Department of Ophthalmology, Eye Institute of Chinese PLA, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, China; Shiley Eye Institute, Department of Ophthalmology, University of California, San Diego, CA, United States.
Department of Ophthalmology, Eye Institute of Chinese PLA, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, China.
Exp Eye Res. 2018 Oct;175:115-123. doi: 10.1016/j.exer.2018.06.010. Epub 2018 Jun 15.
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.
我们之前的研究表明，骨髓来源的细胞（BMCs），包括间充质干细胞（MSCs），作为细胞和血管生成因子的来源，有助于脉络膜新生血管（CNV）的发展。循环 BMC 整合到 CNV 病变中的两个主要步骤是细胞外基质重塑和随后的细胞迁移。MicroRNAs（miRNAs）被发现参与 CNV 的发展；然而，对于 miRNA 是否调节 BMC 对 CNV 的贡献知之甚少。在本研究中，我们发现培养的低氧 MSC 和小鼠激光诱导的 CNV 中 BMC 的 miR-188-5p 表达降低。基质金属蛋白酶 2（MMP-2）和 MMP-13 均被发现是 miR-188-5p 的生物信息学预测和双荧光素酶报告系统的靶标。因此，在 CNV 病变中的低氧 MSC 和 BMC 中发现 MMP-2/13 的表达增加。此外，miR-188-5p 模拟物转染导致低氧 MSC 中 MMP-2/13 的下调，并减少共培养的血管内皮细胞的管状形成。玻璃体内注射 miR-188-5p 激动剂可减轻 CNV 的严重程度，并抑制 BMC 向小鼠 CNV 病变的迁移。我们的研究表明，miR-188-5p 通过靶向 MMP-2/13 介导的细胞外基质降解来调节 BMC 对 CNV 发展的贡献，miR-188-5p 可作为治疗 CNV 相关疾病的治疗靶点。
