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Reprogramming Müller glia via in vivo cell fusion regenerates murine photoreceptors
Daniela Sanges, … , Marta Nicolás, Maria Pia Cosma
Daniela Sanges, … , Marta Nicolás, Maria Pia Cosma
Published July 18, 2016
Citation Information: J Clin Invest. 2016;126(8):3104-3116. https://doi.org/10.1172/JCI85193.
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Research Article Article has an altmetric score of 16

Reprogramming Müller glia via in vivo cell fusion regenerates murine photoreceptors

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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.

Authors

Daniela Sanges, Giacoma Simonte, Umberto Di Vicino, Neus Romo, Isabel Pinilla, Marta Nicolás, Maria Pia Cosma

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Figure 4

MG reprogrammed upon fusion with Wnt-activated HSPCs generates new photoreceptors.

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MG reprogrammed upon fusion with Wnt-activated HSPCs generates new photo...
(A and B) Representative immunostainings of YFP+ (green) hybrids also immunoreactive for either GS (red, white arrows) or recoverin (red, yellow arrows) detected in MNU-damaged Gfap-Cre retinas 1 week after transplantation of untreated (A) or BIO-treated (B) HSPCsR26Y. Nuclei were counterstained with DAPI (blue). n = 3. (C) Statistical analysis of the number of photoreceptor nuclear rows in the ONL of healthy (WT) or MNU-damaged eyes 1 week after treatment with either PBS or untreated (HSPCs) or BIO-treated HSPCs (BIO-HSPCs) or BIO alone. Data are represented as mean ± SD counted in 3 different sections spanning the site of the injection for each mouse. n = 9. ***P < 0.0001, unpaired Student’s t test. (D) Representative immunodetection of BrdU-positive cells (red) also positive for the photoreceptor marker recoverin (green) in the ONL of MNU-damaged Gfap-Cre retinas 1 week after transplantation of BIO-treated HSPCsR26Y. Nuclei were counterstained with DAPI (blue). Insert represents a higher magnification of the region in the white square. (n = 3). Scale bars: 20 μm.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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