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

Shizuka Miura, Kenichi Horisawa, Tokuko Iwamori, Satoshi Tsujino, Kazuya Inoue, Satsuki Karasawa, Junpei Yamamoto, Yasuyuki Ohkawa, Sayaka Sekiya and Atsushi Suzuki ()
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Shizuka Miura: Kyushu University
Kenichi Horisawa: Kyushu University
Tokuko Iwamori: Kyushu University
Satoshi Tsujino: Kyushu University
Kazuya Inoue: Kyushu University
Satsuki Karasawa: Kyushu University
Junpei Yamamoto: Kyushu University
Yasuyuki Ohkawa: Kyushu University
Sayaka Sekiya: Kyushu University
Atsushi Suzuki: Kyushu University

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract Hepatocytes 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.

Date: 2024
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DOI: 10.1038/s41467-024-47869-2

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