One of the mysteries of stem cell biology is how these cells can on the one hand make copies of themselves (called self-renewal), and depending on the needs of the body, become different cells, a process called differentiation. It is known that the process of differentiation is dependent on various chemical signals. For example, if one climbs on a mountain, the lack of oxygen stimulates cells within the kidney to make the hormone erythropoietin which increases the number of bone marrow stem cells that differentiate into red blood cells. While some of the signaling proteins are known, the effector proteins inside the stem cell that dictate its activity are still not very well understood.

In two recent back-to-back publications in the Dec 17 issue of Nature, some progress was reported in the understanding of stem-cell growth and differentiation. It was demonstrated that there exist three critical proteins which first stimulate stem cells to proliferate. Then, as the cells differentiate into their final cell type, these proteins switch function and arrest the cells from dividing any more. Because of their central role, the proteins could offer a safe and novel therapeutic target in many cancers. The proteins that arrest the multiplication of the cell may be considered as "tumor suppressor" proteins.

The published study, which was led by researchers at the Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, demonstrated that three proteins, called E2f1, E2f2 and E2f3, play a fundamental role in the differentiation steps that stem cells undergo as they lose their self-renewal activity. One of the interesting findings of the studies was the importance of the Rb tumor suppressor protein in blocking self-renewal of stem cells that are differentiating.

"We show that these E2fs are gene activators in stem cells but then switch to gene repressors when stem cells begin differentiating," says Gustavo Leone, associate professor of molecular virology, immunology and medical genetics at Ohio State’s James Cancer Hospital and Solove Research Institute. Leone headed the first of the two Nature studies and is a co-author on the second.

"This is a very important step in the process of differentiation," Leone says. "As organs form during development, there comes a time when their growth must stop because an organ needs only a certain number of cells and no more. The switch by these proteins from activators to repressors is essential for that to happen. Before this, there was no suspicion that these regulatory proteins had any role in differentiated cells," says Leone. "It was thought they were important only in proliferating cells like stem cells. But that’s not true."

Another interesting finding was that the E2f1, E2f2 and E2f3 proteins, while being inhibited in differentiated cells, can actually be re-activated in the presence of mutated tumor suppressor genes and lead to unrestricted cell growth. This provides another method of generating cancer cells in vitro for testing.

One of the biggest challenges to the treatment of cancer is overcoming the ability of cancer cells to become resistant to drugs or radiation. The problem of resistance is particularly relevant in brain cancers called gliomas. Research published in the Journal Stem Cells reports one method of overcoming this problem.

Scientists at Duke University and the Cleveland Clinic claim to have identified molecules associated with the ability of certain cells within a glioma, called tumor stem cells, to resist radiation. Specifically, they have identified a protein called "Notch", which is normally involved in embryonic development, that seems to be selectively found in resistant cells. Using genetic engineering methods they have made cells that were previously sensitive to radiation to become resistant by inducing expression of Notch.

Dr. Jialiang Wang of Duke University, who is the lead author of the study. said the finding marked the first report that Notch signaling in tumor tissue is related to the failure of radiation treatments.

"This makes the Notch pathway an attractive drug target," Wang said. "The right drug may be able to stop the real bad guys, the glioma stem cells."
The authors have also demonstrated that by inhibiting activity of the Notch protein, through administration of chemicals known as gamma-secretase inhibitors, can result in making resistant cells sensitive to radiation.

These findings are interesting in light of another very recent publication (Zhen et al. Arsenic trioxide-mediated Notch pathway inhibition depletes the cancer stem-like cell population in gliomas. Cancer Lett. 2009 Dec 3) in which the anti-leukemic drug Arsenic Trioxide was also demonstrated to alter glioma stem cells through manipulation of the Notch pathway. Notch has been found in numerous other types of tumor stem cells such as breast, colon, lung, and prostate cancer. The expression of a protein in cancer cells that is supposed to be only expressed during embryonic development supports the theory that during formation of cancer, mature cells tend to revert to an embryonic-like phenotype. This is also exemplified by the fact that adding cancer genes (oncogenes) in combination with some specific proteins can take an adult skin cell and transform it into a cell that resembles the embryonic stem cell, called an "iPS" cell. This is described in the following video:

Sickle cell anemia is a genetic disorder that affects approximately 80,000 Americans, primarily of African-American origin. It is characterized by defective production of red blood cells which makes them extremely fragile and not capable of fully transporting oxygen.

