Improving electrical properties of iPSC-cardiomyocytes by enhancing Cx43 expression
Abstract The therapeutic potential of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) is limited by immature functional features including low impulse propagation and reduced cell excitability. Key players regulating electrical activity are voltage-gated Na + channels (Na v 1.5) and gap junctions built from connexin-43 (Cx43). Here we tested the hypothesis that enhanced Cx43 expression increases intercellular coupling and influences excitability by modulating Na v 1.5. Using transgenic approaches, Cx43 and Na v 1.5 localization and cell coupling were studied by confocal imaging. Na v 1.5 currents and action potentials (APs) were measured using the patch-clamp technique. Enhanced sarcolemmal Cx43 expression significantly improved intercellular coupling and accelerated dye transfer kinetics. Furthermore, Cx43 modulated Na v 1.5 function leading to significantly higher current and enhanced AP upstroke velocities, thereby improving electrical activity as measured by microelectrode arrays. These findings suggest a mechanistic link between cell coupling and excitability controlled by Cx43 expression in iPSC-CMs. Therefore, we propose Cx43 as novel molecular target for improving electrical properties of iPSC-CMs to match the functional properties of native myocytes. Highlights Enhanced Cx43 expression leads to increased gap junction formation in iPSC-CMs. Spatio-temporal characteristics of signal propagation are significantly improved. Cx43 expression co-regulates Na v 1.5 ion channel function and myocyte excitability.
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