Integration of Kupffer cells into human iPSC-derived liver organoids for modeling liver dysfunction in sepsis
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 fe...
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| Format: | Article |
| Language: | English |
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Elsevier
2024-03-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124724002468 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Yang Li |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-07T14:02:24Z |
| format | Article |
| id | doaj.art-c85fa5cd49224938abb19488da79baeb |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-03-07T14:02:24Z |
| publishDate | 2024-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-c85fa5cd49224938abb19488da79baeb2024-03-07T05:27:27ZengElsevierCell Reports2211-12472024-03-01433113918Integration of Kupffer cells into human iPSC-derived liver organoids for modeling liver dysfunction in sepsisYang Li0Yunzhong Nie1Xia Yang2Yang Liu3Xiaoshan Deng4Yoshihito Hayashi5Riana Plummer6Qinglin Li7Na Luo8Toshiharu Kasai9Takashi Okumura10Yu Kamishibahara11Takemasa Komoto12Takuya Ohkuma13Satoshi Okamoto14Yumiko Isobe15Kiyoshi Yamaguchi16Yoichi Furukawa17Hideki Taniguchi18Department 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, JapanDepartment 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 authorDepartment 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, JapanDepartment of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USADepartment 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, JapanDepartment 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, JapanDepartment 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, JapanDepartment 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, JapanDivision 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, JapanDivision of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Minato, Tokyo 108-8639, JapanDivision of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Minato, Tokyo 108-8639, JapanDivision of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Minato, Tokyo 108-8639, JapanDivision of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Minato, Tokyo 108-8639, JapanDivision of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Minato, Tokyo 108-8639, JapanDivision of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Minato, Tokyo 108-8639, JapanDivision of Clinical Genome Research, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Minato, Tokyo 108-8639, JapanDivision of Clinical Genome Research, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Minato, Tokyo 108-8639, JapanDivision of Clinical Genome Research, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Minato, Tokyo 108-8639, JapanDepartment 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 authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2211124724002468CP: Stem cell research |
| spellingShingle | 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 Integration of Kupffer cells into human iPSC-derived liver organoids for modeling liver dysfunction in sepsis Cell Reports CP: Stem cell research |
| title | Integration of Kupffer cells into human iPSC-derived liver organoids for modeling liver dysfunction in sepsis |
| title_full | Integration of Kupffer cells into human iPSC-derived liver organoids for modeling liver dysfunction in sepsis |
| title_fullStr | Integration of Kupffer cells into human iPSC-derived liver organoids for modeling liver dysfunction in sepsis |
| title_full_unstemmed | Integration of Kupffer cells into human iPSC-derived liver organoids for modeling liver dysfunction in sepsis |
| title_short | Integration of Kupffer cells into human iPSC-derived liver organoids for modeling liver dysfunction in sepsis |
| title_sort | integration of kupffer cells into human ipsc derived liver organoids for modeling liver dysfunction in sepsis |
| topic | CP: Stem cell research |
| url | http://www.sciencedirect.com/science/article/pii/S2211124724002468 |
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