Scientists have successfully transplanted light-sensing cells called photoreceptors directly into the eyes of mice and restored their visual function.
The achievement is based on a novel technology in which the cells are introduced at a particular stage in their development. It was carried out at the London Institute of Ophthalmology using a novel approach developed at the University of Michigan Kellogg Eye Center to tag rod precursor cells and prepare them for transplantation
The team of scientists found that transplanted photoreceptor precursor cells survived and became integrated into the mouse retina--and that the technique succeeded because the cells were isolated when they had reached a certain level of maturity.
Rather than injecting undifferentiated and uncommitted stem cells into the retina in hopes they would develop into photoreceptors, researchers introduced cells at a somewhat later stage. These cells are referred to as "precursors": they are immature cells that are "programmed" to be, but have not yet become, functionally mature photoreceptors--the light-sensitive cells in the retina that are essential for sight.
The findings, reported in the November 9 advance online issue of Nature, come from the collaborative research of Anand Swaroop, Ph.D., the Harold F. Falls Collegiate Professor of Ophthalmology and Visual Sciences at the University of Michigan Medical School, and Robin R. Ali, Ph.D., Professor, Division of Molecular Therapy at the Institute of Ophthalmology in London.
The technology represents a breakthrough in transplantation-based therapies for neuro-degenerative diseases. It suggests that scientists may need to introduce changes in stem cells in order for them to become highly specialized neurons.
Although the experiment has implications for human eye diseases that dim the sight of millions of people, Swaroop anticipates that several years of research using animal models and cell culture systems will still be needed before transplantation can be considered ready for testing in humans.
Restoring visual function in animals is an important advance, but the scientists caution that it shouldn't be considered the same as restoring vision in humans. The next wave of research will focus on characterizing the mechanisms that generate photoreceptor precursors from stem cells. Swaroop believes the research has potential for developing therapies for people with retinal and macular degenerative diseases that are untreatable today.
The Swaroop research team started to develop its approach to transplantation about six years ago.
"Rather than focusing on stem cells," says Swaroop, "we believed that if we could understand how cells develop and become photoreceptors--or any other specific neuron--our transplantation efforts would meet with greater success. This technique gives us new insights in repairing damage to the retina and possibly other parts of the central nervous system."
Drs. Ali, Swaroop and their colleagues report that the transplanted cells in diseased mouse retinas have met several essential requirements: the cells survive; correctly develop into rod photoreceptors; integrate and connect in sufficient numbers to neurons that ultimately carry visual signals to the brain; and they have proven to be functional.
The photoreceptor precursors were transplanted into three different types of mice with retinal degeneration caused by distinct genetic defects involving malfunctioning or degenerating rods. The transplanted cells survived and were functional for the duration of the study. Scientists observed improvements including pupil response to light and response to light stimuli from ganglion cells, which form the circuitry to the brain.
Swaroop explains that photoreceptors constitute "the first line of information capture in vision." They are part of a complex sensory system that delivers visual signals to the brain. Photoreceptors consist of rods and cones, highly specialized cells that capture light and convert it into chemical signals that travel through the inner retina and optic nerve and on to the brain where signals are converted to the images we see. In the majority of macular and retinal degenerative diseases, such as age-related macular degeneration and retinitis pigmentosa, it is the loss of photoreceptors that leads to blindness.
Understanding the birth of photoreceptors In 2001, Swaroop's team first showed that the gene NRL, discovered several years earlier in his U-M lab, is essential for the development of rods. In its absence, all rods were converted to cones.
Earlier this year, Drs. Masayuki Akimoto and Hong Cheng in the Swaroop lab published an important study describing the "birth" of rod cells.* They were able to make this process visible by building on previous research, using an NRL gene regulatory element to tag the rods with a green fluorescent protein. This enabled Kellogg scientists to illuminate the rods, which begin as unspecified cells and gradually differentiate into cells dedicated to light reception. "One of our critical discoveries," says Swaroop, "is that there is a window of opportunity during which a cell has committed itself to becoming a rod but has not yet started to function as such."
The collaboration with Ali's group, funded by the UK's Medical Research Council in London, was critical in testing the next phase of the research. The goal was to learn whether transplanting cells isolated at a specific time period would significantly increase the chances that "precursor" cells would develop into functioning rods and integrate in the retinal milieu.
The new paper shows that successful transplantation requires that cells reach a certain level of maturity before being transplanted into the eye. When the cells were transplanted at a very early stage, before they were assigned their specialized function, they survived but failed to integrate into the mature retina. Only one group of cells remained viable: cells that were not yet mature, but had developed to the point at which they were committed to becoming rods.
After almost two decades of directing fundamental research on retinal development and degenerative diseases, Swaroop believes that scientists are at last entering a period of rapid discovery. "This provides a clear example of how basic fundamental research can contribute to treatment of blinding diseases," he says. "We now have proof of principle that our approach to repairing damaged retina by transplantation of appropriate cells can be successful."
Swaroop sees several next steps in his quest to find treatments for retinal and macular degeneration. His research team will continue to study the properties of photoreceptor cells and mouse models to learn more about the process of transplantation and functional integration. He hopes that he will soon be able to investigate how the concept of transplanting photoreceptor precursors can be adapted to the human retina. "Perhaps within the next five years we will begin to see the first steps toward retinal cell transplants for people with blinding eye disease," says Swaroop.
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