Kuse Yoshiki, Matsumoto Shinya, Tsuzuki Syusaku, Carolina Erica, Okumura Takashi, Kasai Toshiharu, Yamabe Soichiro, Yamaguchi Kiyoshi, Furukawa Yoichi, Tadokoro Tomomi, Ueno Yasuharu, Oba Takayoshi, Tanimizu Naoki, Taniguchi Hideki
Division of Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan.
Nat Commun. 2025 Mar 13;16(1):2493. doi: 10.1038/s41467-025-57551-w.
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.
源自人类诱导多能干细胞（hiPSC）的类器官在再生医学中具有潜在的应用价值。然而，由于缺乏祖细胞扩增，类器官的大小和功能有限，这阻碍了其应用。在此，我们基于对小鼠发育的分析，报告了hiPSC-肝脏类器官中祖细胞扩增的重现。对小鼠胚胎中血液灌注和氧气水平的可视化显示，尽管有活跃的血流，但在肝母细胞扩增期间存在短暂的缺氧环境。在这个特定阶段，胎盘表达多种生长因子。人和小鼠胎盘与肝脏相互作用的分析确定了多种源自胎盘的因子。其中，IL1α在缺氧条件下祖细胞扩增后，能有效诱导hiPSC-肝脏类器官以及小鼠胎儿肝脏的生长。此外，随后的氧合作用表明，由IL1α扩增的祖细胞有助于hiPSC-肝脏类器官的大小和功能。综上所述，我们证明在缺氧条件下用源自胎盘的因子进行处理是一种关键的人类类器官培养技术，可有效诱导祖细胞扩增。
