Dr. Hanna Mikkola and colleagues at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at the University of California at Los Angeles have announced results of the first study ever to definitively demonstrate that blood stem cells originate in the placenta.

In previous studies, researchers working with embryonic stem cells (ESCs) have tried to keep the ESCs in a perpetually self-renewing state after transplantation, but have been unable to prevent the ESCs from differentiating prematurely when transplanted into animal models. Although some success has been achieved through the use of retroviruses to manipulate the cells genetically, such procedures are generally not considered to be safe for use in humans. For this and many other reasons, ESCs have never actually been used in the treatment of human disease in human patients. Now, yet another highly preferable alternative to ESCs may be available as a human therapy.

Using a new type of mouse model, the researchers were able to identify the placenta as the origin of hematopoietic stem cells which exhibit the capacity to differentiate into all the major lineages of blood cells. The placenta can be broadly divided into two different "microenvironments", one of which comprises the large arteries in which the stem cells are manufactured, and from which the stem cells then migrate into the second environment, which is the "labyrinth" that is comprised of the "niches" in which the stem cells are "nurtured" and allowed to expand in number. These niches within the placental labyrinth are a topic of intense focus and study as researchers attempt to understand the molecular signals and cues that regulate the self-renewal of the blood stem cells without triggering differentiation. The labyrinth is also a source of many growth factors and cytokines which contribute to the action of the signaling molecules.

Building upon the work of previous scientists who were able to produce induced pluripotent stem (iPS) cells from adult skin cells, Dr. Mikkola and colleagues hope to be able to replicate the molecular signaling of the placental microenvironment in the laboratory in order to produce and regulate blood stem cells from iPS cells within this type of environment. If blood cells, differentiated from blood stem cells, could be generated from iPS cells that were taken from a person’s own skin cells, the risk of graft-versus-host disease, which is a common problem with transplantation, could be eliminated, as would the need for using embryonic stem cells.

Thalassemia Major is an inherited blood disorder which is characterized at an early age by symptoms of severe anemia. Previously there has been no known cure for the disease, and until now the only known treatment has been constant blood transfusions every 4 to 6 weeks throughout life, one common complication from which is often secondary hemochromatosis, also known as iron overload, which often leads to organ failure and death. Left untreated, this particular form of Thalassemia will cause bone deformities and death within the first decade of life.

Because of this disease, the white blood cell count of this particular 4-year-old boy had dropped to zero. He was admitted to a cancer research institute in his home country of India where he was then treated with his younger sister’s cord blood, which had been banked at the Cryo Stem Cell Institute in Bangalore. The boy’s white blood cell count is now rising and he is expected to be released in 6 weeks. This is the first stem cell transplant of its type in eastern India and it offers new hope not only in the treatment of this disease but also in the treatment of other previously incurable conditions.

New research presented at the annual meeting of the Orthopedic Research Society in San Francisco provides a more detailed elucidation of the molecular and cellular pathways by which cigarette smoke inhibits stem cell activity.

Bone healing is a two-step process which begins when stem cells differentiate into cartilage and ends when the cartilage has matured into bone. Cigarette smoking has been known to delay skeletal healing after fractures and other injuries by as much as 60%, thereby increasing the risk of further re-injury and chronic disability or pain. In 2005, researchers at the University of Rochester Medical Center in New York identified nicotine as a chemical which interferes with bone growth by altering gene expression. Now the same researchers have identified another chemical in cigarette smoke which also inhibits bone healing, namely, hydrocarbon benzo[a]pyrene (BaP). This polyaromatic hydrocarbon has now been found to prevent the stem cells from reaching the first step in the process, so that they are unable even to begin differentiating into cartilage. Through PCR – polymerase chain reaction, a technique which measures the level of gene expression – the scientists were able to use a mouse model in which they measured genetic changes that were caused by exposure to BaP. Gene expression is the process by which proteins are manufactured through the execution of instructions that are encoded within the genes. Many factors may influence gene expression, one of which is a transcription factor known as the "sex determining region Y-box 9" (SOX-9), which is required for the differentiation of cartilage from stem cells. In this study, the scientists were able to demonstrate by PCR that BaP interferes with SOX-9 expression in mesenchymal stem cells by blocking the conversion of the cells into cartilage and also by reducing levels of type II collagen gene expression. Previous studies have demonstrated that stem cells which are involved in cartilage formation contain proteins known as aryl hydrocarbon receptors (AhR) and that are known to react with BaP. When BaP binds with these receptors, SOX-9 activity is suppressed which results in a reduction both in the number of stem cells that differentiate into cartilage and in the amount of collagen that is produced. The receptors are believed to be involved in the cellular signaling pathways that are responsible for the metabolism of toxins. Staining experiments have also demonstrated that BaP inhibits the deposition of collagen nodules which are indicative of differentiated cartilage cells in vitro.

According to Michael Zuscik, Ph.D., associate professor in the Department of Orthopedics and Rehabilitation at the University of Rochester Medical Center, "Smoking reduces the rate at which the two sides of a fracture come together. We believe this new research will establish for the first time the mechanisms by which polyaromatic hydrocarbons interfere with the healing process."

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.