For release: Wednesday, August 30, 2006
For the first time, researchers have found that a protein signal important in embryonic development promotes survival and proliferation of stem cells. Stimulating receptors for this protein, called Notch, led to functional recovery in rats with brain damage from stroke. The results suggest potential new ways of treating stroke and neurodegenerative diseases.
The study was conducted by Ronald D.G. McKay, Ph.D., Andreas Androutsellis-Theotokis, Ph.D., and colleagues at the National Institute of Neurological Disorders and Stroke (NINDS) in Bethesda, Maryland, and published in the August 17, 2006, issue of Nature.*
"This is a new role for the Notch receptor," Dr. McKay says. Previous studies have shown that Notch is important for proper development of embryos, and that it regulates chemical chain reactions, or pathways, that are central to cancer and diabetes. However, this is the first study to show that Notch controls stem cell division and survival and that it can prompt functional recovery after brain injury in an animal model.
Dr. McKay and his colleagues tested chemicals that increase Notch activity in cultured neural stem cells (NSCs). NSCs can form all of the cells that make up the nervous system, but they do not normally develop into other kinds of tissue. The researchers found that one of these chemicals, Dll4, rapidly reduced cell death. They also found that Notch is part of the pathway by which insulin controls cell survival, and they identified several other genes that control cells' responses to Notch. Pumping Dll4 into the brains of normal rats for 7 days increased the number of dividing cells. Many of the newly generated cells showed a marker that is common on immature neurons. These cells survived for at least 45 days in an immature state. These findings suggest that Notch may be important for maintaining populations of stem cells in the brain and other parts of the body.
The researchers also tested Dll4 in cultures of human embryonic stem cells and pancreatic stem cells and found that it improved survival and proliferation of those cells. The results suggested that Notch may be an important control signal for many different kinds of stem cells.
Next, the researchers used a pump to deliver Dll4 and a growth factor called fibroblast growth factor 2 (FGF2) into the brains of rats that had experienced a stroke. The combination of Dll4 and FGF2 increased the number of dividing cells in the brain. Furthermore, rats given this treatment showed a significant improvement in their motor scores (ability to move) during a 45-day test period. In contrast, rats given either Dll4 or FGF2 alone showed no change in their motor scores.
“This study shows that stem cell regeneration is intimately related to mechanisms controlling cancer and diabetes,” says Dr. McKay. The finding suggests that knowledge gained from studying these diseases may lead to improved methods of cultivating stem cells. This is particularly important for embryonic stem cells, which are currently very difficult to grow in culture.
"People often ask, 'If we've got stem cells in our bodies, why don't we recover?'" says Dr. McKay. "If you have a significant injury in the cerebral cortex, you have no time to repair it under natural conditions. The system seems to be designed to immediately limit the injury." These protective responses often override the body's ability to repair itself. The new study shows that raising the activity of Notch can significantly increase the proliferation of cells after an injury and might improve the chances of recovery.
While the study found significant functional recovery in animals treated with Dll4, very few of the newly generated cells appeared to be mature neurons or astrocytes. Therefore it is unclear exactly how the treatment helped the rats recover. The researchers are now planning experiments to define how Notch activation leads to recovery. They also need to learn how to get the cells to the damaged part of the brain and how Notch affects the vascular and immune systems, which are important for normal brain function.
The NINDS is a component of the National Institutes of Health (NIH) in Bethesda, Maryland, and is the nation’s primary supporter of biomedical research on the brain and nervous system. The NIH is comprised of 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary Federal agency for conducting and supporting basic, clinical, and translational medical research, and investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.
*Androutsellis-Theotokis A, Leker RR, Soldner F, Hoeppner DJ, Ravin R, Poser SW, Rueger MA, Bae S-K, Kittappa R, McKay RDG. "Notch signaling regulates stem cell numbers in vitro and in vivo." Nature, August 17, 2006, Vol. 442, pp. 823-826.
-By Natalie Frazin
Last Modified January 31, 2007