title: Stem cell-derived models to improve mechanistic understanding and prediction of human drug-induced liver injury.
abstract: Current preclinical drug testing does not predict some forms of adverse drug reactions in humans. Efforts at improving predictability of drug-induced tissue injury in humans include using stem cell technology to generate human cells for screening for adverse effects of drugs in humans. The advent of induced pluripotent stem cells means that it may ultimately be possible to develop personalized toxicology to determine interindividual susceptibility to adverse drug reactions. However, the complexity of idiosyncratic drug-induced liver injury means that no current single-cell model, whether of primary liver tissue origin, from liver cell lines, or derived from stem cells, adequately emulates what is believed to occur during human drug-induced liver injury. Nevertheless, a single-cell model of a human hepatocyte which emulates key features of a hepatocyte is likely to be valuable in assessing potential chemical risk; furthermore, understanding how to generate a relevant hepatocyte will also be critical to efforts to build complex multicellular models of the liver. Currently, hepatocyte-like cells differentiated from stem cells still fall short of recapitulating the full mature hepatocellular phenotype. Therefore, we convened a number of experts from the areas of preclinical and clinical hepatotoxicity and safety assessment, from industry, academia, and regulatory bodies, to specifically explore the application of stem cells in hepatotoxicity safety assessment and to make recommendations for the way forward. In this short review, we particularly discuss the importance of benchmarking stem cell-derived hepatocyte-like cells to their terminally differentiated human counterparts using defined phenotyping, to make sure the cells are relevant and comparable between labs, and outline why this process is essential before the cells are introduced into chemical safety assessment. (Hepatology 2017;65:710-721).
authors: MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.
authors: Christopher
authors: C
authors: Goldring
authors: MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.
authors: Daniel J
authors: DJ
authors: Antoine
authors: Stem Cells for Safer Medicines, London, UK.
authors: Frank
authors: F
authors: Bonner
authors: European Partnership for Alternative Approaches to Animal Testing, Brussels, Belgium.
authors: Jonathan
authors: J
authors: Crozier
authors: Department of Stem Cell Biology, Centre for Biomolecular Sciences, University of Nottingham, Nottingham, UK.
authors: Chris
authors: C
authors: Denning
authors: Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI.
authors: Robert J
authors: RJ
authors: Fontana
authors: Centre for Endocrinology & Diabetes, University of Manchester, and Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
authors: Neil A
authors: NA
authors: Hanley
authors: MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK.
authors: David C
authors: DC
authors: Hay
authors: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors: Magnus
authors: M
authors: Ingelman-Sundberg
authors: R&D, In Vitro Biology, Orion Pharma, Espoo, Finland.
authors: Satu
authors: S
authors: Juhila
authors: MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.
authors: Neil
authors: N
authors: Kitteringham
authors: Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal.
authors: Beatriz
authors: B
authors: Silva-Lima
authors: MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.
authors: Alan
authors: A
authors: Norris
authors: MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.
authors: Chris
authors: C
authors: Pridgeon
authors: MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK.
authors: James A
authors: JA
authors: Ross
authors: MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.
authors: Rowena Sison
authors: RS
authors: Young
authors: National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD.
authors: Danilo
authors: D
authors: Tagle
authors: Abbvie Global Pharmaceutical Research and Development, North Chicago, IL.
authors: Belen
authors: B
authors: Tornesi
authors: Faculty of Science, Leiden Academic Centre for Drug Research, Gorlaeus Laboratories, University of Leiden, Leiden, The Netherlands.
authors: Bob
authors: B
authors: van de Water
authors: Institut de Recherches Internationales Servier, Suresnes, France.
authors: Richard J
authors: RJ
authors: Weaver
authors: MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.
authors: Fang
authors: F
authors: Zhang
authors: MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.
authors: B Kevin
authors: BK
authors: Park
mesh_terms: D002478:Cells, Cultured / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000175:diagnosis*; D064420:Drug-Related Side Effects and Adverse Reactions / Q000175:diagnosis*; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D039904:Pluripotent Stem Cells / Q000187:drug effects* / Q000378:metabolism; D011237:Predictive Value of Tests; D012680:Sensitivity and Specificity; D018675:Toxicity Tests