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Poster
184

Development of a multiparametric cardiovascular toxicity assay using iPSC derived cardiomyocytes, endothelial cells, and primary cardiac fibroblasts

Authors

K Raniga1; W Stebbeds2; K Ngoc Võ3; C Denning4
1 GSK & University of Nottingham , UK;  2 GlaxoSmithKline (GSK), UK;  3 University of Nottingham, UK;  4 The University of Nottingham, UK

Discussion

Authors

K Raniga1; W Stebbeds2; K Ngoc Võ3; C Denning4
1 GSK & University of Nottingham , UK;  2 GlaxoSmithKline (GSK), UK;  3 University of Nottingham, UK;  4 The University of Nottingham, UK

Discussion

Purpose: Unexpected cardiotoxicity underlies high levels of late-stage attrition and post-market withdrawals. Cardiotoxic effects of compounds are predicted using in vitro expression of single cardiac ion channels, in vivo and ex vivo studies. However, these models fail to reflect the complexity of the human cardiac microenvironment. Approximately 70% of the cells in the human heart are non-myocytes with cardiac fibroblasts and vascular cells forming the majority. HiPSC-derived cardiomyocytes have become an attractive platform for capturing the effects of chronic modulators or toxicants and could complement existing assays to improve cardiac safety assessments. To date, there is no validated multi-cellular human-derived in vitro system for assessing drug-induced changes in contractility. 

Methods: The baseline function of mono-and co-cultures were assessed using calcium flux, kinetic live cell imaging to assess contractility. Design of Experiments was used to evaluate how specific factors influenced endpoint parameters derived from multiple phenotypic assays. 

Results: We successfully implemented design of experiments to test various co-culture combinations. This included optimisation of cell seeding via liquid handling platforms, high-throughput acquisition of beating cardiomyocytes, and derivation of cardiac parameters. Four 
main factors  were 
found  to  have 
a  significant  effect 
on  cardiac  peak amplitude.  Our  results demonstrate the  added value 
of  design  of 
experiments  when  investigating 
multi-factor 
interactions.  Moreover,  co-culturing with non-myocytes may increase the scope, maturity and predictivity of
current assays.