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Published on: March 10, 2023
RPE With ROCK-Mediated Epithelial-Mesenchymal Transition as a Key Contributor of Subretinal Fibrosis in AMD
Iori Wada1, Keijiro Ishikawa1, Muneo Yamaguchi1
1Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Purpose:
To investigate the cellular origin and molecular mechanisms underlying subretinal fibrosis (SRF) in neovascular AMD (nAMD), with a focus on the role of RPE and Rho-associated coiled-coil-containing protein kinase (ROCK)-mediated epithelial-mesenchymal transition (EMT).
Methods:
Fate-mapping with lineage tracing, laser capture microdissection, microarray and RT-PCR analyses, immunohistochemistry, and functional assays with ROCK inhibitors (Ripasudil, Belumosudil) were used to assess EMT/endothelial-to-mesenchymal transition contributions to SRF and ROCK pathway involvement.
Results:
Fate mapping identified RPE and endothelial cells as sources of myofibroblasts. EMT-related gene upregulation and ROCK1/2 expression were observed in SRF lesions. RPE-specific ROCK2 knockout significantly reduced fibrosis and EMT markers. Ripasudil suppressed SRF development and reversed EMT both in vivo and in vitro. ROCK expression was confirmed in human choroidal neovascularization membranes.
Conclusions:
RPE-derived myofibroblasts via ROCK2-mediated EMT play a dominant role in SRF formation. ROCK inhibitors, particularly Ripasudil, may serve as effective therapeutic agents against fibrosis in nAMD.
