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

ABSTRACT: 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 (?i<40?ms, in 4-5 day cultures) and slowly-inactivating ICa (?i??? 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.

SUBMITTER: Fernandez-Morales JC 

PROVIDER: S-EPMC6378877 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature