Archive for the ‘Adult Stem Cells’ Category

What are adult stem cells? – StemExpress Donor Center

Adult Stem Cells | Posted by admin
Feb 01 2019

What are adult stem cells?

Most cells in the adult body are specialized cell types. Specialized cell types are differentiated cells that serve a specific purpose in a particular tissue. For example, red blood cells are specifically designed to carry oxygen through the blood. Red blood cells perform their function for 100-120 days; new red blood cells are being formed daily to make sure the body gets its supply of oxygen. So where do these new red blood cells come from? In a process called hematopoiesis, stem cells located in your bone marrow and blood give rise to the cells in your blood, red and white blood cells. Stem cells are undifferentiated cells that exist in all tissues of the adult body and are capable of developing into specialized cells, not just blood cells but muscle, nerve, liver, etc. They function to replenish dying cells and maintain the overall health of our body.

How can studying adult stem cells help us?

Stem cells can be used to study the development of a specific cell type. More specifically scientist can learn about the genes that influence a stem cell to differentiate into a specific cell type. Why is this important? Understanding the developmental process of a specific cell type can help scientist identify genetic defects or how certain diseases arise. For example, at some point through a cells developmental process it can change and become diseased. What genes were involved in creating these changes? At what point in differentiation did this occur? What if there was a way to fix this gene and prevent the disease? These are just some of the questions scientists are trying to answer.

Stem cells can be used for drug discovery. Scientistsare searching for new drugs that improve stem cell function or alter the progress of a disease by identifying potential therapeutic compounds. For example, mesenchymal stem cells (MSCs) found in the bone marrow give rise to connective tissue such as bone, cartilage, and ligaments. What factors promote one specific cell type over the other? Can synthesizing this factor be used in drug therapy? Finding drugs that can promote bone regrowth could aid in alleviating osteoporosis or promote bone healing.

Stem cells can be used in cell replacement therapy. This treatment uses stem cells to generate healthy tissue that replaces damaged tissue caused by disease, aging or injury. For example, during a heart attack the heart sustains damage to not only the muscle tissue but the blood vessels as well. What if stem cells could be used to restore the function of the heart? Scientists have shown that transplanting healthy human stem cells into animal models with damaged hearts regenerates the heart muscle and blood vessels. Breakthroughs like this could potentially replace cardiac bypass surgery, a surgery that is often necessary to restore the blood flow to damaged area of the heart after a heart attack. Within recent years stem cells have been used in studies that target the treatment of Parkinsons, Alzheimers, spinal cord injury, stroke, severe burns, diabetes, arthritis, and leukemia.

What does StemExpress do with the stem cells isolated from your blood or bone marrow?

Isolating stem cells from donated samples of blood or bone marrow can be a time consuming and arduous process. At StemExpress we have developed the technology to isolate these cells quickly and efficiently. Upon request from scientists, isolated stem cells are sent off to their institution where they can begin their research immediately. Cells from StemExpress have been used in a wide variety of research areas, from inherited genetic disease therapies to cancer research.

As the scope of knowledge regarding stem cells expands so to will the potential for treatments of many debilitating diseases. It is donors like you that allow research like this to advance. Donate today and change the lives of tomorrow.

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What are adult stem cells? - StemExpress Donor Center

Adult Stem Cells // Center for Stem Cells and Regenerative …

Adult Stem Cells | Posted by admin
Feb 01 2019

Adult stem cells, also called somatic stem cells, are undifferentiated cells that are found in many different tissues throughout the body of nearly all organisms, including humans. Unlike embryonic stem cells, which can become any cell in the body (called pluripotent), adult stem cells, which have been found in a wide range of tissues including skin, heart, brain, liver, and bone marrow are usually restricted to become any type of cell in the tissue or organ that they reside (called multipotent). These adult stem cells, which exist in the tissue for decades, serve to replace cells that are lost in the tissue as needed, such as the growth of new skin every day in humans.

Scientists discovered adult stem cells in bone marrow more than 50 years ago. These blood-forming stem cells have been used in transplants for patients with leukemia and several other diseases for decades. By the 1990s, researchers confirmed that nerve cells in the brain can also be regenerated from endogenous stem cells. It is thought that adult stem cells in a variety of different tissues could lead to treatments for numerous conditions that range from type 1 diabetes (providing insulin-producing cells) to heart attack (repairing cardiac muscle) to neurological disease (regenerating lost neurons in the brain or spinal cord).

Efforts are underway to stimulate these adult stem cells to regenerate missing cells within damaged tissues. This approach will utilize the existing tissue organization and molecules to stimulate and guide the adult stem cells to correctly regenerate only the necessary cell types. Alternatively, the adult stem cells could be isolated from the tissue and grown outside of the body, in cultures. This would allow the cells to be easily manipulated, although they are often relatively rare and difficult to grow in culture.

Because the isolation of adult stem cells does not result in the destruction of human life, research involving adult stem cells does not raise any of the ethical issues associated with research utilizing human embryonic stem cells. Thus, research involving adult stem cells has the potential for therapies that will heal disease and ease suffering, a major focus of Notre Dames stem cell research. Combined with our efforts with induced pluripotent stem (iPS) cells, the Center for Stem Cells and Regenerative Medicine will advance the Universitys mission to ease suffering and heal disease.

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Adult Stem Cells // Center for Stem Cells and Regenerative ...

What is Adult Stem Cell Therapy? | Okyanos Center for …

Adult Stem Cells | Posted by admin
Jan 19 2019

Adult stem cell therapy is the process of isolating the stem and regenerative cells found in patients own body fat and re-introducing them into damaged zones of the body and/or systemically to address underlying factors of chronic, degenerative disease. Through minimally invasive adult stem cell therapy, the bodys own natural healing capabilities are put to work for each patient.

Adult stem and regenerative cells are naturally abundant in our fat, skin, liver, teeth, bone marrow and other tissues. These have some remarkable attributes:

In other words, adult stem cells can differentiate (turn into) skin, bone and cartilage, in addition to secreting other beneficial growth and repair factorswhich can turn on the bodys native ability to repair itself.

The adult stem and regenerative cells which reside in body fat have become a very important research focus for scientists and doctors in recent years. Along with a number of other benefits to using body fat as a source of therapeutic cells, Okyanos doctors are able to gain access to Adipose-Derived Stem and Regenerative Cells (ADRCs) in a safe and minimally-invasive way utilizing a modified water-assisted liposuction.

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What is Adult Stem Cell Therapy? | Okyanos Center for ...

Conditions and Diseases Treated | Adult Stem Cell Therapy

Adult Stem Cells | Posted by admin
Dec 12 2018

As pioneers in the field, TruStem Cell Therapy provides evidence-based care customized to suit patient needs in a safe, effective manner. The discovery of stem cells opened a whole new understanding of how healing works in the human body. TruStem Cell Therapy uses that science to provide access to therapy for painful and debilitating conditions.

Adult stem cells are natural healers that have almost limitless capabilities. Emerging evidence shows that adult stem cells are able to create completely unrelated cells making them valuable assets in the fight to treat many diseases.

