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.

Author Response: Possibility of Cytoplasmic Transportation Between Donor–Host Cell Following Photoreceptor Transplantation

“…Another potential approach to regenerate murine photoreceptors, the reprogramming of Müller cells by spontaneous cell fusion with transplanted hematopoietic stem and progenitor cells was recently reported. 8 Altogether, our recent observations further support our strategy that for the development of a photoreceptor replacement therapy, the selection of appropriate animal models is of utmost importance. Severely degenerated models with significant loss of cone and rod photoreceptors, like the Cpfl1/rho -/-double transgenic mouse line described in our study, 2 might represent benchmark models for photoreceptor replacement approaches, as they recapitulate the potential disease stage of patients most likely recruited for initial clinical trials and do not show the described transfer of cytoplasmic materials.…”

Modeling Dynamics and Function of Bone Marrow Cells in Mouse Liver Regeneration

“…Cell fusion is a well-known developmental process and an essential mechanism of regeneration after an injury (Johansson et al., 2008, Lluis and Cosma, 2010, Sanges et al., 2013, Sanges et al., 2016, Sullivan and Eggan, 2006, Altarche-Xifro et al., 2016). We therefore aimed to investigate whether mobilized BMCs could fuse with liver cells and promote regeneration after hepatectomy.…”

“…After BM-derived cell transplantation in damaged organs, the in-vivo-formed hybrids can regenerate the tissues, thereby providing a certain degree of functional recovery (Doyonnas et al., 2004, Johansson et al., 2008, Sanges et al., 2013, Sanges et al., 2016, Altarche-Xifro et al., 2016). These observations indicate the importance of the hybrids in different regenerating tissue contexts.…”

Special Commentary: Early Clinical Development of Cell Replacement Therapy: Considerations for the National Eye Institute Audacious Goals Initiative

“…Fusion of a transplanted cells with an endogenous cell can mimic a differentiated transplanted cell. 8 Release of trophic factors from transplanted or endogenously differentiated cells can also improve viability and function of retinal neurons. These substances can be diffusible or cell contact-dependent.…”