Disarming "Glial" Cells May Solve Retinal Transplantation Barrier

Cells in the retina known as glial cells set up a physical barrier that prevents retinal transplants from migrating, growing and hooking up to the host retina and the optic nerve to restore sight, scientists at Schepens Eye Research Institute have found. They have also found that disarming these cells can free transplanted tissue to make the sight-saving connection to the retina and the optic nerve and ultimately to the brain. These findings, published in the August issue of Nature Neuroscience, will ultimately impact the success of retinal transplantation and restore vision to millions afflicted by retinal diseases such as macular degeneration, glaucoma, and retinitis pigmentosa. These discoveries may also lead to the success of brain tissue transplants for diseases such as Parkinson's disease, according to the authors.

"This is a significant piece of the retinal transplant puzzle," says Dong Feng Chen, MD, PhD, the principle investigator of the study and an assistant scientist at Schepens Eye Research Institute and an assistant professor of the Harvard Medical School. "Because it has been so difficult to transplant neurons to retinas and brains, we have long suspected that there are physical barriers preventing donor cells from surviving, migrating, and integrating into the host environment of these tissues. This study clearly shows us the nature of one major barrier and ways to break it down," says Chen, whose primary area of research is nerve regeneration.

The retina is the paper-thin, light-sensitive tissue at the back of the eye that takes light and images from the outside world and transmits them through the optic nerve to the brain. The brain's interpretation of these signals is the final step in the process known as vision. Retinal cells that sense the light and send the information to the brain are nerve cells. Most importantly, these cells wire together and communicate with each other and with cells in the brain to perform the visual function. Without these connections, vision cannot take place.

Because retinal cells, similar to those in the brain, are unable to regenerate themselves after injury, for many years, scientists have attempted to transplant cells or tissue into eyes to replace or regenerate retinas damaged by injury or disease, using donor retina, brain, and stem cells as transplants. With the possible exception of stem cells, tissues transplanted into the retina do not survive for long and, even those that do survive for a short time are unable to wire or integrate into the host retina.

Glial cells, which are support cells to nerve cells, are found in all nerve tissue, such as the brain, the spinal cord and the retina. In injured or diseased eyes, glial cells (specifically astrocytes and Muller cells) caused the increase of certain proteins called intermediate filament proteins, specifically glial frillary acid protein (GFAP) and vimentin. These proteins helped the glial cells to form a scar around the injured or damaged area and appeared to be essential to the development of these scars.

Chen hypothesized that glial cells might form the same type of scar in response to the injection of transplanted tissue and that the scar might act as a barrier to transplant survival. She further hypothesized that transplants might survive and integrate in mice whose glial cells had been disarmed or had been rendered unable to stimulate the production of the necessary scar-forming proteins.

To test this theory, the research team injected retinal cells from "green mice," (cells of these mice carry a green fluorescence gene and reveal green color so their transplanted tissue can be detected easily in non-green mice) into mice with normal glial cells and also into mice whose glial cells had been manipulated so that the scar-forming proteins were missing or "knocked out."

In the mice with normal glial cells, Chen and her colleagues found that the transplanted green cells remained near the injection site, did not grow or migrate to other area of the retina, and did not grow the nerve tentacles (axons and dendrites) necessary to wire up to the host retinas and the optic nerve. The team also found that the glial cells surrounded the transplanted tissue, formed a scar, a physical barrier that kept the transplanted tissue from integrating into the eye and connecting to the optic nerve.

In contrast, when Chen's team looked at the knockout mice in which the scar-forming proteins were missing, the transplanted green cells had survived, migrated to the retina, grew the necessary tentacles and became entwined in the optic nerve. Divested of the filament proteins, the glial cells did not form a physical scar barrier.

Chen says that this discovery greatly increases the chances that retinal transplants may some day be able to survive in the human eye. And, since glial cells are in other parts of the nervous tissues, their manipulation may lead the way to the survival of other types of neural transplantations, such as those being attempted for Parkinson's disease.

According to Chen, the next immediate steps in her research will be to apply this to the animal models that automatically develop retinal degeneration and blindness. They wish to see that by disarming the glial cells, they could now use retinal transplantation to restore vision in these animals. Long term she hopes to develop therapeutic drugs that will aid neural transplantation to treat retinal and brain diseases in humans.

An online version of the study "Robust neural integration from retinal transplants in mice deficient in GFAP and vimentin" can be obtained at http://www.nature.com/natureneuroscience Or for a copy you may email or [email protected].

Other members of the research team included Reiko Kinouchi, Masumi Takeda, and Liu Yang of Schepens Eye Research Institute and Harvard Medical School; Ulrika Wilhelmsson, Andrea Lundkvist, and Milos Pekny of the Department of Medical Biochemistry at Goteborg University in Sweden.

Chen's research is one of many efforts at Schepens Eye Research Institute aimed at unlocking the mysteries of human vision and finding cures for retinal and other blinding eye diseases.

Schepens Eye Research Institute is an affiliate of Harvard Medical School and the largest independent eye research institute in the world.