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Biomaterials. 2016 Feb;78:1-10. doi: 10.1016/j.biomaterials.2015.11.026. Epub 2015 Nov 17.

Novel human hepatic organoid model enables testing of drug-induced liver fibrosis in vitro.

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Liver Cell Biology Laboratory, Vrije Universiteit Brussel (VUB), Belgium. Electronic address:
Liver Cell Biology Laboratory, Vrije Universiteit Brussel (VUB), Belgium.
Laboratory of Pediatric Hepatology and Cell Therapy, Institute of Experimental and Clinical Research (IREC), Université Catholique de Louvain (UCL), Belgium.
Biochemical Engineering Institute, Saarland University, Germany.
Biopredic International, France.
Liver Cell Biology Laboratory, Vrije Universiteit Brussel (VUB), Belgium. Electronic address:


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.


APAP; Allyl alcohol; DILI; HepaRG; Hepatic stellate cell; Hepatocyte; In vitro; Liver fibrosis; Methotrexate; Organoid

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