Cellular Dynamics International (CDI), the startup company formed by Dr. James Thomson of the University of Wisconsin at Madison, has signed a licensing agreement with Mount Sinai Medical School in New York City.

The exclusive licensing agreement will allow CDI to produce cardiac cells with technology that was originally developed by Dr. Gordon Keller, who served as a professor of gene and cell medicine at Mount Sinai School of Medicine (MSSM) from 1999 to 2006, and after whom the Keller Laboratory at MSSM is named. Currently Dr. Keller directs the McEwen Centre for Regenerative Medicine at the University Health Network in Toronto. The license will allow for the differentiation of human pluripotent stem cells into cardiovascular progenitor cells which can then be further differentiated into more specialized cell lineages such as cardiomyocytes, endothelial cells and vascular smooth muscle cells. The various cardiac cells would then be used for pharmacological drug screening.

CDI, which Dr. Thomson and 3 of his colleagues founded in 2004, has already been selling heart cells to Roche and a number of other pharmaceutical companies for the toxicity testing of drugs. This new licensing agreement significantly increases CDI’s patent portfolio.

This is not the first licensing agreement between CDI and an academic institution, although it is the first that CDI has formally disclosed. The agreement is considered to be unique in a number of ways, not the least of which is its exclusivity, a condition which is rarely granted by academic institutions and which is thought to have cost CDI consideraly more than a nonexclusive licensing agreement would have cost. A senior representative of CDI indicated that the announcement of further licensing agreements could be expected in the near future.

According to Dr. W. Patrick McGrath, executive director of MSSM’s Office of Technology and Business Development (OTBD), "The Mount Sinai School of Medicine is pleased that CDI has selected MSSM’s technology for the production and use of cardiomyocytes and other cardiac cells. OTBD believes that CDI is well qualified to take the final steps to commercially develop MSSM’s translational research into products and services that will benefit the drug development process and, ultimately, cardiac patients worldwide."

As Chris Kendrick-Parker, chief commercialization officer and one of the vice presidents of CDI, adds, "We believe that CDI’s pluripotent stem cell technology will be the pharmaceutical industry’s platform of choice for identifying drug candidates and their probability of success in predictive toxicology. This exclusive license provides CDI complete freedom to operate in our quest to efficiently and effectively produce and provide cardiomyocytes and other cardiac cells for screening purposes. Furthermore, this license strengthens our growing patent portfolio and makes us a preferred collaborator and provider to pharma and biotech companies developing predictive toxicology tools to aid the industry."

As Dr. Thomson has often explained in the past, the most immediate application of pluripotent stem cells is not so much in cell-based therapies for the treatment of actual diseases and injuries, but rather in drug testing and development. Until a number of scientific obstacles are overcome, merely one of which is the danger of teratoma (tumor) formation, pluripotent stem cells carry too many risks to be used as actual clinical therapies. Pluripotent stem cells include not only embryonic stem cells but also the more recently developed iPS (induced pluripotent stem) cells, which, by official definition of pluripotency, are required to form teratomas. Adult stem cells, by sharp contrast, which are multipotent instead of pluripotent, do not, by definition, carry any risk of teratoma formation.

As Mr. Kendrick-Parker further explains, "This gives us multiple methods to arrive at the end goal of making fully functional terminal tissues from pluripotent cells, and really gives us the freedom to operate through a variety of methods to generate large quantities of cardiomyocytes as a tool. We’ve tried to basically create a portfolio of patents that allows us to use the most efficient means necessary to arrive at those cell types, and to have choices to arrive at the best population of cells for our customers. This helps us make sure that we have a marked advantage in this area, and that our customers know that when they do business with us they are unencumbered."

