期刊
BIOMATERIALS
卷 78, 期 -, 页码 1-10出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2015.11.026
关键词
Organoid; Liver fibrosis; DILI; In vitro; Hepatic stellate cell; Hepatocyte; HepaRG; APAP; Methotrexate; Allyl alcohol
资金
- Institute for the Promotion of Innovation through Science and Technology in Flanders (IWT-Vlaanderen) [SB/13170, SB/111008]
- Fund of Scientific Research Flanders FWO-V [12N5415N LV]
- HeMiBio consortium - European Commission
- Cosmetics Europe as part of the SEURAT-1 cluster [HEALTH-F5-2010-266777]
- IWT project HILIM-3D [SBO 140045]
Current models for in vitro fibrosis consist of simple mono-layer cultures of rodent hepatic stellate cells (HSC), ignoring the role of hepatocyte injury. We aimed to develop a method allowing the detection of hepatocyte-mediated and drug-induced liver fibrosis. We used HepaRG (Hep) and primary human HSCs cultured as 3D spheroids in 96-well plates. These resulting scaffold-free organoids were characterized for CYP induction, albumin secretion, and hepatocyte and HSC-specific gene expression by qPCR. The metabolic competence of the organoid over 21 days allows activation of HSCs in the organoid in a drug and hepatocyte-dependent manner. After a single dose or repeated exposure for 14 days to the pro fibrotic compounds Allyl alcohol and Methotrexate, hepatic organoids display fibrotic features such as HSC activation, collagen secretion and deposition. Acetaminophen was identified by these organoids as an inducer of hepatotoxic-mediated HSC activation which was confirmed in vivo in mice. This novel hepatic organoid culture model is the first that can detect hepatocyte-dependent and compound induced HSC activation, thereby representing an important step forward towards in vitro compound testing for drug-induced liver fibrosis. (C) 2015 Elsevier Ltd. All rights reserved.
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