Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
  • Current Issue
  • Past Issues
  • By specialty
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews...
    • Mechanisms Underlying the Metabolic Syndrome (Oct 2019)
    • Reparative Immunology (Jul 2019)
    • Allergy (Apr 2019)
    • Biology of familial cancer predisposition syndromes (Feb 2019)
    • Mitochondrial dysfunction in disease (Aug 2018)
    • Lipid mediators of disease (Jul 2018)
    • Cellular senescence in human disease (Apr 2018)
    • View all review series...
  • Collections
    • Recently published
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Scientific Show Stoppers
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • About
  • Editors
  • Consulting Editors
  • For authors
  • Current issue
  • Past issues
  • By specialty
  • Subscribe
  • Alerts
  • Advertise
  • Contact
  • Conversations with Giants in Medicine
  • Author's Takes
  • Recently published
  • Brief Reports
  • Technical Advances
  • Commentaries
  • Editorials
  • Hindsight
  • Review series
  • Reviews
  • The Attending Physician
  • First Author Perspectives
  • Scientific Show Stoppers
  • Top read articles
  • Concise Communication
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 August 1, 2016; First published July 18, 2016
Citation Information: J Clin Invest. 2016;126(8):3104-3116. https://doi.org/10.1172/JCI85193.
View: Text | PDF
Categories: Research Article Stem cells

Reprogramming Müller glia via in vivo cell fusion regenerates murine photoreceptors

  • Text
  • PDF
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

×

Figure 1

Transplanted HSPCs fuse with MG upon photoreceptor damage.

Options: View larger image (or click on image) Download as PowerPoint
Transplanted HSPCs fuse with MG upon photoreceptor damage.
(A) Schematic...
(A) Schematic representation of the experimental plan. Cell fusion between HSPCs isolated from LoxP-STOP-LoxP-YFP donor mice (R26Y) and recipient Gfap-Cre MG cells leads to excision of the floxed stop codon and, in turn, to the expression of YFP. (B) Representative coimmunostaining of YFP+ hybrids (green) and TUNEL+ (red) apoptotic photoreceptors on retinal sections harvested from MNU-damaged or healthy (control) Gfap-Cre eyes 12 hours after subretinal transplantation of HSPCsR26Y. YFP+ hybrids (green) derived from cell fusion are detected in MNU-damaged retinas, which show TUNEL+ photoreceptors in the ONL, but not in the undamaged eyes (control). Nuclei were counterstained with DAPI (blue). Scale bar: 20 μm. n = 3. (C) Statistical analysis of the percentage of DiD+YFP+ hybrids evaluated on the total amount of DiD-labeled HSPCsR26Y detected by FACS analysis in MNU-damaged or healthy (control) Gfap-Cre retinas 24 hours after transplantation. Data are represented as mean ± SD of 3 independent experiments. n = 3. ***P < 0.0001 by unpaired Student’s t test. (D) Representative immunostaining of YFP+ hybrids (green) also positive for the MG marker (GS, red; yellow arrows) but not for the photoreceptor marker recoverin (red; green arrow) detected 24 hours after transplantation of HSPCsR26Y in MNU-damaged Gfap-Cre retinas. Scale bar: 20 μm. n = 3.
Follow JCI:
Copyright © 2019 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts