Extracellular HSP90 promotes differentiation of lens epithelial cells to fiber cells by activating LRP1‐YAP‐PROX1 axis

Abstract

Capsular residual lens epithelial cells (CRLEC) undergo differentiation to fiber cells for lens regeneration or tansdifferentiation to myofibroblasts leading to posterior capsular opacification (PCO) after cataract surgery. The underlying regulatory mechanism remains unclear. Using human lens epithelial cell lines and the ex vivo cultured rat lens capsular bag model, we found that the lens epithelial cells secrete HSP90α extracellularly (eHSP90) through an autophagy‐associated pathway. Administration of recombinant GST‐HSP90α protein or its M‐domain induces the elongation of rat CRLEC cells with concomitant upregulation of the crucial fiber cell transcriptional factor PROX1and its downstream targets, β‐ and γ‐crystallins and structure proteins. This regulation is abolished by PROX1 siRNA. GST‐HSP90α upregulates PROX1 by binding to LRP1 and activating LRP1‐AKT mediated YAP degradation. The upregulation of GST‐HSP90α on PROX1 expression and CRLEC cell elongation is inhibited by LRP1 and AKT inhibitors, but activated by YAP‐1 inhibitor (VP). These data demonstrated that the capsular residue epithelial cells upregulate and secrete eHSP90α, which in turn drive the differentiation of lens epithelial cell to fiber cells. The recombinant HSP90α protein is a potential novel differentiation regulator during lens regeneration.

The Hippo signalling pathway and its impact on eye diseases

“…Li et al found that the autophagy-associated pathway regulates the YAP pathway by upregulating and secreting HSP90, thereby promoting the differentiation of LECs into fibroblasts and inducing PCO. 40 Transforming growth factorβ (TGFβ) signalling is also activated after cataract surgery, which can induce epithelial-mesenchymal transition (EMT) and fibrosis through the YAP signalling pathway in the PCO. 39 Many factors, such as calponin, 41 fibroblast growth factor, 16 and mechanotransduction of stress, 42 can promote cell differentiation by activating the YAP/TAZ axis and converting LECs into fibrous cells.…”

“…Li et al. found that the autophagy‐associated pathway regulates the YAP pathway by upregulating and secreting HSP90, thereby promoting the differentiation of LECs into fibroblasts and inducing PCO 40 . Transforming growth factor‐β (TGF‐β) signalling is also activated after cataract surgery, which can induce epithelial‐mesenchymal transition (EMT) and fibrosis through the YAP signalling pathway in the PCO 39 .…”