Canadian Journal of Cardiology
Basic Research| Volume 33, ISSUE 2, P269-278, February 2017

Biophysical, Molecular, and Pharmacological Characterization of Voltage-Dependent Sodium Channels From Induced Pluripotent Stem Cell-Derived Cardiomyocytes

Published:October 11, 2016DOI:



      The ability to differentiate patient-specific human induced pluripotent stem cells in cardiac myocytes (hiPSC-CM) offers novel perspectives for cardiovascular research. A number of studies, that reported mainly on current-voltage curves used hiPSC-CM to model voltage-gated Na+ channel (Nav) dysfunction. However, the expression patterns and precise biophysical and pharmacological properties of Nav channels from hiPSC-CM remain unknown. Our objective was to study the characteristics of Nav channels from hiPSC-CM and assess the appropriateness of this novel cell model.


      We generated hiPSC-CM using the recently described monolayer-based differentiation protocol.


      hiPSC-CM expressed cardiac-specific markers, exhibited spontaneous electrical and contractile activities, and expressed distinct Nav channels subtypes. Electrophysiological, pharmacological, and molecular characterizations revealed that, in addition to the main Nav1.5 channel, the neuronal tetrodotoxin (TTX)-sensitive Nav1.7 channel was also significantly expressed in hiPSC-CM. Most of the Na+ currents were resistant to TTX block. Therapeutic concentrations of lidocaine, a class I antiarrhythmic drug, also inhibited Na+ currents in a use-dependent manner. Nav1.5 and Nav1.7 expression and maturation patterns of hiPSC-CM and native human cardiac tissues appeared to be similar. The 4 Navβ regulatory subunits were expressed in hiPSC-CM, with β3 being the preponderant subtype.


      The findings indicated that hiPSC-CM robustly express Nav1.5 channels, which exhibited molecular and pharmacological properties similar to those in native cardiac tissues. Interestingly, neuronal Nav1.7 channels were also expressed in hiPSC-CM and are likely to be responsible for the TTX-sensitive Nav current.



      La capacite de différenciation cardiomyocytaire (hiPSC-CM) des cellules souches pluripotentes induites humaines offre de nouvelles perspectives pour la recherche sur les maladies cardiovasculaires. Un certain nombre d’études qui ont principalement rendu compte des courbes courant-tension utilisaient les hiPSC-CM pour modéliser le dysfonctionnement des canaux sodiques sensibles à la tension (Nav pour voltage-gated Na+ channel). Toutefois, on ignore les profils d’expression et les propriétés biophysiques et pharmacologiques précises des canaux Nav exprimés dans les hiPSC-CM. Notre objectif était donc d'étudier les caractéristiques des canaux Nav exprimés dans les hiPSC-CM et d’évaluer la pertinence de ce nouveau modèle de cellules.


      Nous avons généré des hiPSC-CM en utilisant le protocole de différenciation en monocouche récemment décrit.


      Les hiPSC-CM experiment des marqueurs cardiaques spécifiques, montrent une activité électrique et contractile et experiment des sous-types distincts de canaux Nav. Les caractérisations électrophysiologiques, pharmacologiques et moléculaires ont révélé qu’en plus du canal principal Nav1.5 le canal neuronal Nav1.7 sensible à la tétrodotoxine (TTX) a est également exprimé dans les hiPSC-CM. La plupart des courants Na+ ont été résistants à la TTX. Les concentrations thérapeutiques de lidocaïne, un médicament antiarythmique de classe I, ont également inhibé les courants Nav en fonction de la fréquence de stimulation. Les profils d’expression et de maturation de Nav1.5 et Nav1.7 des hiPSC-CM et des tissus cardiaques humains à l’état natif ont semblé similaires. Les 4 sous-unités régulatrices Navβ ont été exprimées dans les hiPSC-CM, parmi lesquelles β3 a été le sous-type prépondérant.


      Les conclusions ont indiqué que les hiPSC-CM expriment fortement les canaux Nav1.5, lesquels montraient des propriétés moléculaires et pharmacologiques similaires à celles des tissus cardiaques à l’état natif. Il est intéressant de noter que les canaux neuronaux Nav1.7 sont également exprimés dans les hiPSC-CM et qu’ils sont probablement responsables du courant Nav sensible à la TTX.
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