Novel human hepatic organoid model enables testing of drug-induced liver fibrosis in vitro. (February 2016)

• Record Type: Journal Article
• 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.
• Is Part Of: Biomaterials. Volume 78(2016)
• Page Start: 1
• Page End: 10
• Publication Date: 2016-02
• Subjects: Organoid -- Liver fibrosis -- DILI -- In vitro -- Hepatic stellate cell -- Hepatocyte -- HepaRG -- APAP -- Methotrexate -- Allyl alcohol; HSC Hepatic Stellate Cell -- Hep HepaRG -- 3D three-dimensional -- Hep/HSC Hep and HSC co-culture -- hepatic organoid PDGFR-β -- Platelet derived growth factor receptor β CYP -- cytochrome P450 RIF -- Rifampicin BNF -- β-Naphtoflavone PB -- Phenobarbital MRP2 -- Multidrug resistance-associated protein 2 CMFDA -- 5-chloromethylfluorescein diacetate 2D -- two-dimensional mRNA -- messenger Ribonucleic Acid dCT -- deltaCT gene expression relative to house-keeping gene -- TGFβ Transforming Growth Factor β -- LPS Lipopolysaccharide -- APAP Acetaminophen -- ATP Adenosine Triphosphate -- αSMA alpha Smooth Muscle Actin -- HDAC Histone deacetylase -- CK Cytokine mixture -- VPA Valproic Acid -- CCl4 Carbon Tetrachloride -- EC50 Half Maximal Effective Concentration -- OCR Oxygen consumption rate -- ECAR Extracellular acidification -- Oligo Oligomycin -- FCCP Trifluoromethoxy carbonylcyanide phenylhydrazone -- A + R Antimycin A and Rotenone -- MTX Methotrexate -- ALT Alanine Aminotransferase -- AOP Adverse Outcome Pathway -- DILI Drug-induced liver injury; Biomedical materials -- Periodicals; Biocompatible Materials -- Periodicals; Biomatériaux -- Périodiques; 610.28
• DOI: 10.1016/j.biomaterials.2015.11.026
• Languages: English
• ISSNs: 0142-9612

Abstract

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.