Hepatocytes differentiate into intestinal epithelial cells through a hybrid epithelial/mesenchymal cell state in culture

• DOI: 10.1038/s41467-024-47869-2
• Publication Date: 2024-05-15T10:02:27Z
• Authors: Shizuka Miura; Kenichi Horisawa; Tokuko Iwamori; Satoshi Tsujino; Kazuya Inoue; Satsuki Karasawa; Junpei Yamamoto; Yasuyuki Ohkawa; Sayaka Sekiya; Atsushi Suzuki
• Keywords: Male; 0303 health sciences; Epithelial-Mesenchymal Transition; Science; Q; Cell Culture Techniques; Cell Differentiation; Epithelial Cells; Cell Dedifferentiation; Article; Organoids; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Liver; Hepatocytes; Animals; Vimentin; Hippo Signaling Pathway; Intestinal Mucosa; Cells, Cultured; Signal Transduction

AbstractHepatocytes play important roles in the liver, but in culture, they immediately lose function and dedifferentiate into progenitor-like cells. Although this unique feature is well-known, the dynamics and mechanisms of hepatocyte dedifferentiation and the differentiation potential of dedifferentiated hepatocytes (dediHeps) require further investigation. Here, we employ a culture system specifically established for hepatic progenitor cells to study hepatocyte dedifferentiation. We found that hepatocytes dedifferentiate with a hybrid epithelial/mesenchymal phenotype, which is required for the induction and maintenance of dediHeps, and exhibit Vimentin-dependent propagation, upon inhibition of the Hippo signaling pathway. The dediHeps re-differentiate into mature hepatocytes by forming aggregates, enabling reconstitution of hepatic tissues in vivo. Moreover, dediHeps have an unexpected differentiation potential into intestinal epithelial cells that can form organoids in three-dimensional culture and reconstitute colonic epithelia after transplantation. This remarkable plasticity will be useful in the study and treatment of intestinal metaplasia and related diseases in the liver.