Embryonic stem cells are known to carry a number of risks, not the least of which is genetic mutation which may later cause a variety of diseases in any recipient of the embryonic stem cells. Meanwhile, the human genome, which contains the total DNA content of all 46 chromosomes, reveals a wealth of genetic information. Now, researchers at UCLA are examining the specific contents of this information in order to identify certain embryonic stem cell lines that should not be developed therapeutically because of an increased genetic risk of disease.

The researchers used a high-resolution technique known as “array CGH” (comparative genomic hybridization) which allows analysis of certain genetic properties that are below the limit of detectability by standard karyotyping procedures, such as those commonly used to screen for prenatal abnormalities in amniocentesis evaluations. With a resolution that is 100 times sharper than previous techniques, array CGH can detect properties such as duplications or deletions of genes, alterations in single DNA pairs, and chromosomal translocations that are known to increase the risk of certain diseases including some types of cancer.

After examining a pair of human embryonic stem cell (hESC) lines, the UCLA researchers found genetic abnormalities in more than 7 distinct chromosomal locations. In particular, the scientists examined the “copy number variants” (CNVs), which represent differences in the numbers of specific genes, in these 2 hESC lines.

According to Dr. Michael Teitell, of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, and associate professor of pathology and laboratory medicine and a researcher at UCLA’s Jonsson Comprehensive Cancer Center, “Basically, this study shows that the genetic makeup of individual human embryonic stem cell lines is unique in the numbers of copies of certain genes that may control traits and things like disease susceptibility. So in choosing stem cell lines to use for therapeutic applications, you want to know about these differences so you don’t pick a line likely to cause problems for a patient receiving those cells. In studying embryonic stem cell lines in the future, if we find differences in regions of the genome that we know are associated with certain undesirable traits or diseases, we would choose against using such stem cells, provided safer alternative lines are available.”

Many studies throughout the world are currently underway in order to identify the specific genetic “signatures” of various diseases, which, once identified, would then be used to screen for such diseases in existing stem cell lines, before such stem cells would be developed for therapeutic purposes.

Typically, embryonic stem cells have proven to be highly problematic, with genetic mutation being one of the most common problems to plague embryonic stem cells. For this reason, embryonic stem cells have never advanced beyond the laboratory stage, unlike adult stem cells, which are characteristically free of such problems and which are already in clinical use. While the genetic screening of diseases in embryonic stem cells represents an important step in limiting the therapeutic use of such potentially dangerous stem cells, many scientists question whether or not it would be possible at all for embryonic stem cells to pass a thorough and rigorous safety evaluation.

British scientists at the Imperial College in London have reported that respiratory diseases such as asthma and pulmonary fibrosis automatically trigger the release of the body’s own endogenous stem cells from the bone marrow, which is already recognized as an important site of stem cell activity. Not only are blood cells formed in the bone marrow through hematopoiesis, but mature granulocytes and stem cells such as hematopoietic stem cells, mesenchymal stem cells and fibroblasts are known to reside in the bone marrow.

Now the researchers have found that chemical mediators which are released by lung diseases into the blood stream can trigger the mobilization of these various cells from the bone marrow into the blood from which they are then recruited to the lungs, often with competing objectives, such as inflammation which is caused by the granulocytes, and tissue repair or remodelling which is promoted by the stem cells. Both processes, however, play a role in healing and recovery.

As the researchers explain, “Understanding the factors and molecular mechanisms that regulate the mobilization of granulocytes and stem cells from the bone marrow may lead to the identification of novel therapeutic targets for the treatment of a wide range of respiratory disorders.” Even before such mechanisms are fully understood, the administration of externally derived stem cells could also augment the body’s natural implementation of its own endogenous stem cells in the treatment of respiratory diseases.

Dr. Porfirio Hernandez, the Deputy Director of Researchers at the Hematology and Immunology Institute in Cuba, and the main author of a publication entitled, “Autotransplant of Adult Stem Cells in Lower Limb with Critical Ischemia”, has now been awarded with the Dionisio Daza y Chacon prize, granted by the Spanish Magazine of Surgical Research for the best Spanish medical publication of 2007.

After years of conducting laboratory research with animals, Dr. Hernandez and his colleagues began their first adult stem cell clinical trials in 2002, at which time they began using autolgous (in which the donor and the recipient are the same person) stem cell therapy to treat patients who were suffering with peripheral artery disease in their lower limbs.