In the December 10th issue of the New England Journal of Medicine a report describing a clinical trial performed at the Clinical Center of the National Institutes of Health in Bethesda, was published that described successful treatment of 9 out of 10 adults suffering from this condition.

"This trial represents a major milestone in developing a therapy aimed at curing sickle cell disease," said NIDDK Director Griffin P. Rodgers M.D. "Our modified transplant regimen changes the equation for treating adult patients with severe disease in a safer, more effective way."

The use of stem cell transplantation for genetic conditions is now becoming increasingly commonplace. For example, cord blood stem cells have been used to treat conditions such as Krabbe Disease, which is a lethal metabolic abnormality. The reason that the current study is so important was that it used a type of "conditioning regimen" that was substantially less toxic than previously performed.

In an older study about 200 children with severe sickle cell disease were cured with bone marrow transplants after receiving high doses of chemotherapy. That protocol was too toxic for adults, whose organs are damaged from the prolonged exposure to abnormal red blood cells and their breakdown products. The current treatment method is applicable to adults.

Stem cell transplantation for conditions like leukemias require the recipient bone marrow to be destroyed prior to administration of the new stem cells. In conditions such as sickle cell, one does not need to completely destroy the recipient bone marrow but merely to replace it with enough healthy stem cells so as to produce sufficient quantities of healthy red blood cells. Although this has theoretically been discussed in sickle cell anemia, to date, the current study is the first one to actually demonstrate this. It is anticipated that future studies of this sort will be conducted to attempt treatment of other metabolic abnormalities.

The cornea is front part of the eye that is transparent and allows light to enter. The cornea is does not have a blood supply and receives its nutrients from diffusion and oxygen directly from the air. Corneal scarring is a major cause of vision loss and blindness. Today researchers at the University of Cincinnati reported a new method of reducing corneal scarring using stem cells in mice.

Mice that suffer from corneal scarring are used for assessment of possible new treatments for this condition. The researchers conducting the study, lead by Winston Whei-Yang Kao, PhD, professor of ophthalmology, at the University of Cincinnati, used a mouse that was genetically engineered to lack a protein called lumican, which is involved in maintaining a clear cornea.

At the 49th Annual Meeting of the American Society of Cell Biology in San Diego today, the researchers presented data indicating that treatment of the lumican deficient mice with stem cells derived from human umbilical cords leads to preservation of vision. The specific type of stem cells used were called mesenchymal stem cells. These cells have been previously demonstrated to be capable of becoming a variety of other tissues when exposed to specific chemicals.

Although corneal transplantation is a relatively established procedure that has saved the vision of many, researchers believe that the use of umbilical cord blood stem cells in this area still has significant potential. "Corneal transplantation is currently the only true cure for restoration of eyesight that may have been lost due to corneal scarring caused by infection, mechanical and chemical wounds and congenital defects of genetic mutations," Kao says. "However, the number of donated corneas suitable for transplantation is decreasing as the number of individuals receiving refractive surgeries, like LASIK, increases."

Dr. Kao also commented on the potential treatment applications possible with the umbilical cord stem cells. "Our results suggest a potential treatment regimen for congenital and/or acquired corneal diseases," he says, adding that the availability of human umbilical stem cells is almost unlimited. These stem cells are easy to isolate and can be recovered quickly from storage when treating patients. "These findings have the potential to create new and better treatments — and an improved quality of life — for patients with vision loss due to corneal injury."

Mesenchymal stem cells have already been demonstrated safe in clinical trials, however, to date efficacy studies are still underway for a variety of conditions. The data presented today suggests how many new possible uses of stem cells exist, and the almost limitless possibilities in the area of regenerative medicine.