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Retinal cells
A microscopic view documents how glial cells in the retina can be transformed into functioning neurons. (UW Photo / Tom Reh Lab)

University of Washington researchers have found a way to activate cells in the retinas of adult mice to turn into new neurons – a recipe that eventually could lead to new treatments for human eyes damaged by trauma and disease.

UW biologist Tom Reh, one of the authors of a research paper on the experiments published by the journal Nature, said it’s too early to talk about cures – but not too early to talk about hope.

He told GeekWire that the newly published work on cell conversion complements different approaches that rely on cell transplants.

“I hope that one or the other approach starts to deliver results to patients in the near term,” he said. “We’re working really hard every day to make this work for people.”

Making it work for mice was hard enough: Mammalian eyes typically have little capacity for retinal regeneration. However, it’s common to see such regeneration among species of fish, frogs and newts.

To see whether the trick could be transferred to mammals, Reh and his colleagues zeroed in on a gene called Ascl1. The gene codes for a type of protein called a transcription factor, which serves as a switch to turn on other genes involved in cellular function.

In zebrafish, Ascl1 turns on a process that converts glial cells – cells that typically play only a supporting role for neurons – into actual neurons. “They turn into stem cells once the neurons are damaged, and the stem cells turn into neurons, and that fixes the problem,” Reh explained.

The researchers used a viral gene-swapping technique to give their test mice the version of the Ascl1 gene that works so well in zebrafish. Then they gave the mice a variety of drugs to determine the best way to activate the gene.

Initial experiments produced a recipe that involved tamoxifen and tetracycline, but that recipe worked only during the first couple of weeks of a mouse’s life. For the new round of experiments described in Nature, Reh and his colleagues added another drug, trichostatin-A, which is known as a histone deacetylase inhibitor.

Once that drug was added to the mix, the researchers saw that the cellular conversion process worked in adult mice as well as newborns. The newly created neurons integrated themselves into the retina and became functional, all on their own.

“They seemed to know exactly what to do,” Reh said. “They weren’t perfect, but they’re pretty darn good.”

Reh said mammalian retinal cells are programmed through epigenetics to make the cellular conversion process harder to trigger as an organism matures.

“One of the roles of epigenetic regulation is to repress the proliferation of cells in adults so they don’t become cancerous,” Reh explained. The histone deacetylase inhibitor removed that epigenetic roadblock and let the conversion process go forward.

The newly published research found that the glial cells were converted into only one class of retinal neurons, known as interneurons. Reh said those neurons are affected by a type of vision loss known as central retinal artery occlusion.

Other eye conditions hit other types of specialized neurons. For example, glaucoma affects ganglion cells, while macular degeneration involves the loss of photoreceptors, also known as rods and cones.

The researchers’ recipe couldn’t produce those kinds of neurons, but Reh and his colleagues will try working on new recipes while perfecting the one they have.

“We still have our work cut out for us,” Reh said.

UW researcher Nikolas Jorstad is the principal author of the Nature paper, “Stimulation of Functional Neuronal Regeneration From Müller Glia in Adult Mice.” In addition to Reh, co-authors include Matthew Wilken, William Grimes, Stefanie Wohl, Leah VandenBosch, Takeshi Yoshimatsu, Rachel Wong and Fred Rieke.

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