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C. B. Del Debbio, S. Bhattacharya, S. Balasubramanian, A. Chaudhuri, S. Parameswaran, I. Ahmad; Jagged- and Wnt-Activated Muller Stem Cells Participate in Photoreceptor Regeneration. Invest. Ophthalmol. Vis. Sci. 2010;51(13):2647. doi: https://doi.org/.
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Muller cells in the mammalian retina are latent stem cells, capable of differentiating into early (ganglion cells) and late (rod photoreceptors) born retinal neurons (Das et al., 2006, Dev. Biol. 299:283). This raises the prospect of Muller cell-based regenerative repair of diseased retina. Here, we demonstrate a targeted activation of Muller stem cells through Notch and Wnt pathways and that a small subset of activated cells possess potential to differentiate along photoreceptor lineage
Activation of Muller stem cells and their regenerative capacity was examined in two different experimental paradigms: (1) In controlled conditions that consisted of retinal explants from wild type and rd1 mice (2) In S334ter rats where photoreceptor degenerate due to termination mutation in opsin gene. Notch and Wnt pathways were activated in Muller stem cells by Jagged1 peptide and Wnt3A, respectively. Activation was monitored by proliferation, SP cell phenotype and progenitor properties of Muller cells. Following 4 days of activation, BrdU or genetically-tagged Muller cells were chased for another 4 days for their migration and differentiation along photoreceptor lineage
Treatment of the retina with Jagged1/Wnt3A/Jagged1+Wnt3A led to an increase in the number of BrdU-positive cells expressing Muller cell markers. This was accompanied by an increase in the expression of transcripts corresponding to transducers of Notch and Wnt pathways and progenitors markers. The number of Muller SP cells also increased in response to treatments. These changes were abrogated in the presence of inhibitors of Notch and/or Wnt pathways. In the chase phase of the experiments a subset of BrdU-tagged Muller cells were observed to have migrated to the outer nuclear layer. A rare population of the migrated Muller cells expressed immunoreactivities corresponding to rod photoreceptors in both experimental paradigms. Hoechst dye efflux technique was used to confirm and corroborate the differentiation of activated Muller cells along photoreceptor lineage
Our results demonstrate Notch and Wnt pathway-mediated activation of Muller stem cells towards regenerative purposes in different models of photoreceptor degeneration
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