CRX is an intrinsic suppressor of epithelial‒mesenchymal transition in retinal pigment epithelial cells: a promising therapeutic avenue for subretinal fibrosis

TL;DR

This study shows that CRX prevents RPE cell transformation linked to subretinal fibrosis in AMD, offering a new treatment approach.

Contribution

CRX is identified as a novel endogenous suppressor of EMT in RPE cells, providing a new therapeutic target for AMD.

Findings

CRX expression inhibits epithelial-mesenchymal transition in RPE cells.

CRX overexpression reduces subretinal fibrosis in a mouse model of AMD.

CRX suppresses EMT partly by upregulating PPP2R2B expression.

Abstract

The epithelial-mesenchymal transition (EMT) of retinal pigment epithelial (RPE) cells is one of the significant pathogenic mechanisms for the formation of subretinal fibrosis in age-related macular degeneration (AMD). Multiple signaling pathways that promote EMT have been well described, yet the endogenous signaling pathways that inhibit EMT within RPE cells remain largely elusive. In this study, we confirmed the expression of CRX in human RPE cells and human embryonic stem cell-derived RPE (ESC-RPE) cells. By employing sub-culture to disrupt intercellular connections and thereby inhibit the Hippo signaling pathway, combined with TGF-β1 treatment in vitro to mimic the microenvironment for the formation of subretinal fibrosis, it was revealed that Hippo/YAP1 and TGF-β1 synergistically promoted the nuclear translocation of β-catenin, and the latter bound to TCF7 to inhibit the expression of CRX. Overexpression of CRX was capable of suppressing the occurrence of EMT in ESC-RPE cells. CRX exerted its inhibitory effect on EMT partly by upregulating the expression of PPP2R2B. In the laser-induced choroidal neovascularization mouse model, the nuclear translocation of CRX took place in RPE cells, and overexpression of CRX played an inhibitory role in the formation of subretinal fibrosis. This study has identified CRX as an endogenous signaling molecule that inhibits EMT in RPE cells and has provided a new research target and treatment strategy for the treatment of wet AMD and the inhibition of subretinal fibrosis formation.

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