M, Lee RT. Multi-investigator letter on reproducibility of neonatal heart regeneration following apical resection. Stem Cell Reports. 2014; 3(1): 1.

Yen ST, Zhang M, Deng JM, Usman SJ, Smith CN, Parker-Thornburg J, Swinton PG, Martin JF, Behringer RR. Somatic mosaicism and allele complexity induced by CRISPR/Cas9 RNA injections in mouse zygotes. Dev Biol. 2014; 393(1): 3-9.

C. Thomas Caskey, M.D. - FACP, FRSC Schizophrenia disease genes

Katarzyna Cieslik, Ph.D. - Cardiac mesenchymal progenitors

Austin Cooney, Ph.D. - Nuclear receptor regulation of embryonic stem cell function

Thomas Cooper, M.D. - Alternative splicing in cardiac development and disease

Mary Dickinson, Ph.D. - Role of fluid-derived mechanical forces in vascular remodeling and heart morphogenesis

Mark Entman, M.D. - Molecular mechanisms of cardiac injury and repair, inflammatory signaling

Charles Fraser, M.D. - Congenital heart surgery outcomes, bioengineering and assist devices

Peggy Goodell, M.D. - Hematopoietic stem cells, epigenetic modifications

Jeffrey Jacot, Ph.D. - Regenerative therapies for congenital heart disease

Sandra Haudek, Ph.D. - Circulating monocytic fibroblast precursors, cardiac hypertrophy

George Noon, M.D. - Transplant and assist devices

JoAnn Trial, Ph.D. - Origins of fibroblasts in cardiac injury healing

Peter Tsai, M.D., FACS - Custom-fenestrated endovascular stents to repair aortic transections or aneurysms

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