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

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 pri...

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Bibliographic Details
Published in:Biomaterials 2016-02, Vol.78, p.1-10
Main Authors: Leite, Sofia B, Roosens, Tiffany, El Taghdouini, Adil, Mannaerts, Inge, Smout, Ayla J, Najimi, Mustapha, Sokal, Etienne, Noor, Fozia, Chesne, Christophe, van Grunsven, Leo A
Format: Article
Language:English
Subjects:
Activation
Advanced Basic Science
Allyl alcohol
APAP
Biomedical materials
Cell Line
Culture
Dentistry
DILI
Fibrosis
HepaRG
Hepatic stellate cell
Hepatocyte
Humans
In vitro testing
In vitro
Liver
Liver - pathology
Liver Cirrhosis - chemically induced
Liver fibrosis
Methotrexate
Models, Biological
Organoid
Secretions
Surgical implants
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Summary: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.
ISSN:0142-9612
1878-5905
DOI:10.1016/j.biomaterials.2015.11.026