Evaluation of human pluripotent stem cell-derived cardiac myocytes for cardiotoxicity testing

Details

Evaluation of human-induced pluripotent stem cell-derived cardiac myocytes (hiPSC-CMs) for cardiotoxicity testing Potentially fatal cardiac arrhythmias such as Torsades des Pointes (TdP) are linked to adverse side-effects of drugs intended as potential treatments for a variety of clinical disorders. Drugs that, unintentionally, affect ion channels can increase or decrease the cardiac action potential duration, depending on their effect. For example, drugs that inhibit K+ channels can prolong the action potential by delaying repolarisation, which is manifested as the long QT interval in the electrocardiogram and is associated with an increased risk of arrhythmias such as TdP. Potential new medicines must therefore be evaluated for the likelihood of cardiotoxic effects and be screened out as early as possible in the drug development process.

hiPSC-CMs are widely used for cardiotoxicity testing as a desirable alternative to expression systems as well as animal cardiac cells (Zhao et al 2018). However, whether hiPSC-CMs contain ion channels that represent the characteristics of adult human cardiac myocytes has not yet been fully established. This project therefore seeks to characterise the electrophysiological properties of the ion channels expressed in hiPSC-CMs to evaluate their potential significance for cardiotoxicity testing. Experiments to be performed will characterise the inhibitory effects of a wide selection of drugs on ionic currents in hiPSC-CMs (e.g. INa, INaL, ICaL, Ito, IKr, IKs and IK1) as listed in CiPA (Crumb et al 2016).

The proposed experiments will investigate the activation and inactivation characteristics of these (and other) ionic currents, as well as their sensitivity to the selected drugs relevant to these channels. In addition to these ionic current measurements, voltage- and calcium-sensitive dyes will also be used to measure action potentials and intracellular calcium transients, respectively. Results from these measurements will be compared to those where hiPSC-CMs have been co-cultured with other cell types (e.g. fibroblasts and endothelial cells) to form organoids, as well as to ionic currents recorded in cultured expression systems and isolated guinea-pig cardiomyocytes (Chorvatova et al 2004). Results from this study will help develop an improved understanding of how better and safer therapeutic approaches can be developed for the treatment of human disease in the future.

How to apply

Formal applications can be submitted via the University of Bradford web site; applicants will need to register an account, select ‘Postgraduate Research’ as the type of course and then use the keywords ‘biomedical science’. Applicants should then specify the project title in the ‘Research Proposal’ section.

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