TruStem Cell Therapy provides access to the stem cell therapy and the bodys own healing resources as a therapy for life-changing illnesses. Stem cells have the ability to develop into different cell types and aid in repairing the damage done by illness. This means they work with your body to heal tissue, help manage pain and relieve symptoms.

Our board certified surgeons have access to the latest research and state-of-the-art equipment, allowing them to harvest stem cells effectively and efficiently utilizing the least-invasive methods available. The goal is to provide access to patient-centric care with therapy using stem cells, giving the power back to patients. At TruStem Cell Therapy, we specialize in conditions treated with stem cells, such as:

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Conditions and Diseases Treated | Adult Stem Cell Therapy

6 Pros and Cons of Adult Stem Cells | Green Garage

Adult Stem Cells | Posted by admin
Dec 02 2018

Adult stem cells can be found in tissues in the body, including, marrow, skin, brain, skeletal muscle and liver cells. An adult stem cell is an undifferentiated cell that can replicate itself and repair a damaged tissue. Having said this, scientists believe that adult stem cells can play a significant role in the science of medicine. However, despite the potential benefits attributed to these cells, there are also criticisms about them. Here are the contentious views from two opposing groups:

1. Used for Transplants Proponents of the use of adult stem cells posit that for decades, stem cells from the bone marrow have been used for transplants. These are blood-forming cells, also known as adult hematopoetic cells. And since new evidence that they can also be inside the brain and heart, there is a big possibility for scientists can do further research studies to use these cells for therapies based on transplantation.

2. Lesser Possibility of Rejection Supporters of the use of adult stem cells for transplantation claim that since these cells come from the patients own cells, it is less likely for the cells to reject the transplanted cells. This characteristic makes adult stem cells perfect candidates for this procedure.

3. Can Cure Medical Conditions Advocates for adult stem cells stress that they can be used for the treatment of some medical conditions such as Parkinsons disease, rheumatoid arthritis, diabetes and heart disease. By extracting adult stem cells, scientists can grow them directly in laboratories and be used to replace damaged cells like dopamine-producing as well as insulin-producing cells.

1. Limited Availabilty Critics of the use of adult stem cells for transplantation argue that only a small number of stem cells from the tissue can be harvested from a persons body. Moreover, once they are removed, divisibility of these cells is limited, which can be challenging, in terms of generating larger amounts of cells. And since these cells are mature as opposed to embryonic cells, the chances of DNA anomalies are higher since they have been exposed to environment and toxins as they age.

2. One Harvest, One Treatment Another skepticism about the effectiveness of adult stem cells for transplantation is that once these cells are harvested, they can only be used for a particular treatment, say, to replace insulin-producing cells. If a patient gets inflicted with another medical disorder, these cells cannot be used anymore.

3. Expensive and Invasive Apart from the difficulty of harvesting stem cells, the procedure can also be costly such as in hip replacements. It is also an invasive procedure, according to some critics and even if there are companies advertising inexpensive stem cell harvesting, it still costs money. This is also an issue on stem cells harvested and stored for future use. Critics say that the fee for storing cells can be high and patients are at risk of wasting money if the firm closes down.

Adult stem cells will play a major role in the field of medicine with continuous research. However, there will still be controversies surrounding it. By weighing their pros and cons, scientists will be able to develop more ways to maximize the potential of these cells and use it for the betterment of lives.

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6 Pros and Cons of Adult Stem Cells | Green Garage

Adult Stem Cells Show Anti-Aging Potential –

Adult Stem Cells | Posted by admin
Nov 28 2018

April 1, 2018 (Vol. 38, No. 7)

Gail Dutton

Longeveron-Grown Stem Cells Advance on Aging Frailty and Related Disabilities

The stem cell industry took some nasty blows in the early 2000s, when the morality of using embryonic stem cells was questioned and all but a few lines of those cells were excluded from federal research grants. Stem cell experts left the United States for laboratories in Singapore and elsewhere.

In the void that remained, determined stem cell researchers found a way forward: adult stem cells. These cells are found throughout the bodyin bone marrow, hair follicles, and other tissuesand they are multipotent, which means they retain the ability to differentiate into some or all of the specialized cell types of the tissue or organ in which they are embedded. Although adult stem cells lack the pluripotency of embryonic stem cells, they can be reprogrammed to become cells of a specific cell type or induced pluripotent stem cells.

The reprogramming technology developed by stem cell researchers is beginning to bear fruit. Although it is not the low-hanging fruit envisaged at the dawn of stem cell science, it is worth the reach. Applications are being developed for basic research, drug testing, and cell-based therapeutics. This last application area, which promises to generate replacement cells and tissues, may be the most important. It is being explored by several companies that hope to manufacture adult stem cells and thereby reinvigorate regenerative medicine. One of companies is Longeveron. By producing allogeneic mesenchymal stem cells (MSCS) from adult human bone marrow MSCs, Longeveron intends to ameliorate diseases and disabilities associated with aging.

Frailty and Diseases of Aging

Im a cardiologist, but Ive long been interested in medical diseases of aging, begins Joshua M. Hare, M.D., co-founder and CSO, Longeveron. Heart disease primarily affects older people, and age is a huge risk factor.

Frailty associated with aging is an underappreciated problem, he continues, adding that it affects approximately 12% of all people age 65 or older. Besides becoming familiar with the statistics of aging frailty, Dr. Hare saw it in his practice.

Dr. Hare has been thinking about the causes of frailty among otherwise healthy people for at least 20 years. Frailty affects so many people of advanced age, yet almost nothing is being done for this group, he notes. It represents a huge challenge.

Aging, he explains, affects all of our organs. Older hearts dont work as well as younger hearts, all other things being equal. Therefore, we hypothesized that the decline in function was related to the depletion of normal adult stem cells in the body. Then we found a way to replete them. For us, it was a Eureka! moment.

A Biotech Founded to Bring MSCs to Market

Dr. Hare says that he co-founded Longeveron in 2014 for the express purpose of bringing the benefits of MSC technology to a broad population. Universities arent set up to take a new therapeutic through the regulatory steps to bring a drug to market, he points out. Rather than hope a biotech company would be interested in acquiring the research, he took matters into his own hands.

Now Longeveron manufactures MSCs in a proprietary process that the company exclusively licensed from the University of Miami. The cells are introduced into the body intravenously.

The decision to form a company was based on clinical trial results, he says. He and his team had recently conducted and published the results of a 45-patient allogeneiC human mesenchymal stem cells in patients with aging fRAilTy via intravenoUS delivery (CRATUS) study. Not only were the patients showing positive responses, they were doing very, very well, Dr. Hare recalls. This was exciting because there were no successful medical therapies whatsoever for this condition. Those trial results were validated by favorable responses from the geriatric medicine community.

One very public sign of approval came in the form of an editorial in the October 2017 issue of The Journals of Gerontology: Series A. The editorials authors called MSC translation a promising and innovative approach for the treatment of frailty in older humans.

The same issue of the journal also published an article summarizing the results of a small, 30-person study. According to this article, treated patients showed remarkable improvements in physical performance measures and inflammatory biomarkers, both of which characterize frailty syndrome. It concluded that larger trials were warranted.

