Scalable manufacturing of human iPSC-derived functional liver organoids for acute liver failure treatment.
7 affiliations
- 1Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Minato, Tokyo, Japan.
- 2Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Minato, Tokyo, Japan.
- 3Advanced Medical Research Center, Graduate School of Medicine, Yokohama City University, Yokohama, Kanagawa, Japan.
- 4Division of Immunology, Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, PR China.
- 5Department of Pathology, Immunology and Microbiology, Graduate School of Medicine, The University of Tokyo, Minato, Tokyo, Japan.
- 6Department of Clinical Pharmaceutics, Nihon Pharmaceutical University, Saitama, Japan.
- 7Division of Clinical Genome Research, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Abstract
Rationale
Acute liver failure (ALF) is a life-threatening disease associated with high mortality rates. Human induced pluripotent stem cell (hiPSC)-derived liver organoids (LOs) hold considerable promise as cell-based bridging therapies for ALF. However, the scalable production of highly consistent and mature LOs remains a major barrier to their clinical translation. In this study, we aimed to establish a scalable manufacturing platform for the reproducible generation of highly uniform and functionally mature liver organoids.Methods
We generated LOs from hiPSCs and established a differentiation platform designed for high-density LO production using low-attachment culture vessels combined with spin culture. The hepatic functions of conventionally cultured LOs (Con-LOs) and spin-cultured LOs (Spin-LOs) were evaluated using qPCR, albumin secretion assay, and detoxification assay. The molecular effects of spin culture on LO development were further analyzed using RNA sequencing. Furthermore, microwell bags were introduced to enhance manufacturing scalability. Finally, the LOs were transplanted into the intraperitoneal spaces of acetaminophen (APAP)-induced ALF mice to assess their therapeutic potential.Results
Compared to Con-LOs, Spin-LOs exhibited markedly elevated hepatic gene expression and significantly enhanced liver-specific functions. Mechanistically, spin culture enabled a metabolic transition from glycolysis to oxidative phosphorylation, thereby driving further functional maturation of liver organoids, resulting in improved synthetic, metabolic, and detoxification capacities. Moreover, integrating a microwell bag-based LO formation system with spin-culture-driven LO differentiation further promoted the efficiency and scalability of functional LO manufacturing. Importantly, these LOs provided short-term metabolic support following intraperitoneal transplantation into immunocompetent mice and significantly ameliorated APAP-induced liver failure.Conclusion
This study establishes a scalable manufacturing platform for the reproducible generation of highly uniform and functionally mature liver organoids. Our findings provide an evidence-supported foundation for their future clinical translation as cell-based bridging therapies for ALF.
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BibTeX
@article{deng2026scalable,
title = {{Scalable manufacturing of human iPSC-derived functional liver organoids for acute liver failure treatment.}},
author = {Xiaoshan Deng and Yunzhong Nie and Yoshihito Hayashi and Na Luo and Yang Li and Riana Plummer and Qinglin Li and Toshiharu Kasai and Takashi Okumura and Yu Kamishibahara and Takemasa Komoto and Takuya Ohkuma and Yasuhiro Yamada and Yumiko Isobe and Kiyoshi Yamaguchi and Satoshi Okamoto and Yasuharu Ueno and Naoki Tanimizu and Yoichi Furukawa and Hideki Taniguchi},
journal = {Theranostics},
year = {2026},
month = sep,
doi = {10.7150/thno.137714},
url = {https://europepmc.org/article/MED/42909286},
note = {CC BY},
}
RIS
TY - JOUR
TI - Scalable manufacturing of human iPSC-derived functional liver organoids for acute liver failure treatment.
AU - Xiaoshan Deng
AU - Yunzhong Nie
AU - Yoshihito Hayashi
AU - Na Luo
AU - Yang Li
AU - Riana Plummer
AU - Qinglin Li
AU - Toshiharu Kasai
AU - Takashi Okumura
AU - Yu Kamishibahara
AU - Takemasa Komoto
AU - Takuya Ohkuma
AU - Yasuhiro Yamada
AU - Yumiko Isobe
AU - Kiyoshi Yamaguchi
AU - Satoshi Okamoto
AU - Yasuharu Ueno
AU - Naoki Tanimizu
AU - Yoichi Furukawa
AU - Hideki Taniguchi
PY - 2026
DA - 2026/09/18
JO - Theranostics
DO - 10.7150/thno.137714
UR - https://europepmc.org/article/MED/42909286
AB - Rationale Acute liver failure (ALF) is a life-threatening disease associated with high mortality rates. Human induced pluripotent stem cell (hiPSC)-derived liver organoids (LOs) hold considerable promise as cell-based bridging therapies for ALF. However, the scalable production of highly consistent and mature LOs remains a major barrier to their clinical translation. In this study, we aimed to establish a scalable manufacturing platform for the reproducible generation of highly uniform and functionally mature liver organoids.Methods We generated LOs from hiPSCs and established a differentiation platform designed for high-density LO production using low-attachment culture vessels combined with spin culture. The hepatic functions of conventionally cultured LOs (Con-LOs) and spin-cultured LOs (Spin-LOs) were evaluated using qPCR, albumin secretion assay, and detoxification assay. The molecular effects of spin culture on LO development were further analyzed using RNA sequencing. Furthermore, microwell bags were introduced to enhance manufacturing scalability. Finally, the LOs were transplanted into the intraperitoneal spaces of acetaminophen (APAP)-induced ALF mice to assess their therapeutic potential.Results Compared to Con-LOs, Spin-LOs exhibited markedly elevated hepatic gene expression and significantly enhanced liver-specific functions. Mechanistically, spin culture enabled a metabolic transition from glycolysis to oxidative phosphorylation, thereby driving further functional maturation of liver organoids, resulting in improved synthetic, metabolic, and detoxification capacities. Moreover, integrating a microwell bag-based LO formation system with spin-culture-driven LO differentiation further promoted the efficiency and scalability of functional LO manufacturing. Importantly, these LOs provided short-term metabolic support following intraperitoneal transplantation into immunocompetent mice and significantly ameliorated APAP-induced liver failure.Conclusion This study establishes a scalable manufacturing platform for the reproducible generation of highly uniform and functionally mature liver organoids. Our findings provide an evidence-supported foundation for their future clinical translation as cell-based bridging therapies for ALF.
SN - 1838-7640
ER -