Reference : Novel human hepatic organoid model enables testing of drug-induced liver fibrosis in ...
Scientific journals : Article
Life sciences : Biochemistry, biophysics & molecular biology
Novel human hepatic organoid model enables testing of drug-induced liver fibrosis in vitro.
Leite, Sofia B. [> >]
Roosens, Tiffany [> >]
El Taghdouini, Adil [> >]
Mannaerts, Inge [> >]
Smout, Ayla J. [> >]
Najimi, Mustapha [> >]
Sokal, Etienne [> >]
Noor, Fozia mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > > ; Saarland University > Biochemical Engineering]
Chesne, Christophe [> >]
van Grunsven, Leo A. [> >]
Yes (verified by ORBilu)
[en] Cell Line ; Humans ; Liver/pathology ; Liver Cirrhosis/chemically induced ; Models, Biological ; APAP ; Allyl alcohol ; DILI ; HepaRG ; Hepatic stellate cell ; Hepatocyte ; In vitro ; Liver fibrosis ; Methotrexate ; Organoid
[en] 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.
Copyright (c) 2015 Elsevier Ltd. All rights reserved.

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