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

肝再生 再生(生物学) 肝细胞 肝病学 肝移植 乙型肝炎病毒 小RNA 医学 癌症研究 乙型肝炎 微泡 免疫学 肝损伤 细胞生物学 肝功能 丙型肝炎病毒 移植 生物 病毒 药理学 内科学 生物化学 基因 体外
作者
Senquan Zhang,Jie Yu,Keqiang Rao,Jie Cao,Lijie Ma,Yeping Yu,Zhe Li,Zhaokai Zeng,Yongbing Qian,Mo Chen,Hualian Hang
出处
期刊:Hepatology International [Springer Nature]
卷期号:17 (4): 833-849 被引量:9
标识
DOI:10.1007/s12072-023-10513-0
摘要

Impaired liver regeneration in hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) patients is closely related to prognosis; however, the mechanisms are not yet defined. Liver-derived extracellular vesicles (EVs) may be involved in the dysregulation of liver regeneration. Clarifying the underlying mechanisms will improve the treatments for HBV-ACLF. EVs were isolated by ultracentrifugation from liver tissues of HBV-ACLF patients (ACLF_EVs) after liver transplantation, and their function was investigated in acute liver injury (ALI) mice and AML12 cells. Differentially expressed miRNAs (DE-miRNAs) were screened by deep miRNA sequencing. The lipid nanoparticle (LNP) system was applied as a carrier for the targeted delivery of miRNA inhibitors to improve its effect on liver regeneration. ACLF_EVs inhibited hepatocyte proliferation and liver regeneration, with a critical role of miR-218-5p. 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 pathway. Reducing the level of miR-218-5p expression in the liver of ACLF mice partially restored liver regeneration ability. The current data reveal the mechanism underlying impaired liver regeneration in HBV-ACLF that promotes the discovery of new therapeutic approaches.
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