title: Multi-cell type human liver microtissues for hepatotoxicity testing.
abstract: Current 2-dimensional hepatic model systems often fail to predict chemically induced hepatotoxicity due to the loss of a hepatocyte-specific phenotype in culture. For more predictive in vitro models, hepatocytes have to be maintained in a 3-dimensional environment that allows for polarization and cell-cell contacts. Preferably, the model will reflect an in vivo-like multi-cell type environment necessary for liver-like responses. Here, we report the characterization of a multi-cell type microtissue model, generated from primary human hepatocytes and liver-derived non-parenchymal cells. Liver microtissues were stable and functional for 5 weeks in culture enabling, for example, long-term toxicity testing of acetaminophen and diclofenac. In addition, Kupffer cells were responsive to inflammatory stimuli such as LPS demonstrating the possibility to detect inflammation-mediated toxicity as exemplified by the drug trovafloxacin. Herewith, we present a novel 3D liver model for routine testing in 96-well format capable of reducing the risk of unwanted toxic effects in the clinic.
authors.affiliation: InSphero AG, Technoparkstrasse 1, 8005 Zurich, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Messner
authors.forename: I
authors.initials: I
authors.lastname: Agarkova
authors.forename: W
authors.initials: W
authors.lastname: Moritz
authors.forename: J M
authors.initials: JM
authors.lastname: Kelm
mesh_terms: D024841:Fluoroquinolones / Q000633:toxicity; D022781:Hepatocytes / Q000166:cytology* / Q000187:drug effects*; D006801:Humans; D007728:Kupffer Cells / Q000187:drug effects; D008070:Lipopolysaccharides / Q000494:pharmacology; D009287:Naphthyridines / Q000633:toxicity; D046509:Tissue Culture Techniques; D018675:Toxicity Tests / Q000379:methods*
chemical_list: D024841:Fluoroquinolones; D008070:Lipopolysaccharides; D009287:Naphthyridines; C080163:trovafloxacin