Curiously, a certain amount of ambiguity seems to have been built into this news announcement, as neither this nor other related news articles specify the exact source of these newly generated cardiac cells. In other words, nowhere was it mentioned whether the cardiac cells are to be generated from human embryonic stem cells (hESCs) or from induced pluripotent stem (iPS) cells, the latter of which are of adult somatic cell origin. Similarly, the news announcement as posted on the website of CDI merely states that the newly generated cardiac cells are produced from "human pluripotent stem cells (hPSCs)", which could be either of embryonic or of adult cell origin, and even the company’s official announcement also stops short of specifying the precise source of these hPSCs. However, a further examination of the description of "human cardiac cytotoxicity screening" on CDI’s website reveals that these hPSCs are of adult, not embryonic, cell origin, as they are derived from iPS (induced pluripotent stem) cells, not from embryonic stem cells. More precisely, the CDI website displays the following statement: "CDI’s cardiomyocytes are differentiated from hPSCs that are reprogrammed to their pluripotent state from adult cells, thus avoiding the controversial and ethical issues surrounding embryonic stem cells." This is further verified by Mr. Kendrick-Parker’s statement that, "There are a lot of different institutions where we think if we can industrialize the process of making iPS cells, then there is a business to be had in the generation of those materials." Despite the fact that Dr. Keller’s specialty is in the derivation of cardiovascular progenitor cells from embryonic stem cells, therefore, this particular licensing application of the IP that Dr. Keller developed would seem to be intended for cells that are of adult somatic, not embryonic stem cell, origin.

Such a point is not insignificant, especially in light of the fact that Dr. James Thomson, one of the founders of CDI and CDI’s Chief Scientific Officer, is renowned throughout the world for having been the first person ever to isolate an embryonic stem cell in the laboratory, first from a nonhuman primate in 1995 and then from a human in 1998. Known as "the father of embryonic stem cell science", Dr. Thomson is credited with having spawned the entire field of embryonic stem cell research, and the mere mention of his name invokes sincere reverence from embryonic stem cell scientists throughout the world. Yet on numerous occasions, Dr. Thomson himself has emphasized the point that iPS cells hold greater medical potential than embryonic stem cells, and furthermore, unlike embryonic stem cells, iPS cells are created from adult somatic (ordinary, non-stem cell) cells, and are therefore derived without the need for embryos at all. In fact, Dr. Thomson and his colleagues in his laboratory at the University of Wisconsin at Madison were also co-developers of iPS cell technology, although this fact is often overshadowed by Dr. Thomson’s earlier, more dramatic pioneering work in embryonic stem cell research. However, the fact that CDI is now investing so heavily in research that involves iPS cells, not embryonic stem cells, is further evidence for the greater medical usefulness and commercial priority of iPS cells over embryonic stem cells. Why, exactly, this rather crucial and fundamental point was never explicitly clarified in any of the news announcements, however, is anyone’s guess.

CDI has plans that extend beyond cardiovascular progenitor cells, as Mr. Kendrick-Parker explains that the company is developing projects "for a variety of different cell types that run the gamut of tools that are required for pharmacology and toxicity testing." Still, however, the final goal of CDI’s stem cell R&D, regardless of the specific types of cells that are involved, is for purposes of drug screening – and the profitable commercialization of drug screening tools – not for the development of cell-based clinical therapies.

Specific terms of the licensing agreement have not been disclosed.

Why do human embryos develop a fully functioning, beating heart, so early in development? Why is it that the human embryological heart starts beating long before the circulatory system and the bodily tissues that will be served by circulating blood have developed?

Embryologists have often pondered such questions. Now, two independent groups of researchers in Boston may have discovered the answers.

Scientists at Children’s Hospital, Brigham and Women’s Hospital, and the Harvard Stem Cell Institute have found that a beating heart is necessary for the production of blood stem cells. More specifically, the biomechanical forces produced by the early embryological heart trigger the production of chemicals which in turn trigger the cellular formation of hematopoietic cells, which are the stem cells that differentiate into blood.

In other words, mechanical stress triggers the release of chemicals which stimulate cellular development through signaling pathways. The scientists found that one of the most important of these chemicals is nitric oxide, which is produced in the body by mechanical stress and which is one of the key biochemical regulators of a number of physiological processes, not the least of which is the regulation of blood vessel elasticity and growth. Nitric oxide is naturally produced by the body throughout life, and this latest discovery that it plays a key role in increasing stem cell production could have implications for people with immune disorders, blood cancers and other diseases that require bone marrow transplantation. Currently, matching donors are available for only approximately a third of all the patients who require bone marrow transplantation.