Similar to the ischemic cardiopathy that is caused by atherosclerosis, and to the cerebrovascular disease that increases the risk of stroke, critical limb ischemia affects the arteries of the lower limbs. Previously, the only form of treatment for the most advanced cases is amputation. Now, however, physicians around the world such as Dr. Hernandez are demonstrating that adult stem cells regenerate ischemic arteries by stimulating angiogenesis in the areas of damaged tissue, thereby restoring proper circulation to the limbs.

Such stem cell techniques are now also being extended to other applications, especially to those maladies that can benefit the most from increased vascularization, such as problems in opthalmology.

Affiliated with Harvard Medical School, the Joslin Diabetes Center is the world’s largest research center and clinic devoted exclusively to the study and treatment of diabetes. Similarly, the Harvard Stem Cell Institute is one of the leading organizations in the world dedicated to scientific collaboration in stem cell biology. Now, researchers from both organizations have discovered that insulin plays a much greater and more important role, in many other physiological processes, than previously realized.

Primarily, insulin is well known for its importance in carbohydrate metabolism, and an insufficiency of insulin in diabetes has been understood for decades to cause a number of life-threatening problems. Additionally, since the 1990s it has been known that insulin inhibits a specific gene regulator protein known as FOXO, which is active not only in diabetes metabolism but also in tumor suppression, in the maintenance of stem cells, and in the control of a variety of genes that are involved in stress resistance.

Now, as the result of experiments conducted on the digestive system of C. elegans, a microscopic worm that is widely used as a research model in laboratories throughout the world, Harvard researchers have discovered that insulin inhibits a master gene regulator protein known as SKN-1, increased activity of which is known to increase lifespan. Additionally, SKN-1 is recognized as controling what is known as the Phase 2 detoxification pathway, which is a network of genes that collaborate to defend cells against oxidative damage such as that caused by free radicals and environmental toxins. As a result of these studies, a reduction in insulin signaling was found to trigger increased activity of both the FOXO and the SKN-1 proteins, thereby increasing resistance to stress and increasing longevity of life.

According to Dr. T. Keith Blackwell, a senior investigator at the Joslin Diabetes Center, associate professor of pathology at Harvard Medical School, a faculty member at the Harvard Stem Cell Institute, and the primary author of the paper, “We’ve found something new that insulin does and it has to be considered when we think about how insulin is affecting our cells and bodies. This has implications for basic biology since under some circumstances insulin may reduce defense against the damaging effects of oxidative stress more than we realize. The major implication is that we have found something new that affects lifespan and aging, and an important new effect that insulin and/or a related hormone called insulin-like growth factor-1 may have in some tissues. The implications go far beyond diabetes.”

Indeed, the work relates not only to diabetes but also to other diseases which are often secondary complications that result from diabetes, such as vascular and renal problems. Additionally, the findings also have much broader implications for health, stress, lifespan and longevity. According to Dr. Blackwell, “You can manipulate the expression of SKN-1 and the worms live longer.” Currently, Dr. Blackwell’s lab is focused on further delineation of the precise molecular mechanisms that regulate free radical resistance and aging.

Certain types of adult stem cells have already been shown to differentiate into the insulin-producing beta islet cells of the pancreas. Combined with Dr. Blackwell’s recent discovery, stem cells once again enter the realm not merely of disease treatment but also of longevity and extended lifespan.

Parkinson’s disease is a neurodegenerative disorder of the central nervous system that strikes people at the rate of approximately 1.6 per 100 persons over 65 years of age. It is estimated that over half a million people in the United States and over 4 million people worldwide suffer from Parkinson’s disease, and the global figure is expected to rise to nearly 9 million by the year 2030, according to estimates by the Parkinson’s Foundation and by the World Health Organization. Although this debilitating disease is currently considered to be irreversible and a fully effective conventional medical treatment does not exist, researchers in France have now demonstrated the power of adult stem cells to halt and reverse the progression of this disease.

Mesenchymal stem cells derived from the bone marrow of adult rats were used to treat these rats for symptoms of Parkinson’s diease. Significant improvements were measured at various intervals, with a 50% decrease in symptoms being measured as early as one week after treatment with the bone marrow-derived stem cells. Not only were behavioral symptoms restored to normal in the rats, but new neurological dopaminergic (dopamine producing) tissue was actually regenerated which dramatically corrected the characteristic absence of dopamine that typifies the brains of individuals afflicted with Parkinson’s disease.

