Researchers at Baylor College of Medicine in Houston, Duke University Medical School, and the National Institute of Allergy and Infectious Disease have collaborated in a study which resulted in the discovery of a link between immunology and stem cells. That link is a gene which is known as the interferon-inducible GTPase Lrg-47 gene. The study was led by Dr. Margaret Goodell, Professor of Pediatrics and Director of the Stem Cells and Regeneration Center at Baylor.

When mice who lacked this gene were infected with a bacteria that resembled tuberculosis, the natural stem cells of the mice did not respond by making new blood cells as a defense against the infection, as they normally would in healthy mice who have the missing gene, which has been known for the role that it plays in stress response. These results therefore suggest that the gene might also be involved in the production of normal blood cells, which would be needed whenever infection and disease threaten an organism.

This is the first study to indicate a direct link between immunology and stem cell activation, as mediated by a common gene. The interferon gamma proteins are well known as regulators of the immune system, and the discovery that this gene is also regulated by interferon gamma was somewhat of a surprise to the researchers, who also found that mice who are bred to lack this gene have abnormally low blood counts and easily die of infection. Additionally, the mice also were found to have stem cells which did not function well, especially when subjected to chemical or pathological stress. Even bone marrow transplants that were performed on the mice were unsuccessful.

Additional research will investigate further exactly how this gene controls stem cell activity, as well as the precise role that interferons play in the cell. The genetic, molecular and cellular mechanisms at work in these pathways have many applications to human health and disease.

Scientists at the San Diego-based biotechnology company Novocell have reported that they were able to use human embryonic stem cells to produce insulin in diabetic mice, although the treatment also yielded some additional, undesirable consequences. In particular, as a result of receiving the embryonic stem cells, some of the mice developed a particular type of tumor known as a teratoma, which is the defining characteristic of embryonic stem cells. Unlike adult stem cells, embryonic stem cells are identified by their ability to form teratomas, and this remains the gold standard throughout the world by which embryonic stem cells are recognized. If a stem cell can form a teratoma, then it’s identified as an embryonic stem cell, and if it cannot form a teratoma then it is known to be something other than an embryonic stem cell. The study has therefore drawn criticism from experts who point out that embryonic stem cell “therapies” such as this are not applicable to humans, since adverse side effects such as the formation of tumors would also occur in human patients.

Embryonic stem cells have always been defined by their ability to form this particular type of tumor, a danger which does not exist with adult stem cells. But the formation of tumors is not the only risk inherent in embryonic stem cells, which have proven to be highly problematic in a multitude of ways. In 2006, scientists at Novocell reported that they had transformed human embryonic stem cells into insulin-producing beta cells in the laboratory, in vitro, although these cells were of no therapeutic value since they were unresponsive to glucose. In their most recent study, the Novocell scientists implanted “precursor” cells into the mice, where the cells were then allowed to mature in vivo into insulin-producing cells – a procedure which is unlikely to be approved by the FDA for use in humans, according to Dr. Mark Magnuson, Director of the Center for Stem Cell Biology at Vanderbilt University. Novocell representatives admit that any possible applicability of this potential therapy to humans still remains several years away.

Recent headlines have announced the news that ordinary adult non-stem cells were reprogrammed back into a more primitive state in which they resemble embryonic stem cells through a process known as de-differentiation (the reversal of a cell from a differentiated, specialized state to a non-differentiated, non-specialized state.) However, the specific molecular and cellular events that are involved in this cellular reprogramming have previously remained unknown. Now researchers at the Harvard Stem Cell Institute (HSCI) and the Massachusetts General Hospital (MGH) have been able to identify these events using cellular markers.

Previous work by other researchers involved adult mouse skin cells which were transformed into “induced pluripotent stem” (iPS) cells after being treated with 4 reprogramming factors, one of which was an oncogene (a gene that causes cancer) which was administered by retroviruses that act as “vectors” which deliver the gene into the target cells. Oncogenes and retroviruses are not applicable in human treatment, however, so the question remained as to whether or not the work could be translatable to human therapies.

Dr. Konrad Hochedlinger, one of the leaders of the current study, is assistant professor in Harvard’s new Department of Stem Cell and Regenerative Biology, and a recipient of the NIH Director’s New Innovator Award. He and his colleagues have now identified specific cell surface markers that are switched on and off at specific stages, thereby regulating the reprogramming of the cells. Dr. Doug Melton, who is Co-Director of the HSCI, described the discovery as, “an important first step in finding ways to create pluripotent stem cells from adult cells without the need for viruses or oncogenes.” In the future, it might be possible to use such cellular mechanisms to reprogram most types of adult non-stem cells, not only mature skin cells, into earlier cells which behave as pluripotent stem cells.

