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

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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.

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