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.