Biophysical properties of Nav1.5 channel in ventricular-like and atrial-like chamber cardiomyocytes derived from human induced pluripotent stem cells

Cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) is a promising way modeling cardiac diseases and investigating their associated mechanisms. Nevertheless, it is still challenging to differentiate hiPSC-CMs into specific cardiac types to investigate differences in ion channel properties such as for the NaV1.5 channel. In this context, we investigated biophysical properties of NaV1.5 in ventricular-like and atrial-like hiPSC-CMs. Atrial-like cardiomyocytes were obtained from the differentiation of hiPSCs treated with retinoic acid (RA). The quality of atrial specification was assessed by immunocytofluorescence, qPCR and western blot. Calcium and sodium currents were recorded using the Patch-clamp technique and their electrophysiological properties were investigated using optical mapping technique. hiPSC-CMs differentiation with RA induced a higher expression of mlc2a protein, a marker of atrial cardiomyocytes, and a lower expression of mlc2v and Cx43 proteins, markers of ventricular cardiomyocytes. The amplitude, the duration, and the steady-state phase of action potentials (APs) were decreased in RA-differentiated cardiomyocytes, corresponding to the atrial AP shape. Interestingly, no difference in SCN5A gene expression was detected whereas changes in NaV1.5 currents were observed. Indeed, lower current densities and a shift of the activation and inactivation to more depolarized membrane potential were measured in RA-differentiated cardiomyocytes. Furthermore, the kinetics of the fast inactivation were slower in atrial-like cardiomyocytes. These results showed that RA treatment allowed to obtain atrial-like cardiomyocytes and permitted to investigate differences in NaV1.5 channel properties between ventricular and atrial compartments. This approach with RA could represent an interesting way to investigate specific-type channelopathies.