MicroRNA-188-5p regulates contribution of bone marrow-derived cells to choroidal neovascularization development by targeting MMP-2/13

Abstract

Our previous investigations have shown that bone marrow-derived cells (BMCs), including mesenchymal stem cells (MSCs), contribute to the development of choroidal neovascularization (CNV) as sources of cells and angiogenic factors. Two main steps for circulating BMCs to integrate into CNV lesions are extracellular matrix remodeling and consequential cell migration. MicroRNAs (miRNAs) were found to be involved in CNV development; however, little is known about whether miRNAs regulate the contribution of BMCs to CNV. In the present study, we found that the expression of miR-188-5p was decreased in cultured hypoxic MSCs and BMCs within laser-induced CNV in mice. Matrix metalloproteinase 2 (MMP-2) and MMP-13 were both discovered as targets of miR-188-5p by bioinformatics predictions and dual-luciferase reporter system. Accordingly, increased expression of MMP-2/13 was found in hypoxic MSCs and BMCs in CNV lesions. Furthermore, miR-188-5p mimic transfection caused downregulation of MMP-2/13 in hypoxic MSCs and decreased tube formation of co-cultured vascular endothelial cells. Intravitreal injections of a miR-188-5p agomir attenuated the severity of CNV and inhibited the migration of BMCs into CNV lesions in mice. Our study suggests that miR-188-5p regulates the contribution of BMCs to CNV development by targeting MMP-2/13-mediated extracellular matrix degeneration, and miR-188-5p serves as a therapeutic target to treat CNV-related diseases.