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Hepatology. 2017 Feb;65(2):710-721. doi: 10.1002/hep.28886. Epub 2016 Nov 30.

Stem cell-derived models to improve mechanistic understanding and prediction of human drug-induced liver injury.

Author information

1
MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.
2
Stem Cells for Safer Medicines, London, UK.
3
European Partnership for Alternative Approaches to Animal Testing, Brussels, Belgium.
4
Department of Stem Cell Biology, Centre for Biomolecular Sciences, University of Nottingham, Nottingham, UK.
5
Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI.
6
Centre for Endocrinology & Diabetes, University of Manchester, and Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
7
MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK.
8
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
9
R&D, In Vitro Biology, Orion Pharma, Espoo, Finland.
10
Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal.
11
National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD.
12
Abbvie Global Pharmaceutical Research and Development, North Chicago, IL.
13
Faculty of Science, Leiden Academic Centre for Drug Research, Gorlaeus Laboratories, University of Leiden, Leiden, The Netherlands.
14
Institut de Recherches Internationales Servier, Suresnes, France.

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).

PMID:
27775817
PMCID:
PMC5266558
DOI:
10.1002/hep.28886
[Indexed for MEDLINE]
Free PMC Article

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