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Mechanism of automaticity in cardiomyocytes derived from human induced pluripotent stem cells.


ABSTRACT: The creation of cardiomyocytes derived from human induced pluripotent stem cells (hiPS-CMs) has spawned broad excitement borne out of the prospects to diagnose and treat cardiovascular diseases based on personalized medicine. A common feature of hiPS-CMs is their spontaneous contractions but the mechanism(s) remain uncertain.Intrinsic activity was investigated by the voltage-clamp technique, optical mapping of action potentials (APs) and intracellular Ca(2+) (Cai) transients (CaiT) at subcellular-resolution and pharmacological interventions.The frequency of spontaneous CaiT (sCaiT) in monolayers of hiPS-CMs was not altered by ivabradine, an inhibitor of the pacemaker current, If despite high levels of HCN transcripts (1-4). HiPS-CMs had negligible If and IK1 (inwardly-rectifying K(+)-current) and a minimum diastolic potential of -59.1±3.3mV (n=18). APs upstrokes were preceded by a depolarizing-foot coincident with a rise of Cai. Subcellular Cai wavelets varied in amplitude, propagated and died-off; larger Cai-waves triggered cellular sCaTs and APs. SCaiTs increased in frequency with [Ca(2+)]out (0.05-to-1.8mM), isoproterenol (1?M) or caffeine (100?M) (n?5, p<0.05). HiPS-CMs became quiescent with ryanodine receptor stabilizers (K201=2?M); tetracaine; Na-Ca exchange (NCX) inhibition (SEA0400=2?M); higher [K(+)]out (5?8mM), and thiol-reducing agents but could still be electrically stimulated to elicit CaiTs. Cell-cell coupling of hiPS-CM in monolayers was evident from connexin-43 expression and CaiT propagation. SCaiTs from an ensemble of dispersed hiPS-CMs were out-of-phase but became synchronous through the outgrowth of inter-connecting microtubules.Automaticity in hiPS-CMs originates from a Ca(2+)-clock mechanism involving Ca(2+) cycling across the sarcoplasmic reticulum linked to NCX to trigger APs.

SUBMITTER: Kim JJ 

PROVIDER: S-EPMC4409767 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Mechanism of automaticity in cardiomyocytes derived from human induced pluripotent stem cells.

Kim Jong J JJ   Yang Lei L   Lin Bo B   Zhu Xiaodong X   Sun Bin B   Kaplan Aaron D AD   Bett Glenna C L GC   Rasmusson Randall L RL   London Barry B   Salama Guy G  

Journal of molecular and cellular cardiology 20150130


<h4>Background and objectives</h4>The creation of cardiomyocytes derived from human induced pluripotent stem cells (hiPS-CMs) has spawned broad excitement borne out of the prospects to diagnose and treat cardiovascular diseases based on personalized medicine. A common feature of hiPS-CMs is their spontaneous contractions but the mechanism(s) remain uncertain.<h4>Methods</h4>Intrinsic activity was investigated by the voltage-clamp technique, optical mapping of action potentials (APs) and intracel  ...[more]

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