According to Dr. Leonard Zon of the Division of Hematology/Oncology at Children’s Hospital in Boston and director of their stem cell research program, "Basically we cannot offer optimal therapy to two-thirds of patients." Using zebrafish embryos, Dr. Zon and his colleagues created a mutant strain of embryos in which a heartbeat and circulation were absent, and which were also found to be deficient in hematopoietic stem cells. The scientists then discovered that by increasing nitric oxide in the mutant fish embryos, they were able to restore blood stem cell production, and conversely, by inhibiting nitric oxide they were once again able to demonstrate a reduction in the number of blood stem cells. The researchers then conducted the same experiments in mouse embryos and concluded that these phenomena are common across vetebrate species.

As Dr. Zon explains, "Nitric oxide appears to be a critical signal to start the process of blood stem cell production. This finding connects the change in blood flow with the production of new blood cells."

As all embryologists know, the embryonic human heart begins to beat in a regular rhythmic pattern by the 6th week of embryonic development, at which time the septum primum begins to appear, which will later subdivide into the left and right chambers of the heart. It was never fully understood, however, why this early cardiac development precedes development of the full circulatory system and of the tissue throughout the body which the circulating blood will feed. Now it seems as though this advanced cardiac specialization so early in embryogenesis is necessary for the formation of the blood stem cells which will later produce the various lineages of blood cells throughout the body.

In early mammalian embryos, the blood progenitor cells first develop within the walls of the aorta but later migrate into the bone marrow. In this latest study, when the scientists used a drug to block nitric oxide in pregnant mice, the developing embryos were not easily able to form hematopoietic stem cells. The scientists then discovered that an increase in blood flow not only yields an increase in nitric oxide production, but also an increase in activity of the eukaryotic gene RUNX1, which is a "master regulator" of blood stem cells.

A second, independent team of researchers made corroborating discoveries. According to George Q. Daley, M.D., Ph.D., director of the Pediatric Stem Cell Transplantation Program at Children’s Hospital in Boston, and director of the Laboratory for Systems Biology of the Center for Excellence in Vascular Biology at Brigham and Women’s Hospital, "In learning how the heartbeat stimulates blood formation in embryos, we’ve taken a leap forward in understanding how to direct blood formation from embryonic stem cells in the petri dish." According to Dr. Guillermo Garcia-Cardena, director of the Laboratory for Systems Biology of the Center for Excellence in Vascular Biology at Brigham and Women’s Hospital, who also participated in the study, "These observations reveal an unexpected role for biomechanical forces in embryonic development. Our work highlights a critical link between the formation of the cardiovascular and hematopoietic systems." Also collaborating on the study with Dr. Daley’s group were researchers at the Indiana University School of Medicine.

These findings have applications not only in prenatal development and embryogenesis but also in the maintenance of health and the treatment of disease in mature adults. Such a discovery – that the chemical stimulus from nitric oxide produced by the mechanical stress of blood flow is what triggers hematopoietic stem cell production – would also have implications for athletes, as well as for the benefits that moderate physical exercise can impart to anyone. Shear mechanical stress is now seen to hold a new medical importance, since it is the friction created by fluid flowing through the circulatory system which exerts physical pressure on the surface of the cells lining the vessels, which in turn stimulates the expression of chemical regulators of blood formation, which in turn triggers the production of the hematopoietic stem cells.

Biomechanical forces represent the convergence of physics and biology, and although such forces are not usually studied by physicans, they have often been a topic of interest among physicists and mathematicians, as every calculus student will at some point encounter the 18th century mathematician Daniel Bernoulli who is remembered today for his mathematical modeling of fluid dynamics, and Bernoulli’s equation is often applied to the flow of blood through arteries and veins. Of perhaps greater interest to physicans today than the precise physics and mathematics underlying such principles, however, are the prospects that new "drugs" could be engineered which could either mimic the action of blood flow on precursor cells, or stimulate the nitric oxide signaling pathways for therapeutic benefits in patients with blood and other diseases that might otherwise require transplantation.

