Exosomes from intestinal epithelial cells promote hepatic differentiation of liver progenitor cells, as revealed by gut-liver-on-a-chip models

Hepatic progenitor cells (HPCs) are overactivated and their differentiation into hepatocytes is impaired during the development of advanced liver diseases. Therefore, it is essential to explore the mechanisms involved in the differentiation of HPCs into hepatocytes. Here, to explore the effects of the intestinal epithelial cells and their exosomes on the hepatic differentiation of HPCs, coculture systems of Caco-2/HepaRG cell lines and intestine/HPC organoids were established in a novel gut-liver-on-a-chip. Furthermore, exosomes derived from intestinal organoids were administered to treat mice with carbon tetrachloride (CCL4)-induced liver fibrosis as a potential therapeutic intervention. The results showed that coculturing with human intestinal epithelial cells promoted the hepatic differentiation of HPCs, mediated by exosomes derived from intestinal epithelial cells. Treatment with exosomes derived from intestinal organoids demonstrated a substantial amelioration of liver fibrosis and improved liver function in CCL4-induced mouse models. Additionally, a specific cluster of miRNAs, miR-371-373, was identified within the exosomes of intestinal epithelial cells, which modulates the hepatic differentiation of hepatic progenitor cells by targeting RPS6KA2. Our findings demonstrate that exosomes from intestinal epithelial cells promote hepatic differentiation of HPCs. The application of exosomes derived from intestinal organoids may represent a novel therapeutic strategy for advanced liver diseases.

肝祖细胞（hepatic progenitor cells, HPCs）在晚期肝病的发生发展过程中会被过度激活，且其向肝细胞分化的进程会受到损伤。因此，探究肝祖细胞向肝细胞分化的相关机制具有重要意义。本研究为探究肠上皮细胞（intestinal epithelial cells）及其外泌体（exosomes）对肝祖细胞肝向分化（hepatic differentiation）的调控作用，在新型肝肠芯片（gut-liver-on-a-chip）中构建了Caco-2/HepaRG细胞系与肠/肝祖细胞类器官的共培养体系。此外，本研究将肠类器官来源的外泌体作为潜在治疗干预手段，用于干预四氯化碳（carbon tetrachloride, CCL4）诱导的肝纤维化小鼠模型。结果显示，与人类肠上皮细胞共培养可促进肝祖细胞的肝向分化，该过程由肠上皮细胞来源的外泌体介导。肠类器官来源的外泌体治疗可显著改善四氯化碳诱导的小鼠肝纤维化，并提升其肝功能。此外，研究人员在肠上皮细胞的外泌体中鉴定出一个特定的miRNA簇——miR-371-373，其可通过靶向RPS6KA2调控肝祖细胞的肝向分化。本研究结果证实，肠上皮细胞来源的外泌体可促进肝祖细胞的肝向分化。肠类器官来源的外泌体或可为晚期肝病提供一种新型治疗策略。