A recent paper by Bischoff et al. describes the effect of tissue acidification on mesenchymal stem cells. It is known that injured tissue is more acidic in comparison to healthy tissue, since injury is associated with reduced blood flow which results in hypoxic conditions and the accumulation of carbon dioxide, which lowers pH. In this study the investigators exposed mesenchymal stem cells that were derived from human bone marrow to various levels of acidity (7.4, 7.0, 6.7, and 6.4) from which they assessed the ability of the stem cells to generate interleukin-8 (IL-8), which is a pro-inflammatory chemotactic cytokine. The results correlated the lowest pH (6.4) with the maximum transcription of the IL-8 protein. Although the scientists were primarily interested in bone injury, their findings are applicable to a number of medical conditions including to the treatment of various types of tumors which are known to express a lower pH than non-malignant tissue. Further investigations will involve the administration of mesenchymal stem cells to patients with tumors, the lower acidity of which could possibly stimulate IL-8 which in turn could call in neutrophils that would eradicate the tumor via pro-inflammatory cytokines and other cellular mechanisms.

Medical experts have focused their attention on a civilian man in the U.S. who regrew his finger following an accident at his home. After slicing off the end of his finger in the propeller of a hobby shop airplane, Lee Spievack was treated with a powder which he calls “magic dust” and which was applied directly to the injured area. Within 4 weeks, Spievack, who is in his 60s, regrew the entire missing half-an-inch of his finger, which included not only flesh and blood vessels but also bone and nail. The regrown finger has minimal scarring and is once again whole and complete.

The “magic dust” is a medical powder known as “extracellular matrix”, which is derived from the bladders of pigs and which contains a mixture of protein and connective tissue. Surgeons often use this powder in the repair of simple tendon injuries. Now, however, this extracellular matrix is a key component of the new field known as regenerative medicine.

As Dr. Stephen Badylak at the McGowan Institute for Regenerative Medicine at the University of Pittsburgh explains, this powder “tells the body to start that process of tissue regrowth.” Although the precise cellular mechanisms that are at work have not yet been fully elucidated, the extracellular matrix mobilizes the body’s naturally occurring stem cells, thereby stimulating the body’s natural regenerative abilities. According to Dr. Badylak, “It will change the body from thinking that it’s responding to inflammation and injury to thinking that it needs to regrow normal tissue.” When asked if this extracellular matrix could regenerate entire limbs, Dr. Badylak replies, “In theory, yes.”

A number of researchers are now putting this theory to the test. In conjunction with the University of Pittsburgh and in collaboration with Dr. Badylak, the U.S. Army is already applying such a potential therapy to wounded soldiers who are returning from the war in Iraq. Dr. Steven Wolf, at the Army Institute of Surgical Research in Texas, describes how the U.S. military has already invested millions of dollars in regenerative medicine, not only for amputees but also for burn victims. In related studies that are being conducted simultaneously in Europe, a device currently under development by German researchers is being used for spraying a patient’s own cells onto burn wounds, which signals the skin to regrow itself. In a newly developed upcoming surgical procedure, Dr. Badylak will implant the extracellular matrix material, which has been formed into the shape of an esophagus, into patients who are suffering from throat cancer. As he explains, “We fully expect that this material will cause the body to re-form normal esophageal tissue.” Similarly, this same extracellular matrix material has also been placed directly onto heart muscle, like a bandage, to help repair damaged tissue following a heart attack. Dr. Joon Sup Lee, one of the surgeons and researchers at the University of Pittsburgh Medical Center, has been injecting autologous stem cells directly into the hearts of patients in order to expedite recovery following myocardial infarctions.

According to Wyatt Andrews of CBS News, “researchers imagine a time when regrown limbs replace prosthetics, when regrown tissues replace surgery, and when the body does its healing with cells from within.”

In the U.S. alone, more than 98,000 people are currently on waiting lists for organ transplants. Demand greatly outnumbers supply, however, and many patients will die before ever receiving the needed organ. But now, stem cells offer an alternative solution.

