Regulation of Ca2+ signaling by acute hypoxia and acidosis in cardiomyocytes derived from human induced pluripotent stem cells

Aims: The effects of acute (100 s) hypoxia and/or acidosis on Ca2+ signaling parameters of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) are explored here for the first time. Methods and results: 1) hiPSC-CMs express two cell populations: rapidly-inactivating I-Ca myocytes (tau(i) < 40 ms, in 4-5 day cultures) and slowly-inactivating I-Ca (tau(i) >= 40 ms, in 6-8 day cultures). 2) Hypoxia suppressed I-Ca by 10-20% in rapidly- and 40-55% in slowly-inactivating I-Ca cells. 3) Isoproterenol enhanced I-Ca in hiPSC-CMs, but either enhanced or did not alter the hypoxic suppression. 4) Hypoxia had no differential suppressive effects in the two cell-types when Ba2+ was the charge carrier through the calcium channels, implicating Ca2+ -dependent inactivation in O-2 sensing. 5) Acidosis suppressed I-Ca by similar to 35% and similar to 25% in rapidly and slowly inactivating I-Ca cells, respectively. 6) Hypoxia and acidosis suppressive effects on Ca-transients depended on whether global or RyR2-microdomain were measured: with acidosis suppression was similar to 25% in global and similar to 37% in RyR2 Ca2+-microdomains in either cell type, whereas with hypoxia suppression was similar to 20% and similar to 25% respectively in global and RyR2-microdomaine in rapidly and similar to 35% and similar to 45% respectively in global and RyR2-microdomaine in slowly-inactivating cells. Conclusions: Variability in I-Ca inactivation kinetics rather than cellular ancestry seems to underlie the action potential morphology differences generally attributed to mixed atrial and ventricular cell populations in hiPSC-CMs cultures. The differential hypoxic regulation of Ca2+-signaling in the two-cell types arises from differential Ca2+-dependent inactivation of the Ca2+-channel caused by proximity of Ca2+-release stores to the Ca2+ channels.