Exosomal miR-183-5p from human hepatocyte-derived liver progenitor-like cells promotes liver regeneration during acute liver failure

Hepatocyte-derived liver progenitor-like cells (HepLPCs) can reversibly differentiate into mature hepatocytes and play important roles in liver regeneration following acute liver failure. However, the mechanisms by which HepLPCs exert these regulatory effects are unclear. Herein, we report that HepLPCs participate in reinitiating liver regeneration and improving survival during acute liver failure, at least in part, via miRNA-183-5p, which is released from HepLPCs in extracellular vesicles. Thus, these findings may identify novel targets and strategies for the treatment of acute liver failure. Overall design: HepLPC-derived extracellular vesicles (HepLPC-EVs) were isolated from conditioned media and subjected to microRNA (miRNA) sequencing analysis. Primary human hepatocytes were treated with EVs or miRNA mimics and/or inhibitors. C57BL/6J mice were intraperitoneally injected with carbon tetrachloride (CCl4) or acetaminophen (APAP) to induce ALF. These mice were then treated with EVs or a miRNA agomir.

肝细胞源性肝祖细胞样细胞（Hepatocyte-derived liver progenitor-like cells，简称HepLPCs）可可逆分化为成熟肝细胞，并在急性肝衰竭后的肝再生过程中发挥关键调控作用。然而，HepLPCs介导此类调控效应的具体分子机制目前仍不明确。本研究证实，HepLPCs至少可通过细胞外囊泡（extracellular vesicles，简称EVs）释放的miRNA-183-5p，参与重启急性肝衰竭模型中的肝再生并提高小鼠存活率。本研究结果可为急性肝衰竭的临床治疗提供全新的靶点与干预策略。
总体实验设计如下：从HepLPCs的条件培养基中分离其来源的细胞外囊泡（EVs），并开展微小RNA（microRNA，简称miRNA）测序分析。将原代人肝细胞分别经EVs、miRNA模拟物或/和抑制剂处理。向C57BL/6J小鼠腹腔注射四氯化碳（carbon tetrachloride，简称CCl4）或对乙酰氨基酚（acetaminophen，简称APAP）以构建急性肝衰竭（acute liver failure，简称ALF）模型，随后向模型小鼠输注EVs或miRNA激动剂（agomir）。