A Check on Inflammation

The use of MSCs to treat aging is a new and exciting component of biotech, Dr. Hare points out. The theory holds that transplanted MSCs can reduce the chronic inflammation associated with aging and aging-related disease, and thereby improve functional capacity and quality of life. At another level, MSCs have the potential to ameliorate diseases and conditions of aging and, perhaps, even increase longevity.

Despite this potential, Dr. Hare cautions against unrealistic expectations: There are quite a few startups, but few major companies are far along in terms of developing or commercializing this type of therapeutic.

Slightly more than three years old, Longeveron has one therapeutic in Phase IIb clinical trials. Additional trials are open. Some are focused on aging frailty; others are evaluating the cells as a way to treat Alzheimers disease.

Longeveron recently indicated that it had completed enrollment for the second cohort of a Phase I/II trial to test the safety and efficacy of a mesenchymal stem cell therapy for improving influenza vaccine response in patients with aging frailty. The company expects data in 2018.

The Competitive Landscape

Designed from MSCs extracted from bone marrow, the therapeutic product is allogenic. It can be made in large quantities and will be available off-the-shelf. Currently, says Dr. Hare, there are no MSCs on the United States market, although one MSC therapy has been approved. Also, two or three companies are pressing ahead with the development of MSC therapies.

According to Dr. Hare, Longeverons MSCs are unique in two respects: the way they are produced, and the way they are characterized. The specifics of manufacturing and the cells characterization features, however, are confidential. They are trade secrets, Dr. Hare insists.

In a recent interview, Dr. Hare was not only reticent about Longeverons technology, he was also vague about the specific challenges the company has weatheredbut not because all these challenges are particulalry sensitive. He was hurrying to help a patient. He did mention, however, challenges pertaining to the specific (and confidential) methods used to turn a cell into a drug, and the FDA guidances for those methods. The next step for the young company, he said, is to begin negotiations with the FDA to design Phase III trials.

In January, Longeveron won a research grant from the National Institutes of Health (NIH) to develop therapeutics to combat metabolic syndrome. The $1.15 million grant is part of the NIH Fast Track program for small businesses. Earlier, the company received clinical trials funding from Alzheimers Association and Marylands Technology Development Corporation (TEDCO).

Dr. Hare attributes Longeverons success to date to a capable team. Dr. Hare himself is founding director of the University of Miamis Interdisciplinary Stem Cell Institute (ISCI). The scientific advisory board includes thought leaders in geriatrics and cardiology from leading institutions in the United States and Japan. Management team members have histories in academia and corporate operations. None, however, has taken a drug to market.

In the end, a lack of commercialization experience may not matter. Longeveron, recognizing its strengths, plans to partner for that phase of its journey.

A Booming Market

If future trials are as successful as Dr. Hare hopes, Longeverons new therapy will be firmly on the path to commercialization. Given the global population of aging baby boomers, he envisions a broad market for the therapy.

People came to us in droves for the clinical trials, Dr. Hare reports. Having the signs and symptoms of frailty troubles people. They have a palpable sense of becoming disabled simply because they are aging. They want to improve their quality of life.

Regenerative therapies already are gaining regulatory approval for many indications. And, while aging has been largely ignored, it is unlikely to be ignored much longer.

If Longeverons approach is eventually commercialized, in the not-too-distant future, any geriatrician or general practice physician should be able to administer Longeverons MSCs to roll back frailty and possibly reduce other deficits in functional capacity related to aging, such as Alzheimers disease and metabolic syndrome.


Location: Life Science & Technology Park' 1951 NW 7th Avenue, Suite 520, Miami, FL 33136

Phone: (305) 909-0840

Principal: Joshua M. Hare, M.D., Co-Founder and CSO

Number of Employees: 18

Focus: Longeveron, a clinical stage company, produces mesenchymal stem cells to alleviate frailty and other conditions associated with aging.

Originally posted here:
Adult Stem Cells Show Anti-Aging Potential -

Induced pluripotent stem cell – Wikipedia

Adult Stem Cells | Posted by admin
Nov 08 2018

iPSCs are typically derived by introducing products of specific sets of pluripotency-associated genes, or "reprogramming factors", into a given cell type. The original set of reprogramming factors (also dubbed Yamanaka factors) are the transcription factors Oct4 (Pou5f1), Sox2, cMyc, and Klf4. While this combination is most conventional in producing iPSCs, each of the factors can be functionally replaced by related transcription factors, miRNAs, small molecules, or even non-related genes such as lineage specifiers.[6]

iPSC derivation is typically a slow and inefficient process, taking 12 weeks for mouse cells and 34 weeks for human cells, with efficiencies around 0.010.1%. However, considerable advances have been made in improving the efficiency and the time it takes to obtain iPSCs. Upon introduction of reprogramming factors, cells begin to form colonies that resemble pluripotent stem cells, which can be isolated based on their morphology, conditions that select for their growth, or through expression of surface markers or reporter genes.

Induced pluripotent stem cells were first generated by Shinya Yamanaka's team at Kyoto University, Japan, in 2006.[1] They hypothesized that genes important to embryonic stem cell (ESC) function might be able to induce an embryonic state in adult cells. They chose twenty-four genes previously identified as important in ESCs and used retroviruses to deliver these genes to mouse fibroblasts. The fibroblasts were engineered so that any cells reactivating the ESC-specific gene, Fbx15, could be isolated using antibiotic selection.

Upon delivery of all twenty-four factors, ESC-like colonies emerged that reactivated the Fbx15 reporter and could propagate indefinitely. To identify the genes necessary for reprogramming, the researchers removed one factor at a time from the pool of twenty-four. By this process, they identified four factors, Oct4, Sox2, cMyc, and Klf4, which were each necessary and together sufficient to generate ESC-like colonies under selection for reactivation of Fbx15.

In June 2007, three separate research groups, including that of Yamanaka's, a Harvard/University of California, Los Angeles collaboration, and a group at MIT, published studies that substantially improved on the reprogramming approach, giving rise to iPSCs that were indistinguishable from ESCs. Unlike the first generation of iPSCs, these second generation iPSCs produced viable chimeric mice and contributed to the mouse germline, thereby achieving the 'gold standard' for pluripotent stem cells.

These second-generation iPSCs were derived from mouse fibroblasts by retroviral-mediated expression of the same four transcription factors (Oct4, Sox2, cMyc, Klf4). However, instead of using Fbx15 to select for pluripotent cells, the researchers used Nanog, a gene that is functionally important in ESCs. By using this different strategy, the researchers created iPSCs that were functionally identical to ESCs.[7][8][9][10]

Reprogramming of human cells to iPSCs was reported in November 2006 by two independent research groups: Shinya Yamanaka of Kyoto University, Japan, who pioneered the original iPSC method, and James Thomson of University of Wisconsin-Madison who was the first to derive human embryonic stem cells. With the same principle used in mouse reprogramming, Yamanaka's group successfully transformed human fibroblasts into iPSCs with the same four pivotal genes, Oct4, Sox2, Klf4, and cMyc, using a retroviral system,[11] while Thomson and colleagues used a different set of factors, Oct4, Sox2, Nanog, and Lin28, using a lentiviral system.[12]

Obtaining fibroblasts to produce iPSCs involves a skin biopsy, and there has been a push towards identifying cell types that are more easily accessible.[13][14] In 2008, iPSCs were derived from human keratinocytes, which could be obtained from a single hair pluck.[15][16] In 2010, iPSCs were derived from peripheral blood cells,[17][18] and in 2012, iPSCs were made from renal epithelial cells in the urine.[19]

Other considerations for starting cell type include mutational load (for example, skin cells may harbor more mutations due to UV exposure),[13][14] time it takes to expand the population of starting cells,[13] and the ability to differentiate into a given cell type.[20]

[citation needed]

The generation of iPS cells is crucially dependent on the transcription factors used for the induction.

