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Biomaterials. 2019 Feb;192:377-391. doi: 10.1016/j.biomaterials.2018.11.016. Epub 2018 Nov 16.

Generation of mature kupffer cells from human induced pluripotent stem cells.

Author information

1
Institute of Bioengineering and Nanotechnology, #04-01, 31 Biopolis Way, The Nanos, Singapore 138669, Singapore.
2
Institute of Bioengineering and Nanotechnology, #04-01, 31 Biopolis Way, The Nanos, Singapore 138669, Singapore; Department of Physiology, Yong Loo Lin School of Medicine, National University Health System, MD9-03-03, 2 Medical Drive, Singapore 117597, Singapore.
3
Institute of Bioengineering and Nanotechnology, #04-01, 31 Biopolis Way, The Nanos, Singapore 138669, Singapore; Department of Physiology, Yong Loo Lin School of Medicine, National University Health System, MD9-03-03, 2 Medical Drive, Singapore 117597, Singapore; NUS Graduate School for Integrative Sciences and Engineering, Centre for Life Sciences, #05-01, 28 Medical Drive, Singapore 117576, Singapore; Mechanobiology Institute, T-Labs, #05-01, 5A Engineering Drive 1, Singapore 117411, Singapore; Singapore-MIT Alliance for Research and Technology, 3 Science Drive 2, S16-05-08, Singapore 117543, Singapore; Department of Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Ave., Cambridge, MA 02139, USA; Gastroenterology Department, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. Electronic address: hyu@ibn.a-star.edu.sg.

Abstract

Liver macrophages, Kupffer cells (KCs), play a critical role in drug-induced liver injury (DILI) and liver diseases including cholestasis, liver fibrosis and viral hepatitis. Application of KCs in in vitro models of DILI and liver diseases is hindered due to limited source of human KCs. In vivo, KCs originate from MYB-independent macrophage progenitors, which differentiate into liver-specific macrophages in response to hepatic cues in the liver. Here, we recapitulated KCs ontogeny by differentiation of MYB-independent iPSCs to macrophage-precursors and exposing them to hepatic cues to generate iPSC-derived KCs (iKCs). iKCs expressed macrophage markers (CD11/CD14/CD68/CD163/CD32) at 0.3-5 folds of primary adult human KCs (pKCs) and KC-specific CLEC-4F, ID1 and ID3. iKCs phagocytosed and secreted IL-6 and TNFα upon stimulation at levels similar to pKCs but different from non-liver macrophages. Hepatocyte-iKCs co-culture model was more sensitive in detecting hepatotoxicity induced by inflammation-associated drugs, Acetaminophen and Trovafloxacin, and Chlorpromazine-induced cholestasis when compared to hepatocytes alone. Overall, iKCs were mature, liver-specific and functional. Furthermore, donor-matched iKCs and iPSC-hepatocyte co-culture exhibited minimal non-specific background response compared to donor-mismatched counterpart. iKCs offer a mature renewable human cell source for liver-specific macrophages, useful in developing in vitro model to study DILI and liver diseases such as cholestasis.

KEYWORDS:

Cholestasis; Hepatocyte Co-culture; Hepatotoxicity; Kupffer cell; Liver macrophage; Stem cell-derived

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