Abstract
Dedifferentiation of retinal pigment epithelium (RPE) cells and choroidal neovascularization (CNV) contributes to the pathogenesis of age-related macular degeneration (AMD). MicroRNAs (miRNAs) have crucial roles in AMD onset and progression. We thus aim to investigate the effects of miRNAs on RPE dedifferentiation and endothelium cell (EC) behavior, and analyze its downstream pathways. We have previously identified miR-302d-3p as the most downregulated miRNA signature along with RPE differentiation. Herein, in vitro study supported that miR-302d-3p induces RPE dedifferentiation typified by reduction of RPE characteristic markers, interrupts its phagocytosis, and promotes its migration, proliferation, and cell-cycle progression. c-Jun was identified as a potential upstream transcript factor for MIR302D, which might modulate RPE function by regulating miR-302d-3p expression. P21Waf1/Cip1, a cyclin-dependent kinase inhibitor encoded by the CDKN1A gene, was identified as a downstream target of miR-302d-3p. Our data suggested that p21Waf1/Cip1 could promote RPE differentiation, and inhibit its proliferation, migration, and cell-cycle progression. We also demonstrated that miR-302d-3p suppresses RPE differentiation through directly targeting p21Waf1/Cip1. In addition, the miR-302d-3p/CDKN1A axis was also involved in regulating tube formation of ECs, indicating its potential involvement in CNV formation. Taken together, our study implies that miR-302d-3p, regulated by c-Jun, contributes to the pathogenesis of both atrophic and exudative AMD. MiR-302d-3p promotes RPE dedifferentiation, migration, proliferation and cell-cycle progression, inhibits RPE phagocytosis, and induces abnormal EC behavior by targeting p21Waf1/Cip1. Pharmacological miR-302d-3p inhibitors are prospective therapeutic options for prevention and treatment of AMD.
Highlights
Retinal pigment epithelium (RPE), located in the outer retina between photoreceptor outer segments and choroidal vessels, is a monolayer of pigmented cells essential for maintaining regular retinal functions[1]
We have previously identified that RPE dedifferentiation, characterized by reduction of RPE specific proteins, is an early consequence of AMD12
Our results revealed that ectopic miR-302d-3p overexpression suppressed both the mRNA and protein expressions of RPE characteristic markers in human-induced pluripotent stem cells (hiPSC)-RPE cells (Fig. 1c, e, f), while endogenous miR-302d3p insufficiency promoted their expression (Fig. 1d, e, g)
Summary
Retinal pigment epithelium (RPE), located in the outer retina between photoreceptor outer segments and choroidal vessels, is a monolayer of pigmented cells essential for maintaining regular retinal functions[1]. Abnormal RPE behaviors have been implicated in causing many retinal disorders, including age-related macular degeneration (AMD)[2,3]. AMD is a leading cause for irreversible vision loss in people aged over 55, and can be further categorized into the atrophic and exudative forms[4]. RPE dysfunction and depletion have preliminary causative roles in both forms. Other than abnormal RPE functions, exudative AMD is typified by choroidal blood vessels growing through the Bruch’s membrane toward retina (choroidal neovascularization; CNV).
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