Cell Reports (Mar 2024)

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

Journal volume & issue
Vol. 43, no. 3
p. 113918

Abstract

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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.

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