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<sup>+</sup> c...

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Hauptverfasser: Sottas, Valentin (VerfasserIn) , Wahl, Carl-Mattheis (VerfasserIn) , Trache, Cristian (VerfasserIn) , Bartolf-Kopp, Michael (VerfasserIn) , Cambridge, Sidney (VerfasserIn) , Hecker, Markus (VerfasserIn) , Ullrich, Nina D. (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: 16 May 2018
In: Journal of molecular and cellular cardiology
Year: 2018, Jahrgang: 120, Pages: 31-41
ISSN:1095-8584
DOI:10.1016/j.yjmcc.2018.05.010
Online-Zugang:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.yjmcc.2018.05.010
Verlag, lizenzpflichtig, Volltext: https://www.jmmc-online.com/article/S0022-2828(18)30171-8/abstract
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Verfasserangaben:Valentin Sottas, Carl-Mattheis Wahl, Mihnea C. Trache, Michael Bartolf-Kopp, Sidney Cambridge, Markus Hecker, Nina D. Ullrich

MARC

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520 |a 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<sup>+</sup> channels (Na<sub>v</sub>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<sub>v</sub>1.5. Using transgenic approaches, Cx43 and Na<sub>v</sub>1.5 localization and cell coupling were studied by confocal imaging. Na<sub>v</sub>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<sub>v</sub>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. 
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