Abstract

Subtype-specific human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are promising tools, e.g., to assess the potential of drugs to cause chronotropic effects (nodal hiPSC-CMs), atrial fibrillation (atrial hiPSC-CMs), or ventricular arrhythmias (ventricular hiPSC-CMs). We used single-cell patch-clamp reverse transcriptase-quantitative polymerase chain reaction to clarify the composition of the iCell cardiomyocyte population (Fujifilm Cellular Dynamics, Madison, WI, USA) and to compare it with atrial and ventricular Pluricytes (Ncardia, Charleroi, Belgium) and primary human atrial and ventricular cardiomyocytes. The comparison of beating and non-beating iCell cardiomyocytes did not support the presence of true nodal, atrial, and ventricular cells in this hiPSC-CM population. The comparison of atrial and ventricular Pluricytes with primary human cardiomyocytes showed trends, indicating the potential to derive more subtype-specific hiPSC-CM models using appropriate differentiation protocols. Nevertheless, the single-cell phenotypes of the majority of the hiPSC-CMs showed a combination of attributes which may be interpreted as a mixture of traits of adult cardiomyocyte subtypes: (i) nodal: spontaneous action potentials and high HCN4 expression and (ii) non-nodal: prominent INa-driven fast inward current and high expression of SCN5A. This may hamper the interpretation of the drug effects on parameters depending on a combination of ionic currents, such as beat rate. However, the proven expression of specific ion channels supports the evaluation of the drug effects on ionic currents in a more realistic cardiomyocyte environment than in recombinant non-cardiomyocyte systems.

Highlights

  • Human induced pluripotent stem cell-derived cardiomyocytes constitute a promising tool for basic science, regenerative medicine, and drug development [1].Some applications necessitate the availability of ideally homogenous hiPSC-CM cell culture models representing specific cellular subtypes that in the adult human heart can be classified into nodal, atrial, and ventricular cardiomyocytes based on anatomical and functional differences

  • As our analyses revealed that ventricular Pluricytes may to some extent reproduce the molecular physiology of human ventricular cardiomyocytes, we reasoned that they might constitute an adequate model to predict the pro-arrhythmic risk of drugs and research substances

  • Utilizing a single-cell patch-clamp reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) approach, our data show that the three commercially available hiPSC-CM cultures differed with respect to electrophysiological parameters and ion channel expression

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Summary

Introduction

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) constitute a promising tool for basic science, regenerative medicine, and drug development [1]. Some applications necessitate the availability of ideally homogenous hiPSC-CM cell culture models representing specific cellular subtypes that in the adult human heart can be classified into nodal, atrial, and ventricular cardiomyocytes based on anatomical and functional differences. The pump function of the heart is maintained by the atrial and ventricular cells, whereas the smaller nodal cardiomyocytes of the sinoatrial node generate spontaneous action potentials that naturally control excitation of the heart [2]. It is widely accepted that in nodal cells membrane-derived processes, and cellular Ca2+ dynamics—referred to as a membrane clock or a Ca2+ clock, respectively—

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