Regulation of Ca 2+ 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 ICa myocytes (τi <40 ms, in 4-5 day cultures) and slowly-inactivating ICa (τi   ≥ 40 ms, in 6-8 day cultures). 2) Hypoxia suppressed ICa by 10-20% in rapidly- and 40-55% in slowly-inactivating ICa cells. 3) Isoproterenol enhanced ICa 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 O2 sensing. 5) Acidosis suppressed ICa by ∼35% and ∼25% in rapidly and slowly inactivating ICa cells, respectively. 6) Hypoxia and acidosis suppressive effects on Ca-transients depended on whether global or RyR2-microdomain were measured: with acidosis suppression was ∼25% in global and ∼37% in RyR2 Ca2+ -microdomains in either cell type, whereas with hypoxia suppression was ∼20% and ∼25% respectively in global and RyR2-microdomaine in rapidly and ∼35% and ∼45% respectively in global and RyR2-microdomaine in slowly-inactivating cells.

CONCLUSIONS: Variability in ICa 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.