Ligand-Independent Activation of Platelet-Derived Growth Factor Receptor β Promotes Contraction of Retinal Pigment Epithelial Cells

Abstract

Background: Epiretinal membranes in patients with Proliferative Vitreoretinopathy (PVR) consist of extracellular matrix and a number of cell types including Retinal Pigment Epithelial (RPE) cells and fibroblasts, whose contraction causes retinal detachment. In RPE cells depletion of Platelet-Derived Growth Factor (PDGF) receptor (PDGFR) β suppresses vitreous-induced Akt activation, where as in fibroblasts Akt activation through indirect activation of PDGFRa by growth factors outside the PDGF family (non-PDGFs) plays an essential role in experimental PVR. Whether non-PDGFs in the vitreous, however, were also able to activate PDGFRβ in RPE cells remained elusive. Methods: We showed that expression of a truncated PDGFRβ lacking a PDGF-binding domain in the RPE cells whose PDGFRB gene had been silent using the CRISPR/Cas9 technology restored vitreous-induced Akt activation as well as cell proliferation, epithelial-mesenchymal transition, migration and contraction. Results: We found that scavenging Reactive Oxygen Species (ROS) with N-acetyl-cysteine and inhibiting Src Family Kinases (SFKs) with their specific inhibitor SU6656 blunted the vitreous-induced activation of the truncated PDGFRβ and Akt as well as the cellular events related to the PVR pathogenesis. Conclusions: These discoveries suggest that in RPE cells PDGFRβ can be activated indirectly by non-PDGFs in the vitreous via an intracellular pathway of ROS/SFKs to facilitate the development of PVR, thereby providing novel opportunities for PVR therapeutics.