Bone marrow mesenchymal stem cell extracellular vesicle-derived miR-27b-3p activates the Wnt/β-catenin pathway by targeting SMAD4 and aggravates hepatic ischemia–reperfusion injury

INTRODUCTION: To investigate the roles of the extracellular vesicles (EVs) secreted from the bone marrow-mesenchymal stem cell (BMSCs) and miR-27-3p (highly expressed in BMSC EVs) in hepatic ischemia-reperfusion injury (HIRI), we constructed an HIRI mouse model and pretreated it with an injection of BMSC-EVs or control normal PBS into the abdominal cavity. METHOD: Compared with the HIRI group, HIRI mice preinjected with BMSC-EVs had significantly decreased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and alleviated liver necrosis (P<0.05). The miRNA sequencing of BMSC exosomes revealed that miR-27-3p, which is related to I/R injury, was enriched in the exosomes. We then pretreated the HIRI mouse model with an injection of agomir-miR-27-3p and agomir-NC into the abdominal cavity. However, compared with HIRI+NC mice, HIRI+miR-27 mice had significantly increased ALT and AST levels, aggravated liver necrosis, and increased apoptosis-related protein expression (P<0.05). RESULT: The proliferation and apoptosis of AML-12 cells transfected with miR-27-3p were significantly higher than the proliferation and apoptosis of AML-12 cells in the mimic NC group (P<0.01) after hypoxia induction. SMAD4 was proven to be a miR-27-3p target gene. Furthermore, compared to HIRI+NC mice, HIRI+miR-27 mice displayed markedly reduced SMAD4 expression. CONCLUSION: Our findings revealed the role and mechanism of miR-27-3p in HIRI and provide novel insights for the prevention and treatment of HIRI; for example, EVs derived from BMSCs transfected with antimiR-27 might demonstrate better protection against HIRI.