In its second pre-clinical trial for the treatment of ischemic stroke, Pluristem Therapeutics Inc. has reported statistically significant results in both functional and anatomical improvement in an animal model after the use of one of its products which has been developed specifically for the treatment of stroke. Specializing in the commercialization of therapeutic products developed exclusively from adult mesenchymal stromal cells (MSCs) that are derived from the human placenta, Pluristem has developed a number of PLX (PLacental eXpanded) products, one of which, PLX-Stroke, is directly targeted for the treatment of ischemic stroke.

Using the widely accepted standard animal model for ischemic stroke, namely, hypertensive rats that had undergone middle cerebral arterial occlusion, the scientists systemically injected PLX-Stroke into some of the rats while other rats served as controls. In the rats that had received the PLX-Stroke, subsequent improvement was then observed both in functional paramaters such as the neurological severity scores and beam walking capability, as well as in anatomical parameters such as in the reduction of infarct size. The improvements were statistically significant when compared to the corresponding parameters in the control rats.

This pre-clinical study was conducted at the Fraunhofer Institute for Cell Therapy and Immunology in Leipzig, Germany, a branch of the Fraunhofer Society. According to Professor Frank Emmrich, who led the study, “PLX cells possibly show the potential to become a new treatment for the functional recovery from a stroke. The data show that a double injection of PLX cells at two different time points significantly improves the functional recovery and reduces the size of the lesion compared to the controls.” According to the President and CEO of Pluristem, Dr. Zami Aberman, “We are very excited about the results and believe that utilizing our PLX product may successfully treat millions of ischemic stroke patients and lead to a multi-billion dollar market. This independent study, together with the previously announced favorable pre-clinical results of PLX cells to treat limb ischemia and blood cancer, give us a robust pipeline for developing new therapeutic products.”

Approximately 90% of all strokes are ischemic, with the remaining 10% being hemorrhagic. Ischemic strokes are the result of an arterial occlusion in the brain, and it is estimated that approximately 2 million people per year throughout the world suffer ischemic strokes, many of whom either die or are rendered permanently disabled from the stroke. Now, adult stem cell studies such as these conducted by Pluristem offer a realistic and viable therapy which actually regenerates damaged neurological tissue.

Mesenchymal stem cells (MSCs) are recognized as one of the most important types of stem cells, with one of the longest and most clinically advanced histories. Although bone marrow is the usual source from which MSCs are derived, they are also known to exist in many other types of tissue such as umbilical cord and placental blood, menstrual blood, peripheral blood, muscle and teeth.

Now researchers in India have discovered MSCs in the limbus of the human eye. After examining the epithelial cells of limbal tissue from patient biopsy samples collected during eye surgery, the scientists identified cells with a spindle-like morphology. The cells were then characterized for a number of parameters including morphology and immunophenotyping, and upon expansion in the laboratory the cells were found to possess a phenotype similar to that of MSCs that are derived from bone marrow. Most significantly, the cells were found to be capable ot differentiating into adipocytes (fat tissue) and osteocytes (bone and cartilage tissue).

Why would stem cells which are capable of differentiating into cartilage and bone exist in the eye? The answer to questions such as this may shed light not only upon the role that these cells play in limbal stem cell transplants but also on the role of MSCs in wound healing and regeneration in general. Especially in ocular injuries and surgeries, the identification of various subsets of stem cells in the human limbus that are similar to bone marrow-derived MSCs is particularly relevant. Already by 1999, a publication in the New England Journal of Medicine (Tsubota et al.) had reported 70 corneal epithelial stem cell transplants in which a statistically significant improvement in vision had been observed.

The presence of MSCs in the eye represents what the discoverers refer to as cells that are “unique to the adult stem cell niche.” Scientists are now investigating further the precise properties of these unique cells, for additional clues into the nature of molecular and cellular regenerative mechanisms.

At the 2008 annual meeting of the Society for Gynecologic Investigation (SGI), held this month in San Diego, California, researchers from the Yale School of Medicine reported improvement in mice with Parkinson’s disease who were treated with uterine stem cells. A debilitating neurodegenerative disorder, Parkinson’s disease is characterized by insufficient dopamine action in the motor cortex and basal ganglia regions of the brain. In this study, stem cells that were derived from human endometrial stromal cells were successfully cultured to differentiate into neurons, complete with the characteristic axon-like projections and pyramidal cell bodies. When the differentiated cells were then transferred into the brains of the mice with Parkinson’s disease, the researchers observed not only the growth of new brain cells, but also an increase in dopamine levels in the brains of the mice.

According to Hugh Taylor, M.D., professor in the Department of Obstetrics, Gynecology and Reproductive Sciences, and chief of Reproductive Endocrinology and Infertility at the Yale School of Medicine, “Now we have found that we can turn uterine stem cells into neurons that can boost dopamine levels and partially correct the problem of Parkinson’s disease. The implications of our findings are that women have a ready supply of stem cells that are easily obtained, are differentiable into other cell types, and have great potential for other purposes.”

The scientists were awarded the SGI President’s Presenter Award for their publication.

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.