According to the researchers of this study, treatment with adult mesenchymal stem cells “reduces behavioral effects” and “partially restores the dopaminergic markers and vesicular striatal pool of dopamine” in the rats, therefore leading the authors of the study to conclude that, “This cellular approach might be a restorative therapy in Parkinson’s disease.”

At the annual meeting of orthopedic surgeons held in San Francisco during the week of March 3rd, doctors examined the possibility of growing new bone and possibly entire limbs from stem cells.

Currently more than 31,000 U.S. military men and women have been wounded in Iraq, 60 to 70% of whom have sustained musculoskeletal injuries. Traditionally, for blast injuries that destroy bone, military surgeons have usually applied nonorganic materials such as metal to rebuild the bone. Now, however, stem cell therapy offers a new and more effective treatment.

Such stem cell therapy would consist of the administration of stem cells either from external (allogeneic) sources, or fom naturally endogenous (autologous) stem cell sources which have been mobilized to harness the body’s innate abilities for regeneration. Dr. John Huard, Director of the Growth and Development Laboratory at the Children’s Hospital of Pittsburgh, cites animal studies in which scientists were able to regenerate bone that was identical in every way to the lost bone that it
had replaced. Dr. Scott Boden of the Emory Spine Center in Atlanta, Georgia, has been studying the possibility of growing new spinal bone and tissue in humans. Stem cells are known to naturally target those regions of the body that are in need of repair, and Dr. Boden and his colleagues have developed further ways to mobilize and control the action of stem cells within the body by attracting the stem cells with specific protein signals to specific areas that are in need of regeneration.

Dr. Scott Rodeo, co-chief of sports medicine and shoulder service at the Hospital for Special Surgery in New York, and the team physician to the Super Bowl winning team, the New York Giants, sees stem cell therapy as a preferable alternative to current surgical techniques. A major clinical problem for orthopedic surgeons is the high failure rate of “tendon-to-bone” healing in many surgical procedures, which is especially problematic in torn rotator cuffs, the surgery for which often leaves the patients in constant pain and even weaker than they were before the surgery. Infection is also a common problem associated with surgery, especially on the battlefield but also among the civilian population. In 2005 alone, approximately 18,650 people in the U.S. died of staph infections that were acquired while in a hospital. Such infections can be life-threatening because they are often highly resistant to antibiotics. According to Dr. Richard Evans, Chief of Reconstructive Surgery at the University of Arkansas, “It’s an ongoing problem that’s actually getting worse. We have new organisms that are smarter than we are.” By replacing surgery altogether with stem cell therapy, doctors would be able to eliminate such risks as infections that are secondary to surgical procedures, and other related iatrogenic illnesses.

Navy Captain Dana Covey, chairman of orthopedic surgery at the Naval Medical Center in San Diego, has been deployed to Iraq twice. He and many other doctors agree that the injuries which are occurring in Iraq present a major opportunity for medical science. According to Army Major Eric Bluman, Chief of Foot and Ankle Service at the Madigan Army Medical Center at Ft. Lewis, Washington, “There’s a huge wealth of knowledge. Normally we see blunt trauma from car accidents or bike accidents. Iraq was almost like a second fellowship for me.”

Some species, such as the salamander, are well known for their ability to regenerate entire limbs from their own, naturally occurring, endogenous stem cells. Even in many mammals, the natural, spontaneous regeneration of some tissue, on a smaller scale, is known to occur. Although further development of this science is needed before it becomes a routine therapy for humans, the regenerative power of stem cells nevertheless remains an area of intense focus and study by numerous researchers around the world.

It has long been known that stem cells are found in dental pulp, not only in humans but also in other species. Now stem cells from the teeth of dogs have shown remarkable regenerative capacity.

Professor Minoru Ueda and colleagues at the Nagoya University in Japan have performed a new procedure with two sets of dogs, each set consisting of a 2-year-old adult dog and one of its 2-week-old puppies. From the dental pulp of the primary teeth of each of the puppies, stem cells were collected and differentiated into bone cells. After being mixed with plasma from the blood of the parent dogs, the new cells were then injected into holes that had been made in the jawbones of the adult dogs. One month later, in both sets of dogs, newly grown bone was found to have filled the holes, each one of which was approximately 6-tenths of an inch deep and wide.

Bone is one of the most specialized tissues of the body, in any species, and these findings not only offer an effective new therapy for the veterinary treatment of orthopedic injuries in dogs, but canine studies such as these are also translatable to potential new therapies in the treatment of orthopedic injuries in humans.