Integration of Kupffer cells into human iPSC-derived liver organoids for modeling liver dysfunction in sepsis
Yang Li,
Yunzhong Nie,
Xia Yang,
Yang Liu,
Xiaoshan Deng,
Yoshihito Hayashi,
Riana Plummer,
Qinglin Li,
Na Luo,
Toshiharu Kasai,
Takashi Okumura,
Yu Kamishibahara,
Takemasa Komoto,
Takuya Ohkuma,
Satoshi Okamoto,
Yumiko Isobe,
Kiyoshi Yamaguchi,
Yoichi Furukawa,
Hideki Taniguchi
Affiliations
Yang Li
Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Minato, Tokyo 108-8639, Japan; Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Minato, Tokyo 108-8639, Japan
Yunzhong Nie
Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Minato, Tokyo 108-8639, Japan; Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Minato, Tokyo 108-8639, Japan; Advanced Medical Research Center, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan; Corresponding author
Xia Yang
Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Minato, Tokyo 108-8639, Japan; Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Minato, Tokyo 108-8639, Japan
Yang Liu
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Xiaoshan Deng
Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Minato, Tokyo 108-8639, Japan; Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Minato, Tokyo 108-8639, Japan
Yoshihito Hayashi
Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Minato, Tokyo 108-8639, Japan; Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Minato, Tokyo 108-8639, Japan
Riana Plummer
Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Minato, Tokyo 108-8639, Japan; Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Minato, Tokyo 108-8639, Japan
Qinglin Li
Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Minato, Tokyo 108-8639, Japan; Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Minato, Tokyo 108-8639, Japan
Na Luo
Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Minato, Tokyo 108-8639, Japan; Department of Pathology, Immunology and Microbiology, Graduate School of Medicine, The University of Tokyo, Minato, Tokyo 108-8639, Japan
Toshiharu Kasai
Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Minato, Tokyo 108-8639, Japan
Takashi Okumura
Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Minato, Tokyo 108-8639, Japan
Yu Kamishibahara
Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Minato, Tokyo 108-8639, Japan
Takemasa Komoto
Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Minato, Tokyo 108-8639, Japan
Takuya Ohkuma
Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Minato, Tokyo 108-8639, Japan
Satoshi Okamoto
Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Minato, Tokyo 108-8639, Japan
Yumiko Isobe
Division of Clinical Genome Research, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Minato, Tokyo 108-8639, Japan
Kiyoshi Yamaguchi
Division of Clinical Genome Research, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Minato, Tokyo 108-8639, Japan
Yoichi Furukawa
Division of Clinical Genome Research, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Minato, Tokyo 108-8639, Japan
Hideki Taniguchi
Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Minato, Tokyo 108-8639, Japan; Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Minato, Tokyo 108-8639, Japan; Advanced Medical Research Center, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan; Corresponding author
Summary: Maximizing the potential of human liver organoids (LOs) for modeling human septic liver requires the integration of innate immune cells, particularly resident macrophage Kupffer cells. In this study, we present a strategy to generate LOs containing Kupffer cells (KuLOs) by recapitulating fetal liver hematopoiesis using human induced pluripotent stem cell (hiPSC)-derived erythro-myeloid progenitors (EMPs), the origin of tissue-resident macrophages, and hiPSC-derived LOs. Remarkably, LOs actively promote EMP hematopoiesis toward myeloid and erythroid lineages. Moreover, supplementing with macrophage colony-stimulating factor (M-CSF) proves crucial in sustaining the hematopoietic population during the establishment of KuLOs. Exposing KuLOs to sepsis-like endotoxins leads to significant organoid dysfunction that closely resembles the pathological characteristics of the human septic liver. Furthermore, we observe a notable functional recovery in KuLOs upon endotoxin elimination, which is accelerated by using Toll-like receptor-4-directed endotoxin antagonist. Our study represents a comprehensive framework for integrating hematopoietic cells into organoids, facilitating in-depth investigations into inflammation-mediated liver pathologies.
