Article

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: 3.66). 11/2012; 54(1). 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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    • "Of the endogenous retinal stem cells, Müller glia have been induced to dedifferentiate into retinal progenitors which can then transform into multiple retinal phenotypes including photoreceptors in the photoreceptor-damaged eye(Osakada et al., 2007, Liu et al., 2013). "
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    • "However, excessive Wnt activation in certain cell types has deleterious effects, including tumorigenesis and angiogenesis, the extent of which varies with the method of Wnt activation (Zhang et al., 2010; Cui et al., 2013). In contrast to the present study, previous studies that showed deleterious effects from Wnt activation used substantially different models, including mice that were genetically manipulated to be oversensitive to Wnt signaling by knocking-out inhibitor genes, or used acute injury models (laser light, oxidative stress), or a non-cell type-specific Wnt activator (Zhou et al., 2010; Wan et al., 2012; Liu et al., 2013; Sanges et al., 2013). Also, low numbers of cells were shown to have off-target effects, for example, proliferation and expression of neural stem/progenitor genes occurred in less than 1% of Muller glia (Das et al., 2006; Osakada et al., 2007; Del Debbio et al., 2010; Ramachandran et al., 2011), and Wnt does not regulate proliferation in late stages of retinal development (SanchezeSanchez et al., 2010). "
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    • "We then explored the possibility of preventing implant failure by creating an environment of elevated Wnt signalling around the implant. We specifically employed Wnt reporter (Axin2 LacZ/LacZ ) mice for this purpose because of they represent a robust model of enhanced Wnt signalling (Minear et al. 2010, Liu et al. 2013). In doing so, we gained new insights into the biology of fibrous encapsulation and the tantilizing possibility that this endstage failure state may be reversible. "
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