2. Academic Validation
  3. Bile acid-FXR signaling facilitates the long-term maintenance of hepatic characteristics in human iPSC-derived organoids

Bile acid-FXR signaling facilitates the long-term maintenance of hepatic characteristics in human iPSC-derived organoids

  • Cell Rep. 2025 May 27;44(5):115675. doi: 10.1016/j.celrep.2025.115675.
Taro Shimizu 1,  Masato Miyoshi 1,  Sei Kakinuma 2,  Jun Tsuchiya 1,  Daisuke Yamane 3,  Keiya Watakabe 1,  Tomohiro Mochida 1,  Kento Inada 1,  Kaho Yamada 4,  Kotomi Shinozaki 3,  Ayako Sato 1,  Shun Kaneko 1,  Fukiko Kawai-Kitahata 1,  Miyako Murakawa 1,  Sayuri Nitta 1,  Mina Nakagawa 1,  Mamoru Watanabe 5,  Yasuhiro Asahina 6,  Ryuichi Okamoto 1
Affiliations

Affiliations

  • 1 Department of Gastroenterology and Hepatology, Graduate School of Medical and Dental Science, Institute of Science Tokyo (Science Tokyo), Tokyo 1138519, Japan.
  • 2 Department of Gastroenterology and Hepatology, Graduate School of Medical and Dental Science, Institute of Science Tokyo (Science Tokyo), Tokyo 1138519, Japan; Department of Clinical and Diagnostic Laboratory Science, Graduate School of Medical and Dental Science, Institute of Science Tokyo (Science Tokyo), Tokyo 1138519, Japan. Electronic address: skakinuma.gast@tmd.ac.jp.
  • 3 Department of Diseases and Infection, Tokyo Metropolitan Institute of Medical Science, Tokyo 1568506, Japan.
  • 4 Department of Clinical and Diagnostic Laboratory Science, Graduate School of Medical and Dental Science, Institute of Science Tokyo (Science Tokyo), Tokyo 1138519, Japan.
  • 5 School of Medicine, Juntendo University, Tokyo 1138421, Japan.
  • 6 Department of Gastroenterology and Hepatology, Graduate School of Medical and Dental Science, Institute of Science Tokyo (Science Tokyo), Tokyo 1138519, Japan; Division of Hepatic Medical Science, Graduate School of Medical and Dental Science, Institute of Science Tokyo (Science Tokyo), Tokyo 1138519, Japan. Electronic address: asahina.gast@tmd.ac.jp.
PMID: 40367952 DOI: 10.1016/j.celrep.2025.115675
Abstract

Human induced pluripotent stem cells (iPSCs) can be differentiated into hepatocyte-like cells (iPS-Heps); however, maintaining the long-term proliferation and hepatic characteristics of iPS-Heps remains a challenge. In this study, we aimed to develop a human iPSC-derived hepatic Organoid (iHO) culture system that effectively retains hepatic characteristics long term. Our original culture strategy, using bile acids and their receptor (farnesoid X receptor [FXR]) agonists, yielded human iHOs capable of long-term culture with a distinctive "grape-like" structure. Comprehensive analysis showed that these iHOs maintained hepatocyte-like phenotypes, even after multiple passages, whose gene expression profiles were consistent with those of fetal hepatocytes. In addition, the overexpression of small heterodimer partner (SHP), a downstream gene of FXR, in iHOs negatively regulated genes related to the intestine and cholangiocytes. Our data demonstrated that bile acid-FXR signaling promotes both the hepatic characteristics and proliferative potential of iHOs, offering promising potential for future applications in regenerative medicine and as a disease model.

Keywords

CP: Stem cell research; NR0B2; NR1H4; bile canaliculi; fetal hepatocytes; hepatitis C virus; hepatocyte function; liver organoid; pluripotent stem cells; proliferation.

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