Exosomes Derived From Mesenchymal Stem Cells Modulate miR-126 to Ameliorate Hyperglycemia-Induced Retinal Inflammation Via Targeting HMGB1.

Abstract

In this study, we aim to investigate whether mesenchymal stem cell (MSC)-derived exosomes (MSC-Exos) could regulate hyperglycemia-induced retinal inflammation by transferring microRNA-126 (miR-126). MSC-Exos were isolated from the media of human umbilical cord-derived mesenchymal stem cells (hUCMSCs), and this isolation was followed by the transfer of miR-126. MSC-Exos or MSC-Exos overexpressing miR-126 were intravitreally injected into diabetic rats in vivo and were cocultured with high glucose-affected human retinal endothelial cells (HRECs) in vitro. Plasma samples were obtained from the vitreous of rats and from HREC cells after treatment for ELISA assay. Retinal sections were examined using immunohistochemistry. RT-PCR and Western blotting were conducted to assess the levels of high-mobility group box 1 (HMGB1), NLRP3 inflammasome, and NF-κB/P65 in retinas and HRECs. Our results showed that hyperglycemia greatly increased inflammation in diabetic rats or HRECs exposed to high glucose, increasing the levels of caspase-1, interleukin-1β (IL-1β) and IL-18. The administration of MSC-Exos could effectively reverse this reaction. Compared to control MSC-Exos, MSC-Exos overexpressing miR-126 more successfully suppressed the HMGB1 signaling pathway and suppressed inflammation in diabetic rats. The administration of miR-126-expressing MSC-Exos significantly reduced high glucose-induced HMGB1 expression and the activity of the NLRP3 inflammasome in HRECs. miR-126 expression in MSC-Exos reduces hyperglycemia-induced retinal inflammation by downregulating the HMGB1 signaling pathway.