Dr. Anthony Atala and his colleagues at the Wake Forest University in North Carolina believe that “anything inside the body can be grown outside the body.” So far they have already made 18 different types of body tissue from stem cells, which include heart valves and the entire heart of a mouse which was grown from scratch, layer by layer, as well as a new human bladder. Using Dr. Atala’s technique of growing an entirely new bladder, a patient in a clinical trial at the Thomas Jefferson Hospital in Philadelphia successfully received a new bladder transplant that was made from the patient’s own stem cells. It is believed that every tissue of the body contains its own stem cells, and in this particular case the bladder cells were isolated from the patient, expanded and, 8 weeks later, the new bladder was in the operating room and ready for transplantation. As Dr. Patrick Shenot, the transplant surgeon who performed the operation, explained, “It’s very much the future, but it’s today. We are doing this today.”

The research is already translating into big business. The biotech company Tengion, Inc., now exists almost exclusively for the “manufacture” of new bladders from a patient’s own stem cells. According to CBS news, “The Tengion Company has bought the license, built the factory, and is already making the bladders developed at Wake Forest.” According to Tengion’s CEO, Dr. Steven Nichtberger, “We’re actually building a very real business around a very real and compelling patient need. In regenerative medicine, I think it is similar to the semiconductor industry of the 1980s. You don’t know where it’s going to go, but you know it’s big.” Tengion has plans to expand beyond the creation of bladders, and to mass-produce blood vessels and kidneys.

Regenerative medicine is redefining most aspects of conventional medicine, and the field of organ transplantation is no exception. According to Wyatt Andrews of CBS News, “Patients in the future, instead of waiting years for a donated organ, will wait a few weeks and… grow their own.”

Researchers at Mt. Sinai Hospital in New York have identified the mechanisms that regulate the release of stem cells from bone marrow into the blood. It has long been known that bone marrow-derived stem cells regularly circulate throughout the blood, and many bone marrow transplantation procedures involve the harvesting of stem cells from the peripheral blood. Previously, however, the precise mechanisms by which the stem cells were released into the blood remained unknown. Dr. Paul Frenette and colleagues at the Mt. Sinai School of Medicine have now discovered that molecular adrenergic signals originating in the brain are sent via the sympathetic nervous system directly to “niches” within the bone marrow in which the stem cells reside, thereby triggering the release of the stem cells from these niches into the circulating blood.

The sympathetic nervous system is that part of the autonomic nervous system most commonly identified with the “fight or flight” response, but it is also highly sensitive to stress and is therefore easily activated by changes in circadian rhythms. All species exhibit circadian rhythms that are regulated by a biological “master clock” which in humans is anatomically located in the suprachiasmatic nucleus within the hypothalamus. External cues reset the biological clock daily, the most important one of which is light which stimulates highly photosensitive proteins in the photoreceptors of the retina of the eye from which signals are then transmitted across the retinohypothalamic tract to the suprachiasmatic nucleus which reinterprets the signals and retransmits them to the pineal gland where the hormone melatonin is secreted, and which is known to peak at night. From the hypothalamus through sympathetic nervous system pathways throughout the body, all physiological processes are regulated including cellular metabolism, hormone production, brain wave activity, body temperature, reproduction, and patterns of sleeping and eating, all of which are naturally entrained to the 24-hour cycle of the earth’s rotation.

In this particular study, the Mt. Sinai researchers used a mouse model in which the maximum release of stem cells from the bone marrow into the circulating blood was observed to occur during periods of rest, although changes in light and experimentally induced “jet lag” in the mice were found to alter the patterns of stem cell release. These results are the first to indicate a circadian regulatory relationship between the cyclical “biological clock” and naturally produced endogenous stem cells. The discovery holds many implications for the important role of these rhythmic oscillations in regenerative medicine and also in the natural regeneration that continually occurs in healthy individuals on a daily basis. In patients who need stem cell transplantation, for example, the collection of their own stem cells may be optimized by timing the harvesting of the cells to coincide with those peak hours of release. Additionally, the discovery also highlights the importance of maintaining regular sleeping habits, especially in today’s modern society, since the normal release of stem cells from the bone marrow into the circulating blood may be hindered by such factors as jet lag, sleep deprivation and other disruptions in natural circadian rhythms. The results of this study may offer one of the first concrete scientific explanations for the previously suspected correlation between night shift work and cancer, a causality which has been established by a number of previous studies and formally identified by the World Health Organization as well as by the International Agency for Research on Cancer, which in 2007 listed night shift work as “probably carcinogenic to humans.” A disruption in natural sleeping rhythms which in turn disrupt the peak release times of stem cells from bone marrow into the circulating blood could interfere with the body’s natural ability to repair itself daily and could therefore possibly also contribute to the formation of various types of cancer.