Restoration of vision after de novo genesis of rod photoreceptors in mammalian retinas

Abstract

In zebrafish, Müller glia (MG) are a source of retinal stem cells that can replenish damaged retinal neurons and restore vision. In mammals, however, MG do not spontaneously re-enter the cell cycle to generate a population of stem or progenitor cells that differentiate into retinal neurons. Nevertheless, the regenerative machinery may exist in the mammalian retina, as retinal injury can stimulate MG proliferation followed by limited neurogenesis. Therefore, there is still a fundamental question regarding whether MG-derived regeneration can be exploited to restore vision in mammalian retinas. Gene transfer of β-catenin stimulates MG proliferation in the absence of injury in mouse retinas. Here we report that following gene transfer of β-catenin, cell-cycle-reactivated MG can be reprogrammed to generate rod photoreceptors by subsequent gene transfer of transcription factors essential for rod cell fate specification and determination. MG-derived rods restored visual responses in Gnat1Gnat2 double mutant mice, a model of congenital blindness, throughout the visual pathway from the retina to the primary visual cortex. Together, our results provide evidence of vision restoration after de novo MG-derived genesis of rod photoreceptors in mammalian retinas.

In vivo ectopic Ngn1 and Neurod1 convert neonatal cochlear glial cells into spiral ganglion neurons

“…Our lineage tracing analysis showed that neonatal glial cells started to express the SGN markers, Tuj1, Map2, and Prox1, as early as 6 days after expressing Ngn1 and Neurod1; we defined these cells as “glial cell‐derived new SGNs” or “new SGNs” for short. We found that not all neonatal glia cells with Ngn1 and Neurod1 expression became new SGNs, consistent with previous glial cells to neuron conversion studies in retina . Promisingly, the new SGNs also decreased expression of glial genes and could survive at least until 6 weeks of age.…”

“…We found that not all neonatal glia cells with Ngn1 and Neurod1 expression became new SGNs, consistent with previous glial cells to neuron conversion studies in retina. 16,17 Promisingly, the new SGNs also decreased expression of glial genes and could survive at least until 6 weeks of age. More importantly, a smaller subset of new SGNs expressed Mafb, Gata3, and other SGN genes and displayed large rounded somas similar to that of wild-type SGNs.…”

Inflammation‐induced mammalian target of rapamycin signaling is essential for retina regeneration

“…Teleost fish such as zebrafish possess a remarkable capacity to regenerate their damaged retina and restore vision (Goldman, 2014;Lenkowski & Raymond, 2014;Mensinger & Powers, 1999). Although mammals lost the ability to spontaneously regenerate their retina during evolution (Hamon, Roger, Yang, & Perron, 2016), recent studies have shown that gene transfer of key factors known to play critical roles in zebrafish retina regeneration enabled limited neuronal regeneration in the mammalian retina (Elsaeidi et al, 2018;Jorstad et al, 2017;Yao et al, 2018). Further understanding the cellular and molecular mechanisms underlying retina regeneration in zebrafish could therefore be of great importance to improve the therapeutic strategies for repairing a damaged mammalian retina.…”

Small-molecule inhibition of Lats kinases promotes Yap-dependent proliferation in postmitotic mammalian tissues

“…6A-E).Moreover, treated cells developed cytoskeletal rearrangements and protrusions and decreased in size, phenotypes consistent with de-differentiation and proliferation, respectively(Fig. 6F,G)43 .Yap activation may permit retinal regeneration in mammals by stimulating the proliferation of Müller glial cells, progenitors with a capacity to differentiate into photoreceptors and neurons17,44 . To test whether TRULI induces the proliferation of Müller glia, we used retinal organoids derived from human induced pluripotent stem cells.As expected, Müller cells remained largely quiescent in control cultures.…”