Cells in the retina of mice can be coaxed to create new neurons following an injury, according to new research from the University of Washington. This is the most definitive demonstration to date that such regeneration is possible, given the right cues, for a specific type of neuron in the inner retina of a mammal.
Retina revitalized: A regenerated amacrine cell, which is a type of cell found in the inner retina. The nucleus of the cell is labeled in red, while the rest is labeled in green.
If researchers could spur the development of different types of new neurons in the living human eye, they might be able to replace cells that are lost in diseases like macular degeneration and retinitis pigmentosa. Few or no treatment options are currently available for patients with these diseases.
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“This is an excellent, clear demonstration that you can regrow cells of the inner retina,” says Stephen Rose, chief research officer at the nonprofit Foundation Fighting Blindness.
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The retina, which is located in the back of the eye, has an outer layer of cells that detect light and translate it into electrical signals. It also has inner layers, which process the signals and send them to the brain.
In degenerative disorders like macular degeneration and retinitis pigmentosa, outer-layer cells, called photoreceptors, break down in the early stages of disease, leading to loss of vision. Extensive research has focused on replacing these cells, in an effort to restore sight. In people with advanced disease or blindness, however, the inner cell layers may also break down or become disorganized and need to be rebuilt, says Rose.
“The outer retina is like the CPU, and the inner retina is like the motherboard,” he says. “If I attach a new CPU to a dead motherboard, it won’t do any good, no matter how great a CPU it is.”
In the current work, developmental biologist Thomas Reh and his team first damaged the mice’s retinas, using a chemical known to destroy inner retinal cells. Then they injected a cocktail of proteins called growth factors. This process spurred some cells, called muller glia, to return to an immature state. Muller glia normally provide nutrition to other neurons and do not divide. Following chemical treatment, however, some of them returned to an undifferentiated state in which they resembled progenitor cells.
The immature cells then started to proliferate, some of them differentiating into mature neurons. In particular, they formed amacrine cells, which are located in the inner retina. These cells mediate electrical signals coming from the photoreceptors and are particularly important to motion detection and night vision, says Reh.
“We did not get a large number of new neurons,” he adds. “But we showed that we could make new amacrine cells, the cell type that had been lost to damage.” The findings were published this week in the online edition of the Proceedings of the National Academy of Sciences.
The current work may help build a foundation for future therapies in which cells of the inner retina–and potentially other cells, including photoreceptors–are regenerated in situ, in the living human eye, says Reh. In theory, such treatments might allow physicians to replace retinal neurons “precisely at the spot where they’re needed, without disruptions or discontinuities,” he says.
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In lower vertebrates like fish and chickens, retinal cells are known to generate new neurons in response to damage, often restoring sight. While mammals do not have the same self-healing capacity, some previous research has suggested that under particular circumstances, mammals’ retinas might be able to generate new neurons. Reh’s current work offers more definitive evidence that immature cells, derived from muller glia, can differentiate again into mature neurons, says Michael Young of the Schepens Eye Research Institute.
More research is needed before retinal regeneration can be attempted in humans. “We need much more control over the basic cellular processes”–trying to regenerate different types of neurons and making sure that they function properly in vivo–“before we can treat real people with blinding disease,” says Anand Swaroop of the National Eye Institute.
For example, scientists need to show that regenerated neurons behave normally in the eye, integrating into circuits with other cells and contributing to vision. “It is hard enough to grow different cell types,” says Rose. “But will they function? Will they do what the cells they are replacing normally would do? That’s really tough.”
Reh says that growing new cells in the eye could be preferable to transplanting cells, an approach that his team is also working on. “Transplantation involves a tricky surgery; the cells may not go exactly where you want them to go,” says Reh, and some cells could cause an immune reaction. “Developing methods to stimulate regeneration may prove to be the best option in the long run.”
