title: Reprogramming Müller glia via in vivo cell fusion regenerates murine photoreceptors.
abstract: 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 Müller 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 Müller glia and the transplanted cells. Activation of Wnt signaling in the transplanted HSPCs enhanced survival and proliferation of Müller-HSPC 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, Müller-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 Müller glia and that this approach may have potential as a strategy for reversing retinal degeneration.
authors.forename: Daniela
authors.initials: D
authors.lastname: Sanges
authors.forename: Giacoma
authors.initials: G
authors.lastname: Simonte
authors.forename: Umberto
authors.initials: U
authors.lastname: Di Vicino
authors.forename: Neus
authors.initials: N
authors.lastname: Romo
authors.forename: Isabel
authors.initials: I
authors.lastname: Pinilla
authors.forename: Marta
authors.initials: M
authors.lastname: Nicolás
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Cosma
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002459:Cell Fusion; D019070:Cell Lineage; D049109:Cell Proliferation; D065150:Cellular Reprogramming; D004596:Electroretinography; D063928:Ependymoglial Cells / Q000166:cytology*; D005260:Female; D005786:Gene Expression Regulation; D006412:Hematopoietic Stem Cells / Q000166:cytology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009457:Neuroglia / Q000166:cytology*; D010641:Phenotype; D010786:Photoreceptor Cells / Q000166:cytology* / Q000473:pathology; D012160:Retina / Q000166:cytology / Q000254:growth & development*; D012162:Retinal Degeneration / Q000473:pathology; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology*; D051153:Wnt Proteins / Q000378:metabolism
chemical_list: D051153:Wnt Proteins