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Toxicol Sci. 2015 Mar;144(1):173-85. doi: 10.1093/toxsci/kfu269. Epub 2014 Dec 18.

MicroRNA-122: a novel hepatocyte-enriched in vitro marker of drug-induced cellular toxicity.

Author information

1
MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, Sherrington Buildings, Ashton Street, University of Liverpool, Liverpool L69 3GE, UK Stem Cells for Safer Medicines, 7th Floor, Southside, 105 Victoria Street, London SW1E 6QT, UK Faculty of Life Sciences, University of Manchester, Manchester M13 9PL, UK School of Medicine and Dentistry, University of Central Lancashire, Preston PR1 2HE, UK Centre for Endocrinology and Diabetes, Institute of Human Development, Faculty of Medical and Human Sciences, Manchester Academic Health Science Centre, University of Manchester, Manchester M13 9PT, UK Endocrinology Department, Central Manchester University Hospitals NHS Foundation Trust, Oxford Road, Manchester M13 9PT, UK Centre for Regenerative Medicine, Department of Biology and Biochemistry, University of Bath, Bath BA2 7AY, UK, Takara Bio Europe AB (former Cellartis), Arvid Wallgrens Backe 20, 413 46 Göteborg, Sweden, School of Life Sciences, The Systems Biology Research Centre, University of Skövde, Box 408, 541 28 Skövde, Sweden, MRC Centre for Regenerative Medicine, SCRM Building, The University of Edinburgh, Edinburgh Bioquarter, 5 Little France Drive, Edinburgh EH16 4UU, UK, Newcastle University, Institute of Cellular Medicine, The Medical School, Framlington Place, Newcastle upon Tyne NE2 4HH, UK Drug Safety and Metabolism, AstraZeneca R&D, Alderley Park, Cheshire SK10 4TG, UK and North Western Hepatobiliary Unit, Aintree University Hospital NHS Foundation Trust, Longmoor Lane, Liverpool L9 7AL, UK.
2
MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, Sherrington Buildings, Ashton Street, University of Liverpool, Liverpool L69 3GE, UK Stem Cells for Safer Medicines, 7th Floor, Southside, 105 Victoria Street, London SW1E 6QT, UK Faculty of Life Sciences, University of Manchester, Manchester M13 9PL, UK School of Medicine and Dentistry, University of Central Lancashire, Preston PR1 2HE, UK Centre for Endocrinology and Diabetes, Institute of Human Development, Faculty of Medical and Human Sciences, Manchester Academic Health Science Centre, University of Manchester, Manchester M13 9PT, UK Endocrinology Department, Central Manchester University Hospitals NHS Foundation Trust, Oxford Road, Manchester M13 9PT, UK Centre for Regenerative Medicine, Department of Biology and Biochemistry, University of Bath, Bath BA2 7AY, UK, Takara Bio Europe AB (former Cellartis), Arvid Wallgrens Backe 20, 413 46 Göteborg, Sweden, School of Life Sciences, The Systems Biology Research Centre, University of Skövde, Box 408, 541 28 Skövde, Sweden, MRC Centre for Regenerative Medicine, SCRM Building, The University of Edinburgh, Edinburgh Bioquarter, 5 Little France Drive, Edinburgh EH16 4UU, UK, Newcastle University, Institute of Cellular Medicine, The Medical School, Framlington Place, Newcastle upon Tyne NE2 4HH, UK Drug Safety and Metabolism, AstraZeneca R&D, Alderley Park, Cheshire SK10 4TG, UK and North Western Hepatobiliary Unit, Aintree University Hospital NHS Foundation Trust, Longmoor Lane, Liverpool L9 7AL, UK MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, Sherrington Buildings, Ashton Street, University of Liverpool, Liverpool L69 3GE, UK Stem Cells for Safer Medicines, 7th Floor, Southside, 105 Victoria Street, London SW1E 6QT, UK Faculty of Life Sciences, University of Manchester, Manchester M13 9PL, UK School of Medicine and Dentistry, University of Central Lancashire, Preston PR1 2HE, UK Centre fo

Abstract

Emerging hepatic models for the study of drug-induced toxicity include pluripotent stem cell-derived hepatocyte-like cells (HLCs) and complex hepatocyte-non-parenchymal cellular coculture to mimic the complex multicellular interactions that recapitulate the niche environment in the human liver. However, a specific marker of hepatocyte perturbation, required to discriminate hepatocyte damage from non-specific cellular toxicity contributed by non-hepatocyte cell types or immature differentiated cells is currently lacking, as the cytotoxicity assays routinely used in in vitro toxicology research depend on intracellular molecules which are ubiquitously present in all eukaryotic cell types. In this study, we demonstrate that microRNA-122 (miR-122) detection in cell culture media can be used as a hepatocyte-enriched in vitro marker of drug-induced toxicity in homogeneous cultures of hepatic cells, and a cell-specific marker of toxicity of hepatic cells in heterogeneous cultures such as HLCs generated from various differentiation protocols and pluripotent stem cell lines, where conventional cytotoxicity assays using generic cellular markers may not be appropriate. We show that the sensitivity of the miR-122 cytotoxicity assay is similar to conventional assays that measure lactate dehydrogenase activity and intracellular adenosine triphosphate when applied in hepatic models with high levels of intracellular miR-122, and can be multiplexed with other assays. MiR-122 as a biomarker also has the potential to bridge results in in vitro experiments to in vivo animal models and human samples using the same assay, and to link findings from clinical studies in determining the relevance of in vitro models being developed for the study of drug-induced liver injury.

KEYWORDS:

bridging biomarker; cell-specific biomarker; cytotoxicity; drug-induced liver injury; hepatocytes; in vitro model; microRNA

PMID:
25527335
PMCID:
PMC4349141
DOI:
10.1093/toxsci/kfu269
[Indexed for MEDLINE]
Free PMC Article

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