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I. Ahmad, S. Bhattacharya, S. Balasubramanian, M. Antony, K. Mallya; Regulation of Stem Cell Properties of Muller Cells and Their Influence on Retinal Neurogenesis. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5031. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
We have recently demonstrated that the Muller cells in the mammalian retina are latent neural stem cells (Das et al., 2006, Dev. Biol. 299:283). When removed from their niche and cultured in the presence of growth factors or activated in vivo by neurotoxins they display stem cell properties and demonstrate their neurogenic ability to give rise to retinal neurons. Understanding of mechanism that underlie the stem cell properties and potential of Muller cells will allow us to use these cells as a target for regenerative therapy in blinding diseases such as age-related macular degeneration (AMD). Towards this goal, we have examined factors that regulate stem cell properties of Muller cells and determined whether or not these glial cells can influence retinal neurogenesis.
Muller cells, enriched retrospectively and prospectively as SP cells using the Hoechst dye efflux assay, were examined for their ability to express neural/retinal progenitor markers, self renew and generate neurons and glia in response to perturbation of the canonical Wnt/Notch/Shh pathways. Enriched PN1 retinal stem cells/progenitors were co-cultured with Muller cells to determine the influence of the latter on bipolar cell versus Muller cell differentiation.
We observed that the activation of Wnt/Notch/Shh pathways promotes proliferation of Muller cells and the proliferating cells express neural/retinal progenitor markers. These cells can give rise to secondary neurospheres and differentiate into neurons and glia. Inhibition of the pathways compromise their stem cell properties and potential. Exposure of normal or degenerating (S334ter rats, rd mice) retina to Wnt ligands alone activates the latent stem cell properties in Muller cells, which show potential to differentiate along photoreceptor sub-lineage. Enriched Muller cells have profound effects on neuronal versus glial differentiation of PN1 retinal stem cells/progenitors; Muller cells in low and high densities promote neuronal and glial differentiation, respectively. These differential effects of Muller cells on neurogenesis are mediated by CNTF signaling in concert with the Notch pathways.
The stem cell properties and potential of Muller cells, in vitro and in vivo, are regulated by Notch/Wnt/Shh pathways. CNTF signaling is likely to influence whether the Muller cell, in which the latent stem cell properties have been activated, remains glia or differentiates along neuronal lineage.
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