Oct-3/4 and certain products of the Sox gene family (Sox1, Sox2, Sox3, and Sox15) have been identified as crucial transcriptional regulators involved in the induction process whose absence makes induction impossible. Additional genes, however, including certain members of the Klf family (Klf1, Klf2, Klf4, and Klf5), the Myc family (c-myc, L-myc, and N-myc), Nanog, and LIN28, have been identified to increase the induction efficiency.

Although the methods pioneered by Yamanaka and others have demonstrated that adult cells can be reprogrammed to iPS cells, there are still challenges associated with this technology:

The table on the right summarizes the key strategies and techniques used to develop iPS cells in the first five years after Yamanaka et al.'s 2006 breakthrough. Rows of similar colors represent studies that used similar strategies for reprogramming.

One of the main strategies for avoiding problems (1) and (2) has been to use minute compounds that can mimic the effects of transcription factors. These molecule compounds can compensate for a reprogramming factor that does not effectively target the genome or fails at reprogramming for another reason; thus they raise reprogramming efficiency. They also avoid the problem of genomic integration, which in some cases contributes to tumor genesis. Key studies using such strategy were conducted in 2008. Melton et al. studied the effects of histone deacetylase (HDAC) inhibitor valproic acid. They found that it increased reprogramming efficiency 100-fold (compared to Yamanakas traditional transcription factor method).[34] The researchers proposed that this compound was mimicking the signaling that is usually caused by the transcription factor c-Myc. A similar type of compensation mechanism was proposed to mimic the effects of Sox2. In 2008, Ding et al. used the inhibition of histone methyl transferase (HMT) with BIX-01294 in combination with the activation of calcium channels in the plasma membrane in order to increase reprogramming efficiency.[35] Deng et al. of Beijing University reported in July 2013 that induced pluripotent stem cells can be created without any genetic modification. They used a cocktail of seven small-molecule compounds including DZNep to induce the mouse somatic cells into stem cells which they called CiPS cells with the efficiency at 0.2% comparable to those using standard iPSC production techniques. The CiPS cells were introduced into developing mouse embryos and were found to contribute to all major cells types, proving its pluripotency.[36][37]

Ding et al. demonstrated an alternative to transcription factor reprogramming through the use of drug-like chemicals. By studying the MET (mesenchymal-epithelial transition) process in which fibroblasts are pushed to a stem-cell like state, Dings group identified two chemicals ALK5 inhibitor SB431412 and MEK (mitogen-activated protein kinase) inhibitor PD0325901 which was found to increase the efficiency of the classical genetic method by 100 fold. Adding a third compound known to be involved in the cell survival pathway, Thiazovivin further increases the efficiency by 200 fold. Using the combination of these three compounds also decreased the reprogramming process of the human fibroblasts from four weeks to two weeks.[38][39]

In April 2009, it was demonstrated that generation of iPS cells is possible without any genetic alteration of the adult cell: a repeated treatment of the cells with certain proteins channeled into the cells via poly-arginine anchors was sufficient to induce pluripotency.[40] The acronym given for those iPSCs is piPSCs (protein-induced pluripotent stem cells).

Another key strategy for avoiding problems such as tumor genesis and low throughput has been to use alternate forms of vectors: adenovirus, plasmids, and naked DNA and/or protein compounds.

In 2008, Hochedlinger et al. used an adenovirus to transport the requisite four transcription factors into the DNA of skin and liver cells of mice, resulting in cells identical to ESCs. The adenovirus is unique from other vectors like viruses and retroviruses because it does not incorporate any of its own genes into the targeted host and avoids the potential for insertional mutagenesis.[41] In 2009, Freed et al. demonstrated successful reprogramming of human fibroblasts to iPS cells.[42] Another advantage of using adenoviruses is that they only need to present for a brief amount of time in order for effective reprogramming to take place.

Also in 2008, Yamanaka et al. found that they could transfer the four necessary genes with a plasmid.[43] The Yamanaka group successfully reprogrammed mouse cells by transfection with two plasmid constructs carrying the reprogramming factors; the first plasmid expressed c-Myc, while the second expressed the other three factors (Oct4, Klf4, and Sox2). Although the plasmid methods avoid viruses, they still require cancer-promoting genes to accomplish reprogramming. The other main issue with these methods is that they tend to be much less efficient compared to retroviral methods. Furthermore, transfected plasmids have been shown to integrate into the host genome and therefore they still pose the risk of insertional mutagenesis. Because non-retroviral approaches have demonstrated such low efficiency levels, researchers have attempted to effectively rescue the technique with what is known as the PiggyBac Transposon System. Several studies have demonstrated that this system can effectively deliver the key reprogramming factors without leaving footprint mutations in the host cell genome. The PiggyBac Transposon System involves the re-excision of exogenous genes, which eliminates the issue of insertional mutagenesis.[citation needed]

In January 2014, two articles were published claiming that a type of pluripotent stem cell can be generated by subjecting the cells to certain types of stress (bacterial toxin, a low pH of 5.7, or physical squeezing); the resulting cells were called STAP cells, for stimulus-triggered acquisition of pluripotency.[44]

In light of difficulties that other labs had replicating the results of the surprising study, in March 2014, one of the co-authors has called for the articles to be retracted.[45] On 4 June 2014, the lead author, Obokata agreed to retract both the papers [46] after she was found to have committed research misconduct as concluded in an investigation by RIKEN on 1 April 2014.[47]

MicroRNAs are short RNA molecules that bind to complementary sequences on messenger RNA and block expression of a gene. Measuring variations in microRNA expression in iPS cells can be used to predict their differentiation potential.[48] Addition of microRNAs can also be used to enhance iPS potential. Several mechanisms have been proposed.[48] ES cell-specific microRNA molecules (such as miR-291, miR-294 and miR-295) enhance the efficiency of induced pluripotency by acting downstream of c-Myc.[49]microRNAs can also block expression of repressors of Yamanakas four transcription factors, and there may be additional mechanisms induce reprogramming even in the absence of added exogenous transcription factors.[48]

The task of producing iPS cells continues to be challenging due to the six problems mentioned above. A key tradeoff to overcome is that between efficiency and genomic integration. Most methods that do not rely on the integration of transgenes are inefficient, while those that do rely on the integration of transgenes face the problems of incomplete reprogramming and tumor genesis, although a vast number of techniques and methods have been attempted. Another large set of strategies is to perform a proteomic characterization of iPS cells.[64] Further studies and new strategies should generate optimal solutions to the five main challenges. One approach might attempt to combine the positive attributes of these strategies into an ultimately effective technique for reprogramming cells to iPS cells.

