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

Richard Kia, Lorna Kelly, Rowena L C Sison-Young, Fang Zhang, Chris S. Pridgeon, James A. Heslop, Pete Metcalfe, Neil R. Kitteringham, Melissa Baxter, Sean Harrison, Neil A. Hanley, Zoë D. Burke, Michael P. Storm, Melanie J. Welham, David Tosh, Barbara Küppers-Munther, Josefina Edsbagge, Philip J. Starkey Lewis, Frank Bonner, Ernie HarpurJames Sidaway, Joanne Bowes, Stephen W. Fenwick, Hassan Malik, Chris E P Goldring, B. Kevin Park

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25 Citations (Scopus)

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 druginduced 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.

Original languageEnglish
Pages (from-to)173-185
Number of pages13
JournalToxicological Sciences
Volume144
Issue number1
Early online date18 Dec 2014
DOIs
Publication statusPublished - Mar 2015

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Keywords

  • Bridging biomarker
  • Cell-specific biomarker
  • Cytotoxicity
  • Drug-induced liver injury
  • Hepatocytes
  • In vitro model
  • microRNA

Cite this

Kia, R., Kelly, L., Sison-Young, R. L. C., Zhang, F., Pridgeon, C. S., Heslop, J. A., ... Kevin Park, B. (2015). MicroRNA-122: A novel hepatocyte-enriched in vitro marker of drug-induced cellular toxicity. Toxicological Sciences, 144(1), 173-185. https://doi.org/10.1093/toxsci/kfu269