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Physiological calcium combined with electrical pacing accelerates maturation of human engineered