Another approach is the use of iPS cells derived from patients to identify therapeutic drugs able to rescue a phenotype. For instance, iPS cell lines derived from patients affected by ectodermal dysplasia syndrome (EEC), in which the p63 gene is mutated, display abnormal epithelial commitment that could be partially rescued by a small compound[65]

An attractive feature of human iPS cells is the ability to derive them from adult patients to study the cellular basis of human disease. Since iPS cells are self-renewing and pluripotent, they represent a theoretically unlimited source of patient-derived cells which can be turned into any type of cell in the body. This is particularly important because many other types of human cells derived from patients tend to stop growing after a few passages in laboratory culture. iPS cells have been generated for a wide variety of human genetic diseases, including common disorders such as Down syndrome and polycystic kidney disease.[66][67] In many instances, the patient-derived iPS cells exhibit cellular defects not observed in iPS cells from healthy patients, providing insight into the pathophysiology of the disease.[68] An international collaborated project, StemBANCC, was formed in 2012 to build a collection of iPS cell lines for drug screening for a variety of disease. Managed by the University of Oxford, the effort pooled funds and resources from 10 pharmaceutical companies and 23 universities. The goal is to generate a library of 1,500 iPS cell lines which will be used in early drug testing by providing a simulated human disease environment.[69] Furthermore, combining hiPSC technology and genetically-encoded voltage and calcium indicators provided a large-scale and high-throughput platform for cardiovascular drug safety screening.[70]

A proof-of-concept of using induced pluripotent stem cells (iPSCs) to generate human organ for transplantation was reported by researchers from Japan. Human liver buds (iPSC-LBs) were grown from a mixture of three different kinds of stem cells: hepatocytes (for liver function) coaxed from iPSCs; endothelial stem cells (to form lining of blood vessels) from umbilical cord blood; and mesenchymal stem cells (to form connective tissue). This new approach allows different cell types to self-organize into a complex organ, mimicking the process in fetal development. After growing in vitro for a few days, the liver buds were transplanted into mice where the liver quickly connected with the host blood vessels and continued to grow. Most importantly, it performed regular liver functions including metabolizing drugs and producing liver-specific proteins. Further studies will monitor the longevity of the transplanted organ in the host body (ability to integrate or avoid rejection) and whether it will transform into tumors.[71][72] Using this method, cells from one mouse could be used to test 1,000 drug compounds to treat liver disease, and reduce animal use by up to 50,000.[73]

Embryonic cord-blood cells were induced into pluripotent stem cells using plasmid DNA. Using cell surface endothelial/pericytic markers CD31 and CD146, researchers identified 'vascular progenitor', the high-quality, multipotent vascular stem cells. After the iPS cells were injected directly into the vitreous of the damaged retina of mice, the stem cells engrafted into the retina, grew and repaired the vascular vessels.[74][75]

Labelled iPSCs-derived NSCs injected into laboratory animals with brain lesions were shown to migrate to the lesions and some motor function improvement was observed.[76]

Although a pint of donated blood contains about two trillion red blood cells and over 107 million blood donations are collected globally, there is still a critical need for blood for transfusion. In 2014, type O red blood cells were synthesized at the Scottish National Blood Transfusion Service from iPSC. The cells were induced to become a mesoderm and then blood cells and then red blood cells. The final step was to make them eject their nuclei and mature properly. Type O can be transfused into all patients. Human clinical trials were not expected to begin before 2016.[77]

The first human clinical trial using autologous iPSCs was approved by the Japan Ministry Health and was to be conducted in 2014 at the Riken Center for Developmental Biology in Kobe. However the trial was suspended after Japan's new regenerative medicine laws came into effect in November 2015.[78] More specifically, an existing set of guidelines was strengthened to have the force of law (previously mere recommendations).[79] iPSCs derived from skin cells from six patients suffering from wet age-related macular degeneration were reprogrammed to differentiate into retinal pigment epithelial (RPE) cells. The cell sheet would be transplanted into the affected retina where the degenerated RPE tissue was excised. Safety and vision restoration monitoring were to last one to three years.[80][81]

In March 2017 a team led by Masayo Takahashi completed the first successful transplant of iPS-derived retinal cells from a donor into the eye of a person with advanced macular degeneration.[82] However it was reported that they are now having complications.[83] The benefits of using autologous iPSCs are that there is theoretically no risk of rejection and that it eliminates the need to use embryonic stem cells. However, the iPSCs were derived from another person.[81]

The other multipotent mesenchymal stem cell, when induced into pluripotence, holds great promise to slow down the aging process. Such anti-aging properties were demonstrated in early clinical trials in 2017.[84]

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What Are The Similarities And Differences Between Embryonic …

Adult Stem Cells | Posted by admin
Sep 30 2018

Human embryonic and adult stem cells each have advantages and disadvantages regarding potential use for cell-based regenerative therapies. Of course, adult and embryonic stem cells differ in the number and type of differentiated cells types they can become. Embryonic stem cells can become all cell types of the body because they are pluripotent. Adult stem cells are generally limited to differentiating into different cell types of their tissue of origin. However, some evidence suggests that adult stem cell plasticity may exist, increasing the number of cell types a given adult stem cell can become.

Large numbers of embryonic stem cells can be relatively easily grown in culture, while adult stem cells are rare in mature tissues and methods for expanding their numbers in cell culture have not yet been worked out. This is an important distinction, as large numbers of cells are needed for stem cell replacement therapies.

A potential advantage of using stem cells from an adult is that the patient's own cells could be expanded in culture and then reintroduced into the patient. The use of the patient's own adult stem cells would mean that the cells would not be rejected by the immune system. This represents a significant advantage as immune rejection is a difficult problem that can only be circumvented with immunosuppressive drugs.

Embryonic stem cells from a donor introduced into a patient could cause transplant rejection. However, whether the recipient would reject donor embryonic stem cells has not been determined in human experiments.

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

Adult Stem Cells | Posted by admin
Sep 16 2018

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

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cardiovascular disease: Cardiac stem cells

Cardiac stem cells, which have the ability to differentiate (specialize) into mature heart cells and therefore could be used to repair damaged or diseased heart tissue, have garnered significant interest in the development of treatments for heart disease and cardiac defects. Cardiac stem

Embryonic stem cells (often referred to as ES cells) are stem cells that are derived from the inner cell mass of a mammalian embryo at a very early stage of development, when it is composed of a hollow sphere of dividing cells (a blastocyst). Embryonic stem cells from human embryos and from embryos of certain other mammalian species can be grown in tissue culture.

The most-studied embryonic stem cells are mouse embryonic stem cells, which were first reported in 1981. This type of stem cell can be cultured indefinitely in the presence of leukemia inhibitory factor (LIF), a glycoprotein cytokine. If cultured mouse embryonic stem cells are injected into an early mouse embryo at the blastocyst stage, they will become integrated into the embryo and produce cells that differentiate into most or all of the tissue types that subsequently develop. This ability to repopulate mouse embryos is the key defining feature of embryonic stem cells, and because of it they are considered to be pluripotentthat is, able to give rise to any cell type of the adult organism. If the embryonic stem cells are kept in culture in the absence of LIF, they will differentiate into embryoid bodies, which somewhat resemble early mouse embryos at the egg-cylinder stage, with embryonic stem cells inside an outer layer of endoderm. If embryonic stem cells are grafted into an adult mouse, they will develop into a type of tumour called a teratoma, which contains a variety of differentiated tissue types.

