Liver-derived extracellular vesicles from patients with hepatitis B virus-related acute-on-chronic liver failure impair hepatic regeneration by inhibiting on FGFR2 signaling via miR-218-5p

Abstract

Abstract Background: Impaired liver regeneration in hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) patients is closely related to prognosis, whereas the mechanisms are not yet defined. Liver-derived extracellular vesicles (EVs) may be involved in dysregulation of liver regeneration. Clarifying the underlying mechanisms will contribute to the development of improved treatments for HBV-ACLF. Methods: EVs were isolated by ultracentrifuge from liver tissues of HBV-ACLF patients (ACLF_EVs) after liver transplantation and their Function was investigated utilizing acute liver injury (ALI) mice and AML12 cells. Differentially expressed miRNAs (DE-miRNAs) were screened by deep miRNA sequencing. LNP system was applied as a carrier for targeted delivery of miRNA inhibitors to improve their effect on liver regeneration. Results: ACLF_EVs had the capacity to inhibit hepatocyte proliferation and liver regeneration, in which miRNA, especially miR-218-5p, played an important role. Mechanistically, ACLF_EVs fused directly with target hepatocytes and transferred miR-218-5p into hepatocytes, acting by suppressing FGFR2 mRNA and inhibiting the activation of ERK1/2 signaling pathways. Reducing the level of miR-218-5p expression in the liver of ACLF mice could partially restored liver regeneration ability. Conclusion: Our data reveals the mechanism underlying impaired liver regeneration in HBV-ACLF and has significance for the discovery of new therapeutic approaches.