Wnt signaling promotes Muller cell proliferation and survival after injury.

Department of Surgery, Stanford School of Medicine, Division of Plastic and Reconstructive Surgery, Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford, CA, 94305, United States.
Investigative ophthalmology & visual science (Impact Factor: 3.43). 11/2012; DOI: 10.1167/iovs.12-10774
Source: PubMed

ABSTRACT PURPOSE: Muller glia respond to retinal injury by a reactive gliosis but only rarely do mammalian glial cells re-enter the cell cycle and generate new neurons. In the non-mammalian retina, however, Muller glia act as stem/progenitor cells. Here, we test the function of Wnt signaling in the post-injury retina, focusing on its ability to influence mammalian Muller cell de-differentiation, proliferation and neurogenesis. METHODS: A Nd:YAG laser was used to create light burns on the retina of Axin2(LacZ/+) Wnt reporter mice. At various timepoints after injury, retinas were analyzed for evidence of Wnt signaling as well as glial cell response, proliferation, and apoptosis. Laser injuries were also created in Axin2(LacZ/LacZ) mice, and the effect of potentiated Wnt signaling on retinal repair was assessed. RESULTS: A subpopulation of mammalian Muller cells are Wnt responsive and when Wnt signaling is increased these cells showed enchanced proliferation in response to injury. In an environment of heightened Wnt signaling, caused by the loss of Wnt negative regulator Axin2, Muller cells proliferate after injury and adopted the expression patterns of retinal progenitor cells (RPCs). The Wnt-responsive Muller cells also exhibited long-term survival and in some cases, expressed the rod photoreceptor marker, Rhodopsin. CONCLUSIONS: The Wnt pathway is activated by retinal injury, and prolonging the endogenous Wnt signal causes a subset of Muller cells to proliferate and de-differentiate into RPCs. These data raise the possibility that transient amplification of Wnt signaling after retinal damage may unlock the latent regenerative capacity long speculated to reside in mammalian neural tissues.

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    ABSTRACT: Stem cell therapies are being explored extensively as treatments for degenerative eye disease, either for replacing lost neurons, restoring neural circuits or, based on more recent evidence, as paracrine-mediated therapies in which stem cell-derived trophic factors protect compromised endogenous retinal neurons from death and induce the growth of new connections. Retinal progenitor phenotypes induced from embryonic stem cells/induced pluripotent stem cells (ESC/iPSC) and endogenous retinal stem cells may replace lost photoreceptors and retinal pigment epithelial (RPE) cells and restore vision in the diseased eye, whereas treatment of injured retinal ganglion cells (RGC) has so far been reliant on mesenchymal stem cells (MSC). Here, we review the properties of non-retinal-derived adult stem cells, in particular neural stem cells (NSC), MSC derived from bone marrow (BMSC), adipose tissues (ADSC) and dental pulp (DPSC), together with ESC/iPSC and discuss and compare their potential advantages as therapies designed to provide trophic support, repair and replacement of retinal neurons, RPE and glia in degenerative retinal diseases. We conclude that ESC/iPSC have the potential to replace lost retinal cells, whereas MSC may be a useful source of paracrine factors that protect RGC and stimulate regeneration of their axons in the optic nerve in degenerate eye disease. NSC may have potential as both a source of replacement cells and also as mediators of paracrine treatment.
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Sep 25, 2014