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

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) dysfunction. However, the expression patterns and precise biophysical and pharmacological properties of Na channels from hiPSC-CM remain unknown. Our objective was to study the characteristics of Na 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 channels subtypes. Electrophysiological, pharmacological, and molecular characterizations revealed that, in addition to the main Na1.5 channel, the neuronal tetrodotoxin (TTX)-sensitive Na1.7 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. Na1.5 and Na1.7 expression and maturation patterns of hiPSC-CM and native human cardiac tissues appeared to be similar. The 4 Naβ regulatory subunits were expressed in hiPSC-CM, with β3 being the preponderant subtype.

CONCLUSIONS

The findings indicated that hiPSC-CM robustly express Na1.5 channels, which exhibited molecular and pharmacological properties similar to those in native cardiac tissues. Interestingly, neuronal Na1.7 channels were also expressed in hiPSC-CM and are likely to be responsible for the TTX-sensitive Na current.