Reprogramming Mueller glia via in vivo cell fusion regenerates murine photoreceptors

• Published in: The Journal of clinical investigation Vol. 126; no. 8; p. 3104
• Main Authors: Sanges, Daniela, Simonte, Giacoma, Di Vicino, Umberto, Romo, Neus, Pinilla, Isabel, Nicolas, Marta, Cosma, Maria Pia
• Format: Journal Article
• Language: English
• Published: 01-08-2016
• ISSN: 0021-9738
• DOI: 10.1172/JCI85193

Vision impairments and blindness caused by retinitis pigmentosa result from severe neurodegeneration that leads to a loss of photoreceptors, the specialized light-sensitive neurons that enable vision. Although the mammalian nervous system is unable to replace neurons lost due to degeneration, therapeutic approaches to reprogram resident glial cells to replace retinal neurons have been proposed. Here, we demonstrate that retinal Mueller glia can be reprogrammed in vivo into retinal precursors that then differentiate into photoreceptors. We transplanted hematopoietic stem and progenitor cells (HSPCs) into retinas affected by photoreceptor degeneration and observed spontaneous cell fusion events between Mueller glia and the transplanted cells. Activation of Wnt signaling in the transplanted HSPCs enhanced survival and proliferation of MuellerHSPC hybrids as well as their reprogramming into intermediate photoreceptor precursors. This suggests that Wnt signaling drives the reprogrammed cells toward a photoreceptor progenitor fate. Finally, Mueller-HSPC hybrids differentiated into photoreceptors. Transplantation of HSPCs with activated Wnt functionally rescued the retinal degeneration phenotype in rd10 mice, a model for inherited retinitis pigmentosa. Together, these results suggest that photoreceptors can be generated by reprogramming Mueller glia and that this approach may have potential as a strategy for reversing retinal degeneration.