Wnt/β-Catenin Signaling Triggers Neuron Reprogramming and Regeneration in the Mouse Retina

•Retinal neurons can fuse with adult stem cells after tissue damage•Activation of Wnt signaling can induce reprogramming of retinal neurons in vivo•Reprogrammed hybrids differentiate in retinal neurons and regenerate damaged retinas•Reprogramming of retinal neurons occurs after fusion of endogenously recruited BMCs

SummaryCell-fusion-mediated somatic-cell reprogramming can be induced in culture; however, whether this process occurs in mammalian tissues remains enigmatic. Here, we show that upon activation of Wnt/β-catenin signaling, mouse retinal neurons can be transiently reprogrammed in vivo back to a precursor stage. This occurs after their spontaneous fusion with transplanted hematopoietic stem and progenitor cells (HSPCs). Moreover, we demonstrate that retinal damage is essential for cell-hybrid formation in vivo. Newly formed hybrids can proliferate, commit to differentiation toward a neuroectodermal lineage, and finally develop into terminally differentiated neurons. This results in partial regeneration of the damaged retinal tissue, with functional rescue. Following retinal damage and induction of Wnt/β-catenin signaling, cell-fusion-mediated reprogramming also occurs after endogenous recruitment of bone-marrow-derived cells in the eyes. Our data demonstrate that in vivo reprogramming of terminally differentiated retinal neurons after their fusion with HSPCs is a potential mechanism for tissue regeneration.

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