BACKGROUND

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) can recapitulate features of ion channel mutations causing inherited rhythm disease. However, the lack of maturity of these cells is considered a significant limitation of the model. Prolonged culture of hiPSC-CMs promotes maturation of these cells. We studied the electrophysiological effects of the I230T mutation in the sodium channel gene in hiPSC-CMs generated from a homozygous (I230T) and a heterozygous (I230T) individual from a family with recessive cardiac conduction disease. Since the I230T mutation occurs in the developmentally regulated "adult" isoform of we investigated the relationship between the expression fraction of the adult isoform and the electrophysiological phenotype at different time points in culture.

METHODS AND RESULTS

After a culture period of 20 days, sodium current () was mildly reduced in I230T hiPSC-CMs compared with control hiPSC-CMs, while I230T hiPSC-CMs displayed no reduction in . This coincided with a relatively high expression fraction of the "fetal" isoform compared with the adult isoform as measured by quantitative polymerase chain reaction. Following prolonged culture to 66 days, the fraction of adult isoform increased; this was paralleled by a marked decrease in in I230T hiPSC-CMs, in line with the severe clinical phenotype in homozygous patients. At this time in culture, I230T hiPSC-CMs displayed an intermediate loss of , compatible with a gene dosage effect.

CONCLUSIONS

Prolonged culture of hiPSC-CMs leads to an increased expression fraction of the adult sodium channel isoform. This new aspect of electrophysiological immaturity should be taken into account in studies that focus on the effects of mutations in hiPSC-CMs.