Placenta-derived factors contribute to human iPSC-liver organoid growth

  • Nat Commun. 2025 Mar 13;16(1):2493. doi: 10.1038/s41467-025-57551-w.
Yoshiki Kuse  1  2 ,  Shinya Matsumoto  1 ,  Syusaku Tsuzuki  1 ,  Erica Carolina  1  3 ,  Takashi Okumura  1 ,  Toshiharu Kasai  1 ,  Soichiro Yamabe  1  3 ,  Kiyoshi Yamaguchi  4 ,  Yoichi Furukawa  4 ,  Tomomi Tadokoro  5 ,  Yasuharu Ueno  1 ,  Takayoshi Oba  1 ,  Naoki Tanimizu  1 ,  Hideki Taniguchi  6  7
Affiliations
  • 1. Division of Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
  • 2. Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan.
  • 3. Graduate School of Frontier Sciences, Computational Biology and Medical Science, Kashiwa, Japan.
  • 4. Division of Clinical Genome Research, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
  • 5. Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, Kanagawa, Japan.
  • 6. Division of Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. [email protected].
  • 7. Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, Kanagawa, Japan. [email protected].
PMID: 40082402 DOI: 10.1038/s41467-025-57551-w
Abstract

Organoids derived from human induced pluripotent stem cells (hiPSC) are potentially applicable for regenerative medicine. However, the applications have been hampered by limited Organoid size and function as a consequence of a lack of progenitor expansion. Here, we report the recapitulation of progenitor expansion in hiPSC-liver organoids based on the analysis of mouse development. Visualization of blood perfusion and oxygen levels in mouse embryos reveals a transient hypoxic environment during hepatoblast expansion, despite active blood flow. During this specific stage, the placenta expresses various growth factors. Human and mouse placenta-liver interaction analysis identifies various placenta-derived factors. Among them, IL1α efficiently induces the growth in hiPSC-liver organoids as well as mouse fetal livers following progenitor expansion under hypoxia. Furthermore, subsequent oxygenation demonstrates that progenitors expanded by IL1α contribute to hiPSC-liver Organoid size and function. Taken together, we demonstrate that treatment with the placenta-derived factor under hypoxia is a crucial human Organoid culture technique that efficiently induces progenitor expansion.

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