Combining stem cell-derived hepatocytes with impedance sensing to better predict human drug toxicity

ABSTRACT

Background: The liver plays a central role in human drug metabolism. To model drug metabolism, the major cell type of the liver, the hepatocyte, is commonly used. Hepatocytes can be derived from human and animal sources, including pluripotent stem cells. Cell-based models have shown promise in modeling human drug exposure. The assays used in those studies are normally ‘snap-shot’ in nature, and do not provide the complete picture of human drug exposure.

Research design and methods: In this study, we employ stem cell-derived hepatocytes and impedance sensing to model human drug toxicity. This impedance-based stem cell assay reports hepatotoxicity in real time after treatment with compounds provided by industry.

Results: Using electric cell-substrate impedance Sensing (ECIS), we were able to accurately measure drug toxicity post-drug exposure in real time and more quickly than gold standard biochemical assays.

Conclusions: ECIS is robust and non-destructive methodology capable of monitoring human drug exposure with superior performance to current gold standard ‘snapshot’ assays. We believe that the methodology presented within this article could prove valuable in the quest to better predict off-target effects of drugs in humans.

KEYWORDS:

• Electric Cell-Substrate Impedance Sensing (ECIS)
• hepatic differentiation
• human embryonic stem cells
• cytochrome P450
• drug toxicity

Declaration of interest

D Hay is a co-founder, director, and shareholder in Stemnovate Ltd and HigherSteaks Ltd. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

W Zhou, D Hay, P Bagnaninchi and B Lucendo-Villarin were involved in the conception and design, data analysis and interpretation, drafting the manuscript and approval of the manuscript. O Flint provided materials for these studies and provided comments on the manuscript content. K Graham helped with drafting the manuscript and provided comments on the manuscript content.

Additional information

Funding

P Bagnaninchi was supported by the international exchanges grant (ref. IE151106) from The Royal Society of UK. W Zhou was supported by The Royal Society of UK (ref. IE151106) and the National Natural Science Foundation of China (ref. 81300345). D Hay and B Lucendo-Villarin were supported by an award from the Chief Scientist Office (TCS 16/37).