Cell Transplants Offer Hope Of Brain Repair Following Stroke

The stem cells grew in the damaged area and formed connections with neighboring cells, indicating the possibility of someday manipulating brains and spinal cords into repairing trauma from stroke or other diseases, says senior author Daniel M. Rosenbaum, M.D., professor of neurology, neuroscience and ophthalmology at Albert Einstein College of Medicine and director of the stroke center at Montefiore Medical Center, New York.

"We were not sure the transplanted cells would even survive," he says. "But they did in both normal and stroke-damaged brains. In just seven days some cells had begun differentiating into the basic, yet immature types of cells that form the fundamental structure of the brain."

Blood vessels were also seen growing to nourish the transplanted cells. At 21 to 45 days after the transplants most stem cells had developed into mature neurons and other mature brain cells.

"The ultimate goal is to take an adult's own cells, expand them in tissue culture in the laboratory and transplant them back into the individual's brain in a way that would lead to functional recovery," says Rosenbaum.

Stem cells – which are found primarily in bone marrow in adults or in embryonic tissue – lay down the blueprint for development of all the body's organs including the brain. They have the potential and the flexibility to grow and differentiate into the many kinds of cells needed by the human body. Until about 10 years ago, many people believed that the ability to regenerate neurons, or nerve cells, of the brain and spinal cord disappeared soon after birth. However, Rosenbaum's research team has shown that such repair processes can occur in mature brain cells at a very slow rate. In the current study researchers sought to determine whether stem cells would grow and mature into functioning neurons when transplanted into damaged rat brains.

Researchers harvested embryonic cortical cells (which come from the cerebral cortex – the outer layer of the brain) for the transplants. The cerebral cortex is the mantle of gray substance covering each half of the brain. It's the area responsible for higher mental functions such as thought, reasoning, memory and voluntary movement and is also the area most often damaged by strokes.

"Our goal was to replace the dead area of the cortex with neural stem cells that would mature into neurons and other brain cell types," says Gaurav Gupta, M.D., the lead author of the study.

In their experiments, the researchers injected the cortical stem cells into the brains of normal adult rats and adult rats damaged by stroke. The cells were marked with a chemical that glows when viewed under a fluorescent microscope, allowing researchers to record their fate for 90 days. Because the growth of cells is often influenced by the surroundings, researchers grew the cells in different "cellular environments." In both healthy and stroke-damaged brains, donor cells were transplanted into three areas: the cerebral cortex, the subventricular zone - an inner layer of the brain - and the eye cavity.

Within a week, donor cells grew in all three areas in both healthy and damaged brains. Three to six weeks later, most donor cells had become mature neurons, which made connections with other brain cells.

Important differences were found in the rate of growth among the six environments. For example, cortical cells transplanted into healthy rats grew better when transplanted into the cortical area rather than the subventriclular zone, suggesting a preference for cells to grow better in their native environment. However, when the cortical cells were transplanted into stroke-damaged rats, the cells grew more profusely in the subventricular zone (the area that was not as severely damaged) than in the damaged cortex. "Because tissue in the stroke damaged cortex, is replaced by scar tissue and fluid-filled cavities there is relatively poor structural and nutritional support. The transplanted cells do not grow as well as they do in the more fertile subventricular regions which have supportive factors that help the cells grow," says Gupta.

"We've demonstrated that transplanted stem cells can survive, multiply and differentiate," Rosenbaum explains. "The other significant finding is that differences in the cell growth depend on the local factors in the areas of the brain in which they're implanted. A greater understanding of what these local factors are may enable us to better manipulate the stem cells to grow new brain tissue." For his work in this area, Gupta has been selected to receive the American Stroke Association Mordecai Y.T. Globus Young Investigator of the Year Award during the conference.

Co-authors include Solen Gokhan, M.D.; Manjeet Singh, M.D.; Bella I. Cohen, M.D.; Pearl S. Rosenbaum, M.D.; Leonore C. Ocava, M.D., John A. Kessler, M.D.; and Mark F. Mehler, M.D.