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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