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

Abstract

Background: 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 (Na_v) dysfunction. However, the expression patterns and precise biophysical and pharmacological properties of Na_v channels from hiPSC-CM remain unknown. Our objective was to study the characteristics of Na_v channels from hiPSC-CM and assess the appropriateness of this novel cell model.

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

Results: hiPSC-CM expressed cardiac-specific markers, exhibited spontaneous electrical and contractile activities, and expressed distinct Na_v channels subtypes. Electrophysiological, pharmacological, and molecular characterizations revealed that, in addition to the main Na_v1.5 channel, the neuronal tetrodotoxin (TTX)-sensitive Na_v1.7 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. Na_v1.5 and Na_v1.7 expression and maturation patterns of hiPSC-CM and native human cardiac tissues appeared to be similar. The 4 Na_vβ regulatory subunits were expressed in hiPSC-CM, with β3 being the preponderant subtype.

Conclusions: The findings indicated that hiPSC-CM robustly express Na_v1.5 channels, which exhibited molecular and pharmacological properties similar to those in native cardiac tissues. Interestingly, neuronal Na_v1.7 channels were also expressed in hiPSC-CM and are likely to be responsible for the TTX-sensitive Na_v current.