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Visit Poster #206C at Advances in Drug Discovery/Stem Cells in Drug Discovery 2017 6-7th March

SCDD Cambridge#206C: Investigating Cardiomyocyte Dysfunction through Combined Analysis of Beating, Metabolic Flux and Cellular Oxygenation

Conn Carey1, Cristina Bertinetti-Lapatki2, Tristan Pritchard-Meaker 3 , Adrian Roth2, James Hynes1

1Luxcel Biosciences, Cork, Ireland, 2Pharmaceutical Sciences, Pharma Research & Early Development, Roche Innovation Center, Basel, Switzerland, 3 Axiogenesis AG, Cologne, Germany

Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) are finding increased use as an in vitro model to assess drug-induced cardiotoxicity, prompting parallel developments in multi-parametric high-throughput assays to measure cardiomyocyte function. Metabolic perturbations are of particular importance in this regard given the aerobic poise of cardiac tissue and the implication of mitochondrial dysfunction in the etiology of drug-induced cardiotoxicity. Here we combine measurement of cardiomyocyte contractility, metabolism and oxygenation on a single plate to better characterise cellular responses to drug treatment. This is achieved by integrating microelectrode-based contractility measurements (E-plates) with a multiplexed fluorescence-based bioenergetics assessment, measuring O2 consumption, glycolytic flux and cellular oxygenation. This combination facilitates an interrogation of the relationship between metabolism and contractility, allowing a delineation of altered beat rate and concomitant metabolic perturbation. Using a panel of classical mitochondrial modulators, we show that iPS-derived cardiomyocytes can circumvent mitochondrial impairment and maintain beating by increasing glycolysis-derived ATP supply. In addition, pharmacological beat rate modulation (increase) impacts metabolic flux (shift to OxPhos) and significantly reduces cellular oxygenation, which in turn can affect signaling pathways. This combined analysis of critical cardiomyocyte functions facilities the design of more physiologically relevant in vitro assays and provides a more holistic cardiotoxicity screen.

Summary: Stem cell-derived cardiomyocytes are increasingly used as in vitro model for drug-induced cardiotoxicity, prompting parallel developments in multi-parametric high-throughput assays to measure critical cardiomyocyte function. This results in more physiologically relevant in vitro assays and provides more holistic cardiotoxicity screens.

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