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

Biomaterials. 2016 Feb;78:1-10. doi: 10.1016/j.biomaterials.2015.11.026. Epub 2015 Nov 17.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Humans
  • Liver / pathology*
  • Liver Cirrhosis / chemically induced*
  • Models, Biological*