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J Mol Cell Cardiol. 2018 Jul;120:31-41. doi: 10.1016/j.yjmcc.2018.05.010. Epub 2018 May 16.

Improving electrical properties of iPSC-cardiomyocytes by enhancing Cx43 expression.

Author information

1
Institute of Physiology and Pathophysiology, Division of Cardiovascular Physiology, Heidelberg University, Im Neuenheimer Feld 307, 69120 Heidelberg, Germany.
2
Institute of Anatomy, Functional Neuroanatomy, Heidelberg University, Im Neuenheimer Feld 307, 69120 Heidelberg, Germany.
3
Institute of Physiology and Pathophysiology, Division of Cardiovascular Physiology, Heidelberg University, Im Neuenheimer Feld 326, 69120 Heidelberg, Germany.
4
Institute of Physiology and Pathophysiology, Division of Cardiovascular Physiology, Heidelberg University, Im Neuenheimer Feld 307, 69120 Heidelberg, Germany. Electronic address: nina.ullrich@physiologie.uni-heidelberg.de.

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 (Nav1.5) 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 Nav1.5. Using transgenic approaches, Cx43 and Nav1.5 localization and cell coupling were studied by confocal imaging. Nav1.5 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 Nav1.5 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.

KEYWORDS:

Action potential; Connexin-43; Excitability; Intercellular coupling; Na(v)1.5; Pluripotent stem cell-derived cardiomyocytes

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