Exosomal miR-1246 derived from human umbilical cord blood mesenchymal stem cells attenuates hepatic ischemia reperfusion injury by modulating T helper 17/regulatory T balance.

Abstract

The purpose of this study was to explore the mechanism by which human umbilical cord blood mesenchymal stem cells (hUCB-MSCs)-derived exosomes exerted protective effect in hepatic ischemia/reperfusion injury (IRI). hUCB-MSCs-derived exosomes were administrated into hepatic IRI mice or cocultured with naïve CD4+ T cells exposed to hepatic hypoxia/reoxygenation microenvironment. Hepatic function was assessed by determining serum transaminases. Histological changes were observed using hematoxylin and eosin staining. The proportion of T helper 17 (Th17) and regulatory T (Treg) cells were analyzed by flow cytometry. The concentration of inflammatory cytokines was determined by enzyme-linked immunosorbent assay. The interaction between miR-1246 and interleukin 6 (IL-6) signal transducer (also known as gp130) was verified by luciferase activity assay. The miR-1246 expression, Th17/Treg-related genes, and gp130-signal transducer and activator of transcription 3 (STAT3) pathway were detected by quantitative real-time polymerase chain reaction and western blotting. hUCB-MSCs-derived exosomes ameliorated IRI-induced hepatic dysfunction and decreased Th17/Treg ratio in CD4+ T cells in vitro, whereas treatment of hUCB-MSCs with miR-1246 inhibitor showed opposite effects, which was mediated via the IL-6-gp130-STAT3 pathway. hUCB-MSCs-derived exosomes could alleviate hepatic IRI through modulating the balance between Tregs and Th17 cells via miR-1246-mediated IL-6-gp130-STAT3 axis.