Perhaps the natural benefits of physical exercise could also be employed toward such an end, conscientiously and therapeutically, with a greater respect for the complex molecular mechanisms that are responsible for the cardiovascular benefits of exercise. Among other researchers, Dr. Douglas Seals of the University of Colorado at Boulder has already been publishing extensive studies for years on the role of nitric oxide in physical exercise, on which he has repeatedly reported that the increased blood flow which results from physical exercise is what increases shear stress on the surface of the endothelium, which in turn triggers adaptive responses in gene expression and in the phosphorylation of nitric oxide synthase, which is the enzyme responsible for nitric oxide production. Endothelium-derived nitric oxide has thus already been well understood to play a number of important anti-atherosclerotic roles, not the least of which include anti-inflammatory and anti-thrombotic effects as well as vasodilation. It is nitric oxide, or the absence thereof, which is primarily responsible for determining vascular tone. As Dr. Seals was quoted as saying in 2008, "There are multiple lines of evidence that regular aerobic exercise improves the function and health of arteries largely by improving the bioavailability of nitric oxide." Indeed, vasoconstrictor and vasodilator proteins in the vascular endothelium are quantitatively measurable, and for years Dr. Seals has been publishing studies on the correlation of vascular endothelial dysfunction to aging, as nitric oxide and nitric oxide synthase progressively diminish in the absence, over years and decades, of aerobic activity. Now, the missing link has been found, making the connection between nitric oxide and stem cell stimulation.

Exercise and physical fitness have long been recognized as important factors both in the prevention and in the treatment of cardiovascular disease, and now the complex role of stem cells in such phenomena is gradually being understood in more and more detail. A mechanically stimulated chemical phenomenon which regulates the earliest developmental stages of life may now also be harnessed and utilized for the maintenance and restoration of health at all stages throughout the entire human life span.

The results of these studies appeared today in both the journals Cell and Nature.

After suffering a stroke on March 25th, 61-year-old Roland “Bud” Henrich arrived at the hospital too late to be given tPA (tissue plasminogen activator), the only previously existing treatment for ischemic stroke. He therefore became the first person to be enrolled in a clinical trial in which autologous adult stem cells are used for the treatment of stroke.

Nine more patients will be enrolled in the FDA-approved, NIH (National Institutes of Health) funded Phase I clinical trial, all of whom will be treated within 24 to 72 hours after showing initial stroke symptoms.

According to Dr. Sean Savitz, the lead investigator of the clinical trial and an assistant professor of neurology at the UT-Houston Medical School, “It’s still very early in this safety study, but this could be an exciting new therapeutic approach for people who have just suffered a stroke. Animal studies have shown that when you administer stem cells after stroke, the cells enhance the healing. We know that stem cells have some kind of guidance system and migrate to the area of injury. They’re not making new brain cells but they may be enhancing the repair processes and reducing inflammatory damage.”

In the study, autologous (in which the donor and recipient are the same person) mesenchymal stem cells are derived from each patient’s own bone marrow, and then readministered intravenously. Because the stem cells are autologous, there is no risk of immune rejection.

Approximately 800,000 people per year suffer a stroke in the U.S. alone, where stroke ranks as the third leading cause of death, after heart disease and cancer. Approximately one person every 40 seconds suffers a stroke, and approximately one person every 3 minutes dies from a stroke.

As Dr. Savitz explains, “This will be our first attempt to look at the safety of using stem cells in acute stroke patients. There’s a lot of promise behind this but we want to do it in a slow, rigorous fashion. Because we are injecting them intravenously, these cells can disperse to lots of different parts of the body and that’s why we’re looking at safety parameters.”

