Assessment of drug effects on the (electro)physiology of human induced pluripotent stem cell derived (hiPSC) cardiomyocytes in vitro using a multiparametric approach

In drug development it is important to assess potential cardiotoxicity of drug candidates as early in the drug development pipeline as possible. Human pluripotent stem cell (hiPSC) derived cardiomyocytes can be used as a highly useful in vitro  model for this purpose, for example in MEA- and/or impedance-based measurements to investigate drug effects on cardiac (electro)physiology. Pluriomics has recently developed a serum-free and well-defined maturation medium (Pluricyte? Cardiomyocyte Medium, PCM) and hiPSC-derived ventricular cardiomyocytes (Pluricyte? Cardiomyocytes) which exhibit a relatively high level of maturity. This was demonstrated by an increased contraction profile, as well as by electrophysiological properties (low negative resting membrane potential, well defined action potential plateau and rapid depolarization) and gene expression patterns comparable to mature cardiomyocytes [1]. FACS analysis showed high protein expression of the cardiac marker TNNT2 (>90%) and the ventricular marker MLC2V (>70%). To further investigate the (electro)physiology of Pluricyte? Cardiomyocytes, and the potential of these cells to study cardiotoxicity, the effects of a set of cardioactive compounds (e.g. E4031, diltiazem, nifedipine, flecainide, isoproterenol, blebbistatin, BayK8644 and lapatinib)  on the electrophysiological behaviour and contractility of the cells were analysed using different MEA/impedance platforms as well as high-throughput Ca2+-signalling assays on a Hamamatsu Photonics FDSS/?Cell system. MEA analysis showed field potentials of the Pluricyte? Cardiomyocyte monolayers with a pronounced repolarization peak. Impedance measurements showed a profile that was in line with the Ca2+ -transient data of the cells. Multiparametric analyses of the effects of the cardioactive compounds revealed relevant pharmacological responses of the Pluricyte? Cardiomyocytes, and showed the added value of each of the different assays for obtaining a more complete in vitro cardiotoxicity profile of test compounds in Pluricyte? Cardiomyocytes. Our multiparametric approach, which combines hiPSC-derived cardiomyocytes with various electrophysiology and contractility-based assays, enables early cardiotoxicity screening with the potential to greatly reduce the use of animal experiments in preclinical development.

[1] Ribeiro et al., Biomaterials, 2015.