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

In zebrafish, Müller glial cells (MGs) are a source of retinal stem cells that can replenish damaged retinal neurons and restore vision(1). In mammals, however, MGs lack regenerative capability as they do not spontaneously re-enter the cell cycle to generate a population of stem/progenitor cells that differentiate into retinal neurons. The regenerative machinery may exist in the mammalian retina, however, as retinal injury can stimulate MG proliferation followed by limited neurogenesis(2–7). The fundamental question remains whether MG-derived regeneration can be exploited to restore vision in mammalian retinas. Previously, we showed that gene transfer of β-catenin stimulates MG proliferation in the absence of injury in mouse retinas(8). Here, we report that following gene transfer of β-catenin, cell-cycle-reactivated MGs can be reprogrammed into rod photoreceptors via a subsequent gene transfer of transcription factors that are essential for rod cell fate specification and determination. MG-derived rods restored visual responses in Gnat1(rd17):Gnat2(cpfl3) double mutant mice, a model of congenital blindness(9,10), 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.