Abstract
Müller glia are responsible for the retina regeneration observed in zebrafish. Although the human retina harbors Müller glia with stem cell characteristics, there is no evidence that they regenerate the retina after disease or injury. Transforming growth factor-β (TGFβ) and Wnt signaling regulate retinal neurogenesis and inflammation, but their roles in the neural differentiation of human Müller stem cells (hMSC) are not known. We examined hMSC lines in vitro for the expression of various Wnt signaling components and for their modulation by TGFβ1, as well as the effect of this cytokine on the photoreceptor differentiation of these cells. Culture of hMSC with a combination of factors that induce photoreceptor differentiation of hMSC (FGF2, taurine, retinoic acid, and insulin-like growth factor type1; FTRI), markedly upregulated the expression of components of the canonical Wnt signaling pathway, including WNT2B, DKK1, and active β-CATENIN. Although FTRI did not modify mRNA expression of WNT5B, a component of the noncanonical/planar cell polarity Wnt pathway, it upregulated its secretion. Furthermore, TGFβ1 not only decreased WNT2B expression, but also inhibited FTRI-induced photoreceptor differentiation of hMSC, as determined by expression of the photoreceptor markers NR2E3, RHODOPSIN, and RECOVERIN. Inhibition of TGFβ1 signaling by an ALK5 inhibitor prevented TGFβ1-induced changes in the expression of the two Wnt ligands examined. More importantly, inhibition of the canonical WNT signaling by XAV-939 prevented FTRI-induced photoreceptor differentiation. These observations suggest that TGFβ may play a key role in preventing neural differentiation of hMSC and may constitute a potential target for induction of endogenous regeneration of the human retina.
Highlights
The spontaneous retinal regeneration observed in zebrafish has been ascribed to the ability of a population of Muller glia to dedifferentiate and become progenitors that give rise to retinal neurons [1]
A population of Muller glia isolated from the adult human retina exhibit stem cell characteristics in vitro [2], there is no indication that these cells have any regenerative ability in vivo
Activation of the Transforming growth factor-b (TGFb) and Wnt signaling pathways require the expression of specific receptors on the cell surface, and as previously shown, mammalian Muller glia express TGFb and Wnt receptors and their ligands [19,33,34,35], for which it is possible that activation of these pathways may trigger the neurogenic properties of human Muller glia as observed in other species
Summary
The spontaneous retinal regeneration observed in zebrafish has been ascribed to the ability of a population of Muller glia to dedifferentiate and become progenitors that give rise to retinal neurons [1]. Most retinal degenerative conditions that lead to blindness, including inflammatory, proangiogenic, and dystrophic retinal diseases, have been associated with abnormal proliferation of Muller glia that does not lead to repair, but to the formation of glial scarring [6]. Many of these conditions are accompanied by local increased production of proinflammatory cytokines, such as transforming growth factor-b (TGFb) [7,8,9], which may potentially modify the neural progenicity of hMSC
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