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

Sofia Batista Leite, Tiffany Roosens, Adil El Taghdouini, Inge Mannaerts, Ayla J Smout, Mustapha Najimi, Etienne Sokal, Fozia Noor, Christophe Chesne, Leo A van Grunsven

Research output: Contribution to journalArticle

103 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1-10
Number of pages10
JournalBIOMATERIALS
Volume78
Early online date17 Nov 2015
DOIs
Publication statusPublished - Feb 2016

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