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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.

Author information

1
Liver Cell Biology Laboratory, Vrije Universiteit Brussel (VUB), Belgium. Electronic address: sofia.batista.leite@vub.ac.be.
2
Liver Cell Biology Laboratory, Vrije Universiteit Brussel (VUB), Belgium.
3
Laboratory of Pediatric Hepatology and Cell Therapy, Institute of Experimental and Clinical Research (IREC), Université Catholique de Louvain (UCL), Belgium.
4
Biochemical Engineering Institute, Saarland University, Germany.
5
Biopredic International, France.
6
Liver Cell Biology Laboratory, Vrije Universiteit Brussel (VUB), Belgium. Electronic address: lvgrunsv@vub.ac.be.

Abstract

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.

KEYWORDS:

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

[Indexed for MEDLINE]

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