Mouse embryonic stem cells are widely used to create genetically modified mice. This is done by introducing new genes into embryonic stem cells in tissue culture, selecting the particular genetic variant that is desired, and then inserting the genetically modified cells into mouse embryos. The resulting chimeric mice are composed partly of host cells and partly of the donor embryonic stem cells. As long as some of the chimeric mice have germ cells (sperm or eggs) that have been derived from the embryonic stem cells, it is possible to breed a line of mice that have the same genetic constitution as the embryonic stem cells and therefore incorporate the genetic modification that was made in vitro. This method has been used to produce thousands of new genetic lines of mice. In many such genetic lines, individual genes have been ablated in order to study their biological function; in others, genes have been introduced that have the same mutations that are found in various human genetic diseases. These mouse models for human disease are used in research to investigate both the pathology of the disease and new methods for therapy.

Extensive experience with mouse embryonic stem cells made it possible for scientists to grow human embryonic stem cells from early human embryos, and the first human stem cell line was created in 1998. Human embryonic stem cells are in many respects similar to mouse embryonic stem cells, but they do not require LIF for their maintenance. The human embryonic stem cells form a wide variety of differentiated tissues in vitro, and they form teratomas when grafted into immunosuppressed mice. It is not known whether the cells can colonize all the tissues of a human embryo, but it is presumed from their other properties that they are indeed pluripotent cells, and they therefore are regarded as a possible source of differentiated cells for cell therapythe replacement of a patients defective cell type with healthy cells. Large quantities of cells, such as dopamine-secreting neurons for the treatment of Parkinson disease and insulin-secreting pancreatic beta cells for the treatment of diabetes, could be produced from embryonic stem cells for cell transplantation. Cells for this purpose have previously been obtainable only from sources in very limited supply, such as the pancreatic beta cells obtained from the cadavers of human organ donors.

The use of human embryonic stem cells evokes ethical concerns, because the blastocyst-stage embryos are destroyed in the process of obtaining the stem cells. The embryos from which stem cells have been obtained are produced through in vitro fertilization, and people who consider preimplantation human embryos to be human beings generally believe that such work is morally wrong. Others accept it because they regard the blastocysts to be simply balls of cells, and human cells used in laboratories have not previously been accorded any special moral or legal status. Moreover, it is known that none of the cells of the inner cell mass are exclusively destined to become part of the embryo itselfall of the cells contribute some or all of their cell offspring to the placenta, which also has not been accorded any special legal status. The divergence of views on this issue is illustrated by the fact that the use of human embryonic stem cells is allowed in some countries and prohibited in others.

In 2009 the U.S. Food and Drug Administration approved the first clinical trial designed to test a human embryonic stem cell-based therapy, but the trial was halted in late 2011 because of a lack of funding and a change in lead American biotech company Gerons business directives. The therapy to be tested was known as GRNOPC1, which consisted of progenitor cells (partially differentiated cells) that, once inside the body, matured into neural cells known as oligodendrocytes. The oligodendrocyte progenitors of GRNOPC1 were derived from human embryonic stem cells. The therapy was designed for the restoration of nerve function in persons suffering from acute spinal cord injury.

Embryonic germ (EG) cells, derived from primordial germ cells found in the gonadal ridge of a late embryo, have many of the properties of embryonic stem cells. The primordial germ cells in an embryo develop into stem cells that in an adult generate the reproductive gametes (sperm or eggs). In mice and humans it is possible to grow embryonic germ cells in tissue culture with the appropriate growth factorsnamely, LIF and another cytokine called fibroblast growth factor.

Some tissues in the adult body, such as the epidermis of the skin, the lining of the small intestine, and bone marrow, undergo continuous cellular turnover. They contain stem cells, which persist indefinitely, and a much larger number of transit amplifying cells, which arise from the stem cells and divide a finite number of times until they become differentiated. The stem cells exist in niches formed by other cells, which secrete substances that keep the stem cells alive and active. Some types of tissue, such as liver tissue, show minimal cell division or undergo cell division only when injured. In such tissues there is probably no special stem-cell population, and any cell can participate in tissue regeneration when required.

The epidermis of the skin contains layers of cells called keratinocytes. Only the basal layer, next to the dermis, contains cells that divide. A number of these cells are stem cells, but the majority are transit amplifying cells. The keratinocytes slowly move outward through the epidermis as they mature, and they eventually die and are sloughed off at the surface of the skin. The epithelium of the small intestine forms projections called villi, which are interspersed with small pits called crypts. The dividing cells are located in the crypts, with the stem cells lying near the base of each crypt. Cells are continuously produced in the crypts, migrate onto the villi, and are eventually shed into the lumen of the intestine. As they migrate, they differentiate into the cell types characteristic of the intestinal epithelium.

Bone marrow contains cells called hematopoietic stem cells, which generate all the cell types of the blood and the immune system. Hematopoietic stem cells are also found in small numbers in peripheral blood and in larger numbers in umbilical cord blood. In bone marrow, hematopoietic stem cells are anchored to osteoblasts of the trabecular bone and to blood vessels. They generate progeny that can become lymphocytes, granulocytes, red blood cells, and certain other cell types, depending on the balance of growth factors in their immediate environment.

Work with experimental animals has shown that transplants of hematopoietic stem cells can occasionally colonize other tissues, with the transplanted cells becoming neurons, muscle cells, or epithelia. The degree to which transplanted hematopoietic stem cells are able to colonize other tissues is exceedingly small. Despite this, the use of hematopoietic stem cell transplants is being explored for conditions such as heart disease or autoimmune disorders. It is an especially attractive option for those opposed to the use of embryonic stem cells.

Bone marrow transplants (also known as bone marrow grafts) represent a type of stem cell therapy that is in common use. They are used to allow cancer patients to survive otherwise lethal doses of radiation therapy or chemotherapy that destroy the stem cells in bone marrow. For this procedure, the patients own marrow is harvested before the cancer treatment and is then reinfused into the body after treatment. The hematopoietic stem cells of the transplant colonize the damaged marrow and eventually repopulate the blood and the immune system with functional cells. Bone marrow transplants are also often carried out between individuals (allograft). In this case the grafted marrow has some beneficial antitumour effect. Risks associated with bone marrow allografts include rejection of the graft by the patients immune system and reaction of immune cells of the graft against the patients tissues (graft-versus-host disease).

Bone marrow is a source for mesenchymal stem cells (sometimes called marrow stromal cells, or MSCs), which are precursors to non-hematopoietic stem cells that have the potential to differentiate into several different types of cells, including cells that form bone, muscle, and connective tissue. In cell cultures, bone-marrow-derived mesenchymal stem cells demonstrate pluripotency when exposed to substances that influence cell differentiation. Harnessing these pluripotent properties has become highly valuable in the generation of transplantable tissues and organs. In 2008 scientists used mesenchymal stem cells to bioengineer a section of trachea that was transplanted into a woman whose upper airway had been severely damaged by tuberculosis. The stem cells were derived from the womans bone marrow, cultured in a laboratory, and used for tissue engineering. In the engineering process, a donor trachea was stripped of its interior and exterior cell linings, leaving behind a trachea scaffold of connective tissue. The stem cells derived from the recipient were then used to recolonize the interior of the scaffold, and normal epithelial cells, also isolated from the recipient, were used to recolonize the exterior of the trachea. The use of the recipients own cells to populate the trachea scaffold prevented immune rejection and eliminated the need for immunosuppression therapy. The transplant, which was successful, was the first of its kind.

