Stimulation of Retinal Pigment Epithelium With an α7 nAChR Agonist Leads to Müller Glia Dependent Neurogenesis in the Adult Mammalian Retina

PURPOSE: The adult mammalian retina is typically incapable of regeneration when damaged by disease or trauma. Restoration of function would require generation of new adult neurons, something that until recently, mammals were thought to be incapable of doing. However, previous studies from this laboratory have shown that the α7 nicotinic acetylcholine receptor (α7 nAChR) agonist, PNU-282987, induces cell cycle reentry of Müller glia and generation of mature retinal neurons in adult rats, in the absence of detectible injury. This study analyzes how PNU-282987 treatment in RPE leads to robust BrdU incorporation in Müller glia in adult mice and leads to generation of Müller-derived retinal progenitors and neuronal differentiation. METHODS: Retinal BrdU incorporation was examined after eye drop application of PNU-282987 in adult wild-type and transgenic mice that contain tamoxifen-inducible tdTomato Müller glia, or after intraocular injection of conditioned medium from PNU-282987–treated cultured RPE cells. RESULTS: PNU-282987 induced robust incorporation of BrdU in all layers of the adult mouse retina. The α7 nAChR agonist was found to stimulate cell cycle reentry of Müller glia and their generation of new retinal progenitors indirectly, via the RPE, in an α7 nAChR-dependent fashion. CONCLUSIONS: The results from this study point to RPE as a contributor to Müller glial neurogenic responses. The manipulation of the RPE to stimulate retinal neurogenesis offers a new direction for developing novel and potentially transformative treatments to reverse the loss of neurons associated with neurodegenerative disease, traumatic injury, or aging.