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 I_Ca myocytes (τ_i<40 ms, in 4-5 day cultures) and slowly-inactivating I_Ca (τ_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 O₂ sensing. 5) Acidosis suppressed I_Ca by ∼35% and ∼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 ∼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 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.

SUBMITTER: Fernandez-Morales JC 

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

REPOSITORIES: biostudies-literature