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Kazuhiko Umazume, LanHsin Liu, Kevin McDonald, Hiroshi Goto, Henry Kaplan, Shigeo Tamiya; β-catenin signaling in RPE in experimental PVR. Invest. Ophthalmol. Vis. Sci. 2013;54(15):6252.
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β-catenin signaling is an essential pathway that regulates numerous cellular processes. In this study, we investigated the role of β-catenin signaling in RPE cells in the development of proliferative vitreoretinopathy (PVR) using a swine model.
Western blot analysis and immunostaining were used to detect total β-catenin and active β-catenin (ABC) expression on RPE sheets. The role of β-catenin in RPE during epithelial-mesenchymal transition (EMT), cell migration, cell proliferation and cell contraction were assessed by marker protein staining using a scratch assay and type 1 collagen contraction assay. The effect of FH535, a β-catenin/TCF signaling inhibitor, on these features of cell de-differentiation was also investigated. The swine model of experimental PVR, in which RPE cells were injected into vitrectomized eyes, was used to assess the efficacy of FH535 in preventing a traction retinal detachment (TRD).
Staining for ABC was detected in the nucleus of de-differentiated RPE cells but not in the nucleus of differentiated cells. Nuclear ABC expression in de-differentiated RPE cells was accompanied by reduced total β-catenin expression, suggesting that signaling and the subsequent degradation of β-catenin is occurring during or after EMT. FH535 prevented RPE cell EMT, migration, proliferation, and ECM contraction in a dose-dependent manner. Furthermore, FH535 significantly prevented TRD in vivo in the experimental swine PVR model. While TRD was observed in 7 out of 8 animals under control conditions, no animals treated with FH535 developed TRD (0/9).
β-catenin signaling is involved in EMT, migration, proliferation, and contraction of RPE cells and could be acting as one of the key regulators of PVR progression. The β-catenin/TCF signaling inhibitor FH535 significantly inhibited PVR-related RPE changes in vitro and prevented TRD in an experimental PVR model in the swine in vivo.
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