In collaboration with CERA scientists, the team has reported microRNA-143 as a potential therapeutic target to attenuate retinal angiogenesis.
An integrative multi-omics analysis reveals microRNA-143 as potential therapeutics to attenuate retinal angiogenesis
Jiang-Hui Wang, Yu-Fan Chuang, Jinying Chen, Vikrant Singh, Fan-Li Lin, Richard Wilson, Leilei Tu, Chenkai Ma, Raymond Ching-Bong Wong, Peng-Yuan Wang, Jingxiang Zhong, Alex W. Hewitt, Peter van Wijngaarden, Gregory Dusting, Guei-Sheung Liu
Nuclei Acid Therapeutics, accepted 2022.02.04 (IF=5.48)
Abstract Retinal neovascularization is a severe complication of several neovascular retinal diseases, including proliferative diabetic retinopathy, central retinal vein occlusion and retinopathy of prematurity. MicroRNAs (miRNAs) are master regulators of gene expression that play an important role in retinal neovascularization. Here, we investigate the retinal miRNA expression profile in a rat model of oxygen-induced retinopathy (OIR) using miRNA-Seq. We show that miR-143-3p, miR-126-3p, and miR-150-5p are significantly downregulated in the retina of OIR rats, and intravitreal injection of synthetic mimics of these miRNAs significantly ameliorate retinal neovascularization in this animal model. Of these identified miRNAs, miR-143 which is highly expressed in the neural retina and retinal vasculature is here identified for the first time to be associated with retinal neovascularization. With a focus on miR-143 expression in primary human retinal endothelial cells, we explore its effects through a multi-omics analysis. In miR-143 treated cells, the functional evaluation showed a decrease in cell migration and delayed endothelial vessel-like tube remodeling. Consequently, the multi-omics analysis suggests that miR-143 negatively impacts endothelial cell activity through regulating cell-matrix adhesion and mediating HIF-1 signaling. Furthermore, using cytoHubba, a topological analysis method to assess the essentiality of genes, we predict the 20 top hub genes regulated by miR-143 that may be involved in mediating endothelial cell function. Using CIBERSORTx, a bulk gene expression deconvolution algorithm, we analyze a public RNA-Seq dataset (GSE102485) and demonstrate that the retinal neovascular membranes in patients with proliferative diabetic retinopathy (PDR) principally consist of endothelial cells. We then identify 2 hub genes, THBS1 and SERPINE1, direct targets of miR-143, which on further analysis demonstrate an expression level significantly altered in the PDR patients compared to controls. These findings suggest that miR-143 appears to be essential for limiting endothelial cell-matrix adhesion, thus suppressing retinal neovascularization. The present study might have important implications for the exploration of potential therapeutic targets for the treatment of neovascular ocular diseases.
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