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Lookup NU author(s): Dr Ernest Harpur
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
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.
Author(s): Kia R, Kelly L, Sison-Young RLC, Zhang F, Pridgeon CS, Heslop JA, Metcalfe P, Kitteringham NR, Baxter M, Harrison S, Hanley NA, Burke ZD, Storm MP, Welham MJ, Tosh D, Kuppers-Munther B, Edsbagge J, Lewis PJS, Bonner F, Harpur E, Sidaway J, Bowes J, Fenwick SW, Malik H, Goldring CEP, Park BK
Publication type: Article
Publication status: Published
Journal: Toxicological Sciences
Year: 2015
Volume: 144
Issue: 1
Pages: 173-185
Print publication date: 01/03/2015
Online publication date: 18/12/2014
Acceptance date: 01/01/1900
Date deposited: 01/07/2016
ISSN (print): 1096-6080
ISSN (electronic): 1096-0929
Publisher: Oxford University Press
URL: http://dx.doi.org/10.1093/toxsci/kfu269
DOI: 10.1093/toxsci/kfu269
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