Research has shown that there are also stem cells in the brain. In mammals very few new neurons are formed after birth, but some neurons in the olfactory bulbs and in the hippocampus are continually being formed. These neurons arise from neural stem cells, which can be cultured in vitro in the form of neurospheressmall cell clusters that contain stem cells and some of their progeny. This type of stem cell is being studied for use in cell therapy to treat Parkinson disease and other forms of neurodegeneration or traumatic damage to the central nervous system.

Following experiments in animals, including those used to create Dolly the sheep, there has been much discussion about the use of somatic cell nuclear transfer (SCNT) to create pluripotent human cells. In SCNT the nucleus of a somatic cell (a fully differentiated cell, excluding germ cells), which contains the majority of the cells DNA (deoxyribonucleic acid), is removed and transferred into an unfertilized egg cell that has had its own nuclear DNA removed. The egg cell is grown in culture until it reaches the blastocyst stage. The inner cell mass is then removed from the egg, and the cells are grown in culture to form an embryonic stem cell line (generations of cells originating from the same group of parent cells). These cells can then be stimulated to differentiate into various types of cells needed for transplantation. Since these cells would be genetically identical to the original donor, they could be used to treat the donor with no problems of immune rejection. Scientists generated human embryonic stem cells successfully from SCNT human embryos for the first time in 2013.

While promising, the generation and use of SCNT-derived embryonic stem cells is controversial for several reasons. One is that SCNT can require more than a dozen eggs before one egg successfully produces embryonic stem cells. Human eggs are in short supply, and there are many legal and ethical problems associated with egg donation. There are also unknown risks involved with transplanting SCNT-derived stem cells into humans, because the mechanism by which the unfertilized egg is able to reprogram the nuclear DNA of a differentiated cell is not entirely understood. In addition, SCNT is commonly used to produce clones of animals (such as Dolly). Although the cloning of humans is currently illegal throughout the world, the egg cell that contains nuclear DNA from an adult cell could in theory be implanted into a womans uterus and come to term as an actual cloned human. Thus, there exists strong opposition among some groups to the use of SCNT to generate human embryonic stem cells.

Due to the ethical and moral issues surrounding the use of embryonic stem cells, scientists have searched for ways to reprogram adult somatic cells. Studies of cell fusion, in which differentiated adult somatic cells grown in culture with embryonic stem cells fuse with the stem cells and acquire embryonic stem-cell-like properties, led to the idea that specific genes could reprogram differentiated adult cells. An advantage of cell fusion is that it relies on existing embryonic stem cells instead of eggs. However, fused cells stimulate an immune response when transplanted into humans, which leads to transplant rejection. As a result, research has become increasingly focused on the genes and proteins capable of reprogramming adult cells to a pluripotent state. In order to make adult cells pluripotent without fusing them to embryonic stem cells, regulatory genes that induce pluripotency must be introduced into the nuclei of adult cells. To do this, adult cells are grown in cell culture, and specific combinations of regulatory genes are inserted into retroviruses (viruses that convert RNA [ribonucleic acid] into DNA), which are then introduced to the culture medium. The retroviruses transport the RNA of the regulatory genes into the nuclei of the adult cells, where the genes are then incorporated into the DNA of the cells. About 1 out of every 10,000 cells acquires embryonic stem cell properties. Although the mechanism is still uncertain, it is clear that some of the genes confer embryonic stem cell properties by means of the regulation of numerous other genes. Adult cells that become reprogrammed in this way are known as induced pluripotent stem cells (iPS).

Similar to embryonic stem cells, induced pluripotent stem cells can be stimulated to differentiate into select types of cells that could in principle be used for disease-specific treatments. In addition, the generation of induced pluripotent stem cells from the adult cells of patients affected by genetic diseases can be used to model the diseases in the laboratory. For example, in 2008 researchers isolated skin cells from a child with an inherited neurological disease called spinal muscular atrophy and then reprogrammed these cells into induced pluripotent stem cells. The reprogrammed cells retained the disease genotype of the adult cells and were stimulated to differentiate into motor neurons that displayed functional insufficiencies associated with spinal muscular atrophy. By recapitulating the disease in the laboratory, scientists were able to study closely the cellular changes that occurred as the disease progressed. Such models promise not only to improve scientists understanding of genetic diseases but also to facilitate the development of new therapeutic strategies tailored to each type of genetic disease.

In 2009 scientists successfully generated retinal cells of the human eye by reprogramming adult skin cells. This advance enabled detailed investigation of the embryonic development of retinal cells and opened avenues for the generation of novel therapies for eye diseases. The production of retinal cells from reprogrammed skin cells may be particularly useful in the treatment of retinitis pigmentosa, which is characterized by the progressive degeneration of the retina, eventually leading to night blindness and other complications of vision. Although retinal cells also have been produced from human embryonic stem cells, induced pluripotency represents a less controversial approach. Scientists have also explored the possibility of combining induced pluripotent stem cell technology with gene therapy, which would be of value particularly for patients with genetic disease who would benefit from autologous transplantation.

Researchers have also been able to generate cardiac stem cells for the treatment of certain forms of heart disease through the process of dedifferentiation, in which mature heart cells are stimulated to revert to stem cells. The first attempt at the transplantation of autologous cardiac stem cells was performed in 2009, when doctors isolated heart tissue from a patient, cultured the tissue in a laboratory, stimulated cell dedifferentiation, and then reinfused the cardiac stem cells directly into the patients heart. A similar study involving 14 patients who underwent cardiac bypass surgery followed by cardiac stem cell transplantation was reported in 2011. More than three months after stem cell transplantation, the patients experienced a slight but detectable improvement in heart function.

Patient-specific induced pluripotent stem cells and dedifferentiated cells are highly valuable in terms of their therapeutic applications because they are unlikely to be rejected by the immune system. However, before induced pluripotent stem cells can be used to treat human diseases, researchers must find a way to introduce the active reprogramming genes without using retroviruses, which can cause diseases such as leukemia in humans. A possible alternative to the use of retroviruses to transport regulatory genes into the nuclei of adult cells is the use of plasmids, which are less tumourigenic than viruses.

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Fact Sheet: Adult Stem Cell Research and Transplants …

Adult Stem Cells | Posted by admin
Sep 16 2018

To view as PDF, see: CLI Fact Sheet Adult Stem Cell Research and Transplants

Last updated: November 21, 2017

Adult stem cell transplants are already widely used to the benefit of over a million people.

Adult stem cell transplants are being used to treat dozens of conditions in patients.

[i] Gratwohl A et al., One million haematopoietic stem-cell transplants: a retrospective observational study, Lancet Haematology 2, e91-e100, March 2015. doi:10.1016/S2352-3026(15)00028-9.

