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
  • 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: [email protected].
  • 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: [email protected].
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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