肝损伤
细胞生物学
胆汁淤积
生物
炎症
巨噬细胞
川地68
库普弗电池
诱导多能干细胞
肝细胞
肝细胞学
免疫学
癌症研究
病理
胚胎干细胞
体外
医学
药理学
免疫组织化学
内分泌学
生物化学
基因
肝脏代谢
作者
Farah Tasnim,Jiangwa Xing,Xiaozhong Huang,Shupei Mo,Xiaona Wang,Min‐Han Tan,Hanry Yu
出处
期刊:Biomaterials
[Elsevier]
日期:2019-02-01
卷期号:192: 377-391
被引量:66
标识
DOI:10.1016/j.biomaterials.2018.11.016
摘要
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.
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