[ii]Niederwieser D, Baldomero H, Szer J, Gratwohl M, et al., Hematopoietic stem cell transplantation activity worldwide in 2012 and a SWOT analysis of the Worldwide Network for Blood and Marrow Transplantation Group including the global survey. Bone Marrow Transplant. 51(6):778-785, 2016. doi:10.1038/bmt.2016.18.

[iii] General FAQ. U.S. Department of Health and Human Services, Health Resources and Services Administration., accessed August 3, 2016.

[iv] Ballen KK, Gluckman E, Broxmeyer HE, Umbilical cord blood transplantation: the first 25 years and beyond, Blood. 122:491-498, 2013. doi:10.1182/blood-2013-02-453175.

[v] Gratwohl A et al., One million haematopoietic stem-cell transplants: a retrospective observational study, Lancet Haematology 2, e91-e100, March 2015. doi:10.1016/S2352-3026(15)00028-9.

[vi] Search term:, accessed August 2, 2016.

[vii] Patel AN et al., Ixmyelocel-T for patients with ischaemic heart failure: a prospective randomised double-blind trial. Lancet 387:2412-2421, 2016. doi: 10.1016/S0140-6736(16)30137-4.

[viii] Steinberg GK, Kondziolka D, Wechsker LR et al., Clinical Outcomes of Transplanted Modified Bone MarrowDerived Mesenchymal Stem Cells in Stroke: A Phase 1/2a Study. Stroke. 447: 1817-1824, 2016. doi: 10.1161/STROKEAHA.116.012995; Cox CS, Hetz RA, Liao GP, et al., Treatment of Severe Adult Traumatic Brain Injury Using Bone Marrow Mononuclear Cells. Stem Cells. 35:1065-1079, 2017. doi: 10.1002/stem.2538; Hess, DC et al., Safety and Efficacy of Multipotent Adult Progenitor Cells in Acute Ischaemic Stroke (MASTERS): A Randomised, Double-Blind, Placebo-Controlled, Phase 2 Trials. Lancet. 16 (5):360-368, 2017. doi: 10.1016/S1474-4422(17)30046-7; Savitz SI, Misra V, Kasam M, et al., Intravenous Autologous Bone Marrow Mononuclear Cells for Ischemic Stroke. Annals of Neurology. 70:59-69, 2011. doi: 10.1002/ana.22458.

[ix]See Bernaudin F et al., Long-term results of related myeloablative stem-cell transplantation to cure sickle cell disease. Blood. 110:2749-2756,2007. doi: 10.1182/blood-2007-03-079665. Hematopoietic stem cell transplantation (HSCT) is the only curative therapy for sickle cell disease.

[x] Lima C, Pratas-Vital J, Escada P, Hasse-Ferreira A, Capucho C, Peduzzi JD. Olfactory Mucosal Autografts and Rehabilitation for Chronic Traumatic Spinal Cord Injury. Neurorehabil Neural Repair January 24:10-22, 2010. doi: 10.1177/1545968309347685; Lima C, Pratas-Vital J, Escada P, Hasse-Ferreira A, Capucho C, Peduzzi JD. Olfactory Mucosa Autografts in Human Spinal Cord Injury: A Pilot Clinical Study. The Journal of Spinal Cord Medicine. 29(3):191-203, 2006.

[xi] Burt RK et al., Association of Nonmyeloablative Hematopoietic Stem Cell Transplantation With Neurological Disability in Patients With Relapsing-Remitting Multiple Sclerosis, JAMA. 313(3):275-284, 2015. doi: 10.1001/jama.2014.17986.

[xii] Cai J et al., Umbilical Cord Mesenchymal Stromal Cell With Autologous Bone Marrow Cell Transplantation in Established Type 1 Diabetes: A Pilot Randomized Controlled Open-Label Clinical Study to Assess Safety and Impact on Insulin Secretion, Diabetes Care. 39, 149, 2016. doi: 10.2337/dc15-0171; Gaipov, A et al., Autologous Bone-Marrow-Derived Stem Cells Transplantation in Type 1 Diabetes Mellitus. Nephrol. Dial. Transplant. 31 (suppl 1):i217, 2016. doi: 10.1093/ndt/gfw169.03; DAddio F et al., Autologous Nonmyeloablative Hematopoietic Stem Cell Transplantation in New-Onset Type 1 Diabetes: A Multicenter Analysis, Diabetes.63(9),3041-3046, 2014.doi:10.2337/db14-0295; Zhao et al., Reversal of type 1 diabetes via islet cell regeneration following immune modulation by cord blood-derived multipotent stem cells. BMC Medicine. 10(3), 2012. doi: 10.1186/1741-7015-10-3; Voltarelli JC and Couri CEB, Stem cell transplantation for type 1 diabetes mellitus, Diabetology & Metabolic Syndrome 1, 4, 2009. doi: 10.1186/1758-5996-1-4; Couri CEB et al., C-Peptide Levels and Insulin Independence Following Autologous Nonmyeloablative Hematopoietic Stem Cell Transplantation in Newly Diagnosed Type 1 Diabetes Mellitus, JAMA 301, 1573-1579, 2009; Voltarelli JC et al., Autologous Nonmyeloablative Hematopoietic Stem Cell Transplantation in Newly Diagnosed Type 1 Diabetes Mellitus, JAMA. 297, 1568-1576, 2007.

[xiii] Weiss JN, Levy S, Malkin A. Stem Cell Ophthalmology Treatment Study (SCOTS) for retinal and optic nerve diseases: a preliminary report. Neural Regen Res 2015; 10:982-8; Weiss JN, Levy S, Benes SC. Stem Cell Ophthalmology Treatment Study (SCOTS) for retinal and optic nerve diseases: a case report of improvement in relapsing auto-immune optic neuropathy. Neural Regen Res 2015; 10:1507-15.

[xiv] Burt RK et al., Nonmyeloablative Hematopoietic Stem Cell Transplantation for Systemic Lupus Erythematosus, JAMA 295, 527-535, 2006, doi: 10.1001/jama.295.5.527; Illei GG et al., Current state and future directions of autologous hematopoietic stem cell transplantation in systemic lupus erythematosus, Annals of the Rheumatic Diseases 70, 2071-2074, 2011 doi: 10.1136/ard.2010.148049; Szodoray P et al., Immunological reconstitution after autologous stem cell transplantation in patients with refractory systemic autoimmune diseases, Scandinavian Journal of Rheumatology 41, 110-115, 2012, doi: 10.3109/03009742.2011.606788; Alchi B et al., Autologous haematopoietic stem cell transplantation for systemic lupus erythematosus: data from the European Group for Blood and Marrow Transplantation registry, Lupus 22, 245-253, 2013, doi: 10.1177/0961203312470729; Alexander T et al., Autologous hematopoietic stem cell transplantation in systemic lupus erythematosus, Z. Rheumatologie 75, 770-779, 2016, doi: 10.1007/s00393-016-0190-3

[xv]Search term selection: multiple myeloma/plasma cell disease (PCD), accessed August 3, 2016.

[xvi] Press release: The Lancet Hematology: Experts warn of stem cell underuse as transplants reach 1 million worldwide (Feb 26, 2016), accessed August 2, 2016.

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