Already Mr. Heinrich is showing significant improvement. When he first arrived at the hospital, he was unable to speak and had partial paralysis on the right side of his body. After less than two weeks of hospitalization and rehabilitation following the stem cell therapy, not only was he able to walk and climb stairs without assistance, but he also began to speak his first words and phrases again.

According to Dr. James Grotta, chairman of the Department of Neurology at the UT-Houston Medical School, “This study is the critical first step in translating laboratory work with stem cells into benefit for patients. If effective, this treatment could be helpful to a huge segment of stroke patients to reduce their disability. We are fortunate here at UT-Houston and the Texas Medical Center to have the resources needed to carry out this work, and to have attracted someone of Dr. Savitz’s caliber to lead this study.”

The study is open to patients who show symptoms of an immediate stroke and who are either admitted to the Emergency Center at Memorial Hermann-Texas Medical Center or through the UT Stroke Team.

Since 2006, the UT-Houston Medical School has also been conducting a similar study in which autologous adult stem cells are used in the treatment of children with acute brain injuries, at Children’s Memorial Hermann Hospital.

One of the leading clinical and research organizations in the world, the University of Texas Health Science Center at Houston was established in 1972 by the UT System Board of Regents and the Texas State Legislature. The Center brings together the Dental Branch, the Graduate School of Biomedical Sciences, the Medical School, the School of Public Health, the School of Nursing, the School of Health Information Sciences, the UT Harris County Psychiatric Center, and the Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases. As of 2008, the UT Health Sciences Center at Houston had received 220 NIH grants, thereby ranking 60th out of 535 in the NIH funding of domestic institutes of higher education. The Institute of Molecular Medicine is directed by Ferid Murad, M.D., Ph.D., who also created the new departments of integrative biology, pharmacology and physiology at UT and who coshared the 1998 Nobel Prize in Physiology or Medicine for his work with nitroglycerine and signaling molecules in the cardiovascular system.

Achilles tendinopathies can cause severe distress in humans, but in horses such conditions can be fatal. Now, after having treated over 1,500 race horses with an autologous adult stem cell therapy that has demonstrated both safety and efficacy in the horses, researchers will begin testing the procedure on humans.

The privately owned British biotech firm MedCell Bioscience announced today that it would begin clinical trials within 12 months, and plans are also being formulated to conduct a larger study at several participating European hospitals in 2011. As with the horses, the human adult stem cell therapy will consist of autologous (in which the donor and recipient are the same individual) adult stem cells, thereby eliminating any risk of immune rejection.

According to Dr. Nicola Maffulli, an orthopedic surgeon and specialist in sports medicine, “The move from clinical veterinary to human medicine is inspiring and unusual. We normally see the translation happening the other way around. I am very excited to be involved in the human studies and hope that the results will herald a new era in the treatment of musculoskeletal soft tissue injuries. At present the management of human tendinopathy is more an art than a science, but this approach could potentially reverse that situation.”

A number of adult canine and equine stem cell therapies have already been used with great success for conditions that include, among other ailments, compressive spinal cord damage, bone fractures, diabetes, laminitis (an inflammatory hoof condition that is common in horses), arthritis, joint and cartilage injuries as well as diseases of the heart and liver. The use of autologous adult stem cell therapy is becoming increasingly popular in veterinary clinics around the world, and the U.S. biotech company Vet-Stem is frequently in the news for the consistent success that it achieves in the commercialization of this procedure. Likewise, a number of similar companies in other countries are also reporting similar success, such as MedCell Biotech in the U.K., which was originally formed as a spin-off from research conducted by surgeons at the Royal Veterinary College of London.

