Müller glia-derived exosomal miR-9-3p promotes angiogenesis by restricting sphingosine-1-phosphate receptor S1P1 in diabetic retinopathy

Diabetic retinopathy is a heterogeneous retinal degenerative disease with the microvascular dysfunction being recognized as a hallmark of the advanced stage. In this study, we demonstrated that exosomes collected from the vitreous humor of proliferative diabetic retinopathy patients promoted proliferation, migration and tube formation ability of primary human retinal endothelial cells via its elevated miR-9-3p expression level. Müller glia cells were further recognized as the sole source of the aberrantly expressed miR-9-3p, and both in vitro and in vivo experiments validated that Müller glia-derived exosomes aggravate vascular dysfunction under high glucose. Mechanistically, exosomal miRNA-9-3p was transferred to retinal endothelial cells and bound to the sphingosine-1-phosphate receptor S1P1 coding sequence, which subsequently activated VEGFR2 phosphorylation and internalization in the presence or absence of exogenous VEGF-A. We successfully orchestrated the dynamic crosstalk between retinal Müller glia cells and endothelial cells in pathological condition, which may provide a novel biomarker or promising therapeutic agents for the treatment of diabetic retinopathy. [Display omitted] Liu et al. show that, in the vitreous humor of diabetic retinopathy patients, exosomal miRNA-9-3p secreted by Müller cells promote retinal angiogenesis by restricting sphingosine-1-phosphate receptor S1P1. This provides a better understanding on molecular mechanisms underlying diabetic retinopathy and sheds light on new potential therapeutic targets in future.