Eyeworld

EW RETINA 74 by Lauren Lipuma EyeWorld Contributing Writer Researchers stimulate neuron regeneration in the mouse retina Scientists show it's possible to reprogram mammalian cells to make new neurons after injury M ouse glial cells can be coaxed into becoming replacement neurons after a retinal injury, a new study finds. 1 The study's results show regenerated neurons can successfully incorporate themselves into the eye's existing circuitry, a finding that could pave the way for new treatments for degenerative retinal diseases in hu- mans, according to the authors. A team of researchers at the Uni- versity of Washington, Seattle, used clues from the eyes of fish and am- phibians to unlock the regenerative potential of the murine retina. They used a combination of genomic and epigenomic reprogramming to coax Müller glia cells into regenerating in- ner retinal neurons that could form synapses with existing, uninjured neurons and even respond to light. "Regeneration in the mamma- lian retina is possible now, using a combination of genetic and epi- genetic reprogrammers, and once neurons are made, they seem to know what to do," said Tom Reh, PhD, a biologist at the University of Washington and lead author of the new study. "So if we build them, they'll fit in." Dr. Reh said his team hopes to one day tailor the regeneration pro- cess to make cone photoreceptors and retinal ganglion cells that could help patients suffering from macular degeneration or glaucoma. "This combination could be tested in people someday to stimu- late repair of neurons that have been lost by one of these degenerations," Dr. Reh said. Mammals versus fish Mammalian retinas can't regenerate neurons after injury, but retinas of most fish and some amphibians can. In fish, glial cells differentiate into neurons to replace those that are lost. While mammals also have glial cells in their retinas, they can't dif- ferentiate into neurons after injury. Instead, they undergo reactive glio- sis, walling off the injury and some- times forming a glial scar. Dr. Reh is interested in understanding why fish and amphibians can regenerate lost neurons but mammals can't. During mammalian development, progeni- tor cells differentiate into both glia and neurons. Dr. Reh suspected the way to coax mammalian glial cells into regenerating neurons after inju- ry would be to engineer them to be more like the progenitor cells. Several years ago, Dr. Reh and his research team compared genes in progenitor cells to those of glial cells and found several transcription factors expressed in progenitor cells that aren't expressed in glial cells. One transcription factor they identi- fied, Ascl1, is known to help pro- genitors differentiate into neurons during human development and is critical to the neuron regeneration process in zebrafish. Armed with the knowledge that fish need Ascl1 to regenerate and human retinas need it to develop, Dr. Reh and his team engineered a mouse strain that would express Ascl1 in Müller glial cells. They then induced retinal injury in those mice with a toxin that injures ganglion cells and interneurons that transmit signals from photoreceptors to the brain. They found that young mice with the Ascl1 gene could regenerate neurons, but adult mice couldn't, so they reasoned that something was blocking Ascl1 from doing its job in the adult mice. They thought one culprit might be histone modifica- tions that made mouse DNA less accessible to the transcription factor as the mouse got older. In the new study, Dr. Reh and his team undid the histone mod- ifications by blocking a specific enzyme so that Ascl1 could access the mouse DNA, a process called epigenetic modification. Then, when they injured the retinas in adult mice that expressed Ascl1, the neu- rons regenerated. "It was that combination of genomic reprogramming and epig- enomic reprogramming together that did the trick and made the mouse's retina more like that of the fish," Dr. Reh said. Working like neurons should The regenerated neurons in Dr. Reh's study not only looked and acted like normal neurons, they also functioned like normal neurons; they integrated themselves into the retina's existing electrical circuitry and picked up light signals from photoreceptor cells. Teaming up with two electro- physiologists at the University of Washington, the researchers looked at the cells' electrical activity, taking advantage of the fact that reti- nal neurons respond to light in a distinct, measurable pattern. They found that about 2 weeks post-inju- ry, the cells responded to light and formed functional synapses as if they were interneurons. The regen- erated cells also integrated with retinal cells that convey signals to the brain. "When we made the new neu- rons, we weren't sure they were go- ing to wire into the circuit because this is an adult, fully mature circuit," Dr. Reh said. "It is a bit like putting a new chip into an old circuit board and plugging it back in and hoping all the wires are in the right spot. But these new neurons, once we made them, fit right into the circuit. To me, that was good news because now we know that if you make the right neurons, they'll wire up—they know what to do." Dr. Reh envisions testing the combination method in humans someday to stimulate repair of neurons after acute eye injuries or central retinal arterial occlusion. But the next step is to boost Müller glia numbers. Retinal injuries tend to cause a massive loss of neurons, and Dr. Reh wants to develop a way to stimulate the regeneration of Müller glia as well as replace lost neurons. He also hopes to be able to tailor the regeneration process to make specific types of neurons, such as cone photoreceptors or retinal ganglion cells, that could help pa- tients with macular degeneration or glaucoma. EW Reference 1. Jorstad NL, et al. Stimulation of functional neuronal regeneration from Müller glia in adult mice. Nature. 2017;548:103–107. Editors' note: Dr. Reh has no financial interests related to his comments. Contact information Reh: tomreh@uw.edu November 2017 Regenerating Müller glia (yellow) in the mouse retina. A new study finds Müller glia can be coaxed into regenerating lost neurons after an eye injury. Source: Tom Reh, PhD Research highlight

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