Some species have a natural capacity for regenerating large quantities of their tissue whenever they suffer damage, the ultimate example of which is the salamander, in which spontaneous regrowth of entire limbs and even of large parts of its heart and brain have been well documented. Similarly, the popular aquarium resident, the zebrafish, has also been found to be capable of regrowing entire pieces of its heart, whenever necessary, due either to unfortunate accident or to the deliberate experimentation of curious humans. In any case, and regardless of the species, such regeneration is possible because of naturally occurring, endogenous, adult stem cells which exist within the organism precisely for this very reason: namely, to wait patiently until activated by injury or illness, at which time the adult stem cells valliantly come to the rescue to repair and replace damaged or missing tissue. However, biological regeneration is generally believed to be inversely proportional to evolutionary complexity, so that, in other words, the more biologically advanced a species is, the less natural regenerative ability that species possesses, and vice versa. Such a theory would explain why, for example, regeneration of entire limbs and organs is spontaneously seen in amphibians and fish but rarely in humans or other mammals.

However, such a theory may be incorrect.

Generally considered (at least by themselves) to be the most highly evolved and advanced species on the planet, human beings are now showing a natural ability for biological regeneration, at least at a cardiovascular level.

In developed countries such as the United States and Canada, cardiovascular disease continues to rank as the number one cause of death, and conventional medical therapies which consist of surgical procedures in combination with pharmaceuticals have not offered a satisfactory treatment for the disease and its numerous complications. Now, adult stem cells offer the first actual therapy which is capable not only of restoring full function to the damaged heart but also of regrowing healthy heart tissue; and such therapies are most successful when they work in combination with the body’s own reservoir of endogenous adult stem cells.

Dr. Christopher Glover, an associate professor of medicine at the University of Ottawa and a cardiologist at the University of Ottawa Heart Institute, has been conducting a clinical trial in which endogenous adult stem cells are activated in patients following a heart attack. The clinical trial consists of 86 heart attack patients to whom a proprietary “drug” was given which activates the migration of each patient’s own endogenous adult stem cells from the bone marrow into the bloodstream, from which the stem cells then automatically “home in” on, and target, the damaged tissue of the heart. As Dr. Glover describes, “There are some repairs that our bodies can [automatically] do. If we amplify the response, perhaps we’d get more repair.” This treatment is meant to amplify the body’s natural response mechanisms, and although the clinical trial is still in progress and has not yet concluded, the patients are already improving “even better than expected”, according to Dr. Glover.

A similar study was conducted last year in an animal model in which an organic, collagen-based gel was injected directly into damaged tissue in laboratory rats and was subsequently found to stimulate angiogenesis, which is the formation of new blood vessels. The use of various agents, including externally derived stem cells, to stimulate naturally occurring endogenous adult stem cells is a popular and widely validated procedure that has been independently corroborated by a number of scientists in a number of studies conducted around the world.

The successful stimulation of the body’s own adult stem cells extends far beyond the cardiovascular realm, however, and has already been applied to a wide range of therapies that require much more than mere angiogenesis. In fact, even in humans, a number of sources have documented the natural ability of the body’s own adult stem cells to repair damaged tissue, even without external stimulation. For example, in human children prior to the age of approximately 10 years, the regrowth of entire fingertips that have been lost in accidents has been reported, as long as the wound is not deliberately sealed with a skin flap, which, unfortunately, is the usual de facto emergency treatment that is administered to such accidents, and which reliably prevents the natural regrowth of the finger by the artificial physical barrier that it creates. Without such physical barriers, however, and with a more enlightened medical approach, regrowth of digits is not uncommon in humanns. A particularly remarkable demonstration of such regeneration involved the case of Lee Spievack who, in his 60s, accidentally sliced off the end of one of his fingers in the propeller of a hobby shop airplane, after which he was treated with a powder that was applied directly to the injured area. Within four weeks, the missing half-inch of his finger completely regrew, including not only the flesh and blood vessels but also the bone and nail. The powder contained a proprietary extracellular matrix compound which stimulated and cooperated with the man’s own endogenous adult stem cells in regrowing his missing finger. Likewise, the U.S. Army has already been applying adult stem cell technology to the regrowth of limbs for wounded soldiers returning from Iraq and Afghanistan. (Please see the related news articles on this website, entitled, “Grow Your Own Replacement Parts” and “Growing Miracles”, dated February 6th and February 7th of 2008, respectively, each originally reported by CBS Evening News).

