SEMA3A in Proliferative Vitreoretinopathy: Exogenous Activity, Endogenous Regulation, and the MicroRNA Hypothesis

Proliferative vitreoretinopathy (PVR) remains a leading cause of surgical failure after rhegmatogenous retinal detachment (RRD) repair. Although PVR involves multiple cell types and signaling pathways, epithelial–mesenchymal transition (EMT) and related plasticity of retinal pigment epithelial (RPE) cells are major contributors to fibrocellular membrane formation and contraction. Semaphorin 3A (SEMA3A) has therefore attracted interest as a potential negative regulator of these pathogenic RPE responses. Recombinant SEMA3A inhibits RPE migration and proliferation and attenuates experimental PVR when administered at model induction. Yet this benefit does not establish that endogenous SEMA3A transcript levels are reduced. Published Source Data from a mouse model of traumatic PVR show significantly increased endogenous Sema3a transcript levels in RPE preparations compared with controls. The question is therefore why PVR progresses despite increased endogenous Sema3a transcript levels in this model. Possible explanations include microRNA-mediated translational repression, altered protein processing or secretion, reduced extracellular availability, and impaired NRP1/plexin signaling. MicroRNAs (miRNAs) are particularly relevant because they can reduce protein output without a parallel decline in mRNA and can regulate multiple features of RPE EMT. This narrative review examines current evidence for SEMA3A in PVR, summarizes miRNA regulation of RPE EMT and related PVR phenotypes, and evaluates direct and indirect evidence for miRNA–SEMA3A interactions. We also compare the miRNA hypothesis with alternative explanations for inadequate endogenous SEMA3A activity and consider its implications for ocular biomarkers and target-site-selective RNA therapy. Current evidence makes miRNA-mediated regulation of SEMA3A a plausible and testable mechanism, although a causal role has yet to be demonstrated in RPE cells or PVR.