Molecular mechanisms of subretinal fibrosis in age-related macular degeneration

Abstract

Subretinal fibrosis is a result of a wound healing response that follows choroidal neovascularization in neovascular age-related macular degeneration (nAMD). Although anti-vascular endothelial growth factor therapy has become a standard treatment that improves visual acuity in many nAMD patients, unsuccessful treatment outcomes have often been attributed to the progression of subretinal fibrosis. In this review, we summarize the cellular and extracellular components of subretinal fibrous membranes and also discuss the possible molecular mechanisms including the functional involvement of growth factors and the inflammatory response in the process. Moreover, we present an murine animal model of subretinal fibrosis that might facilitate greater understanding of the pathophysiology and the development of novel therapeutic strategies for the inhibition of subretinal fibrosis in nAMD.

αB-Crystallin Regulates Subretinal Fibrosis by Modulation of Epithelial-Mesenchymal Transition

“…This enables RPE to assume a mesenchymal cell phenotype, which includes enhanced migratory capacity and elevated resistance to apoptosis, as well as increased production of ECM components and proangiogenic factors, including VEGF. 8,53,54 Therefore, the novel property of aB-crystallin as an EMT inducer of RPE might account for the known functional roles of aB-crystallin in AMD, such as cytoprotection and VEGF production in response to stress stimuli. 21,22 The physiological RPE monolayer with cell-cell contact showed no difference in the expression of EMT markers between WT and aB-crystallin knockout mice.…”

“…8,40 Fibronectin and collagen I are the most prominent ECM components in human subretinal fibrotic lesions. 41 Fibronectin provides a provisional matrix for cell migration of RPE cells.…”

“…Previous histological studies imply that the source of myofibroblasts can be both bone marrowederived cells and retinal pigment epithelium (RPE) cells. 7,8 After injury to RPE, the cells undergo epithelial-mesenchymal transition (EMT), which enables transdifferentiation, resulting in the conversion of epithelial cells to myofibroblasts. CNV induction can result in the recruitment of more inflammatory cells and fibroblasts, which can be a direct or indirect source of additional myofibroblasts.…”

“…Myofibroblasts play important roles in the development of subretinal fibrosis, such as proliferation, migration, and extracellular matrix remodeling. 8 Although previous studies have indicated the involvement of several growth factors and cytokines in EMT, 8 the precise molecular mechanism and the critical regulators of this process remain to be determined.…”

Inhibition of development of laser-induced choroidal neovascularization with suppression of infiltration of macrophages in Smad3-null mice

“…Immunohistochemistry in flat-mounted choroidal tissue obtained at day 35 suggested that Smad3 deletion inhibited myofibroblast generation in the laser-injured area. 47 It was also reported that the expression level of GFAP represents the degree of fibrotic reaction of neural retina. 48 In the current study, protein expression of GFAP in the laser-irradiated neural retina was also suppressed by the loss of Smad3.…”