Regardless of the species, and across all species, the physiological body of each organism has a natural and strong genetic tendency to heal itself; even in humans, our very DNA is programmed to repair the cellular damage that results from the various injuries and illnesses of life. Regardless of the specific type of medical therapy that is used for any particular ailment, the greatest medical successes will result from those therapies that harness, to the fullest possible extent, the body’s own natural healing abilities. In the realm of stem cells and regenerative medicine, we are thus far only barely able to glimpse the tip of the iceberg.

As Dr. Marc Ruel, a cardiac surgeon at the University of Ottawa Heart Institute, puts it, "We know it’s going to work. We are living proof of it. Nature proves this concept every day."

Researchers at the Washington University School of Medicine in St. Louis report some interesting discoveries with the enzyme known as adenosine monophosphate-activated protein kinase (AMPK). Already known to be involved in a number of diseases, AMPK has been well studied by scientists for many years, but these new findings are the first of their kind to demonstrate that the enzyme is essential for the health of neural stem cells.

In a study led by Jeffrey Milbrandt, M.D., Ph.D., the researchers found that when they selectively deactivated the enzyme in mouse embryos, the overall brain size of each mouse shrunk by 50%, with dramatic shrinkage in both the cerebrum and the cerebellum to such an extent that the mice died within 3 weeks of birth. AMPK, it turns out, is a critical component for the survival of neural stem cells which in turn create and maintain the cells of the central nervous system, including the cells that are necessary for learning and memory. When AMPK is deactivated or absent altogether, normal neurological health cannot be maintained at the cellular level.

According to Dr. Milbrandt, “For years, scientists have shown how AMPK regulates multiple metabolic processes, and revealed how that influence can affect cancer, diabetes, and many other diseases. Now, for the first time, we’ve shown that AMPK can cause lasting changes in cell development. That’s very exciting because it opens the possibility of modifying AMPK activity to improve brain function and health.”

AMPK is directly involved in the regulation of cellular energy usage, and the enzyme is specifically activated whenever energy resources are low, such as during times of caloric restriction or sustained physical exercise. When activated, AMPK promotes cellular glucose uptake, mitochondria formation, fatty acid oxidation and other energy-producing cellular processes, while simultaneously inhibiting protein and fatty acid synthesis as well as cell reproduction and other energy-consuming cellular processes.

When activated, there is one particular version of AMPK that is capable of making its way into the nucleus of cells where it inactivates the retinoblastoma protein, “a master regulator” of cell production, which in turn allows neural stem cells to survive and proliferate. That particular version of AMPK, which contains the beta 1 subunit and which is only one of several versions of AMPK, is capable of penetrating both the cytoplasm and the nucleus of cells, whereas other versions, such as that which contains the beta 2 subunit, have only been found in the cytoplasm but never in the cell nucleus. As Dr. Biplab Dasgupta, a lead author of the paper, describes, “Inhibiting AMPK is something that most cells don’t like. It can lead to a variety of consequences, including cell death, but many cell types can tolerate it. In contrast, neural stem cells undergo catastrophic cell death in the absence of AMPK containing the beta 1 subunit. We also suspect loss of this form of AMPK may cause severe problems for other stem cells.”

Because of the role of cancer stem cells in some types of cancer, and the possibility of manipulating AMPK in cancer therapies, ideally the trick would be to inactivate AMPK in the cancer stem cells themselves, while simultaneously activating AMPK in the normal, non-cancerous cells.

Since the protein retinoblastoma, which the AMPK version with the beta 1 subunit regulates in the cell nucleus, plays such an important role in the differentiation of stem cells, these findings also have possible implications for the long-term health effects of malnutrion. According to a study that was conducted in 1977 on the children of women who were starved by the Nazis during World War II, these children remained at a high risk of various diseases throughout their lives, which included diabetes, heart disease and stroke. Even though these children, themselves, had never been subjected to starvation, their mothers may have incurred long-term damage to their stem cells as a result of their experiences, which in turn influenced the cellular health and development of their offspring.

