title: High Content Analysis of Human Pluripotent Stem Cell Derived Hepatocytes Reveals Drug Induced Steatosis and Phospholipidosis.
abstract: Hepatotoxicity is one of the most cited reasons for withdrawal of approved drugs from the market. The use of nonclinically relevant in vitro and in vivo testing systems contributes to the high attrition rates. Recent advances in differentiating human induced pluripotent stem cells (hiPSCs) into pure cultures of hepatocyte-like cells expressing functional drug metabolizing enzymes open up possibilities for novel, more relevant human cell based toxicity models. The present study aimed to investigate the use of hiPSC derived hepatocytes for conducting mechanistic toxicity testing by image based high content analysis (HCA). The hiPSC derived hepatocytes were exposed to drugs known to cause hepatotoxicity through steatosis and phospholipidosis, measuring several endpoints representing different mechanisms involved in drug induced hepatotoxicity. The hiPSC derived hepatocytes were benchmarked to the HepG2 cell line and generated robust HCA data with low imprecision between plates and batches. The different parameters measured were detected at subcytotoxic concentrations and the order of which the compounds were categorized (as severe, moderate, mild, or nontoxic) based on the degree of injury at isomolar concentration corresponded to previously published data. Taken together, the present study shows how hiPSC derived hepatocytes can be used as a platform for screening drug induced hepatotoxicity by HCA.
authors.affiliation: Takara Bio Europe AB (Former Cellectis AB/Cellartis AB), Arvid Wallgrens Backe 20, 413 46 Göteborg, Sweden; Novo Nordisk A/S, Stem Cell Development, 2880 Bagsværd, Denmark.
authors.forename: Arvind
authors.initials: A
authors.lastname: Pradip
authors.affiliation: Takara Bio Europe AB (Former Cellectis AB/Cellartis AB), Arvid Wallgrens Backe 20, 413 46 Göteborg, Sweden; Horizon Discovery Ltd, 7100 Cambridge Research Park, Waterbeach, Cambridge CB25 9TL, UK.
authors.forename: Daniella
authors.initials: D
authors.lastname: Steel
authors.affiliation: Takara Bio Europe AB (Former Cellectis AB/Cellartis AB), Arvid Wallgrens Backe 20, 413 46 Göteborg, Sweden.
authors.forename: Susanna
authors.initials: S
authors.lastname: Jacobsson
authors.affiliation: Takara Bio Europe AB (Former Cellectis AB/Cellartis AB), Arvid Wallgrens Backe 20, 413 46 Göteborg, Sweden; Systems Biology Research Center, School of Bioscience, University of Skövde, 541 28 Skövde, Sweden.
authors.forename: Gustav
authors.initials: G
authors.lastname: Holmgren
authors.affiliation: Department of Physiology and Pharmacology, Section of Pharmacogenetics, Karolinska Institutet, 171 77 Stockholm, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Ingelman-Sundberg
authors.affiliation: Takara Bio Europe AB (Former Cellectis AB/Cellartis AB), Arvid Wallgrens Backe 20, 413 46 Göteborg, Sweden; Systems Biology Research Center, School of Bioscience, University of Skövde, 541 28 Skövde, Sweden; AstraZeneca R&D, GMD CVMD GMed, 431 83 Mölndal, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Sartipy
authors.affiliation: Takara Bio Europe AB (Former Cellectis AB/Cellartis AB), Arvid Wallgrens Backe 20, 413 46 Göteborg, Sweden; NovaHep AB, Arvid Wallgrens Backe 20, 413 46 Göteborg, Sweden.
authors.forename: Petter
authors.initials: P
authors.lastname: Björquist
authors.affiliation: Department of Physiology and Pharmacology, Section of Pharmacogenetics, Karolinska Institutet, 171 77 Stockholm, Sweden.
authors.forename: Inger
authors.initials: I
authors.lastname: Johansson
authors.affiliation: Takara Bio Europe AB (Former Cellectis AB/Cellartis AB), Arvid Wallgrens Backe 20, 413 46 Göteborg, Sweden.
authors.forename: Josefina
authors.initials: J
authors.lastname: Edsbagge