On a lighter note, Dr. Dasgupta adds, “Exercise activates AMPK and improves cognitive function. Our results suggest brain function may improve because additional activated AMPK makes it easier for adult neural stem cells to reproduce and become new brain cells.”

As Dr. Milbrandt concludes, “Manipulating this regulation may enable us to encourage the development of new brain cells. We might use that not only to treat medical conditions where brain development is hampered, but also to improve cognitive function generally.”

The company Osiris Therapeutics, which is focused exclusively on the development of adult stem cell therapies, not embryonic stem cell therapies, today reported the final data from its two-year-long Phase I clinical trial in which one of its adult stem cell products, Prochymal, was evaluated for safety and preliminary efficacy in the treatment of heart attack. The double-blind, placebo-controlled study consisted of 53 participants who had suffered acute myocardial infarction (MI), all of whom were fully immunocompetent patients, and none of whom exhibited any signs of adverse immune response or infusional toxicities from the Prochymal. In fact, Prochymal demonstrated even greater safety than a placebo, since the patients who received the placebo instead of Prochymal exhibited a higher rate of adverse events. For the patients who received Prochymal instead of a placebo, Prochymal resulted in the improvement of a number of parameters including a drop in repeat hospitalizations as well as significant improvement in cardiac function and reduced incidents of cardiac arrhythmia. Not only did the clinical trial met its primary endpoint for demonstrating the safety of Prochymal in an acute MI setting, but in all aspects Prochymal has exhibited an extremely favorable safety profile. Additionally, experts describe the procedure as being so simple that even community hospitals could easily adopt the protocol.

Data from this ground-breaking adult stem cell therapeutic product indicate that Prochymal does indeed expedite patient recovery from heart trauma, which previously has always been extremely difficult to treat with much success. According to the president and CEO of Osiris Therapeutics, Dr. C. Randall Mills, “This study adds convincing long-term data to the excellent safety profile of Prochymal, having now treated hundreds of patients in trials over the past decade. We are excited that Prochymal demonstrated strong evidence of efficacy beyond the best cardiac care available today. We are now advancing this program into a larger Phase II trial, focusing on patients with more severe heart damage.”

Osiris is developing its Prochymal therapy in collaboration with Genzyme, with whom Osiris formed a strategic alliance last year for the development and commercialization of Prochymal, and for which enrollment was recently completed in a Phase III clinical trial for the treatment of steroid-refractory acute graft-versus-host disease. Additionally, in January Osiris received FDA approval to broaden its expanded access program for Prochymal, which is a proprietary preparation of mesenchymal stem cells that are derived from the bone marrow of healthy adult donors and specifically formulated for intravenous infusion.

According to Dr. Timothy Henry, director of research at the Minneapolis Heart Institue Foundation at Abbott Northwestern, “This placebo-controlled study was truly the first of its kind and the data produced are promising. It clearly suggests that allogeneic adult stem cells have significant potential to improve recovery following a heart attack and can prevent long-term adverse effects. Given the fact that we can administer this drug through a standard I.V. in an acute setting, Prochymal could become an integral part of standard-of-care for the treatment of heart attacks everywhere.”

Osiris is focused on the treatment of a variety of inflammatory, orthopedic and cardiovascular diseases. As described on their website, “Prochymal is currently being evaluated in Phase III trials for steroid refractory GvHD, acute GvHD, and Crohn’s disease. Prochymal has been granted Fast Track status by the FDA for all three of these indications. Prochymal also obtained Orphan Drug status by the FDA and the European Medicines Agency for GvHD. Prochymal is being studied in Phase II trials for the treatment of COPD (chronic obstructive pulmonary disease), type 1 diabetes, and acute myocardial infarction. Additionally, the U.S. Depaartment of Defense recently awarded Osiris a contract to develop Prochymal as a treatment for acute radiation syndrome.”

Osiris Therapeutics is the leading stem cell therapeutic company in the world, involved in the research and development of therapeutic products that are based exclusively upon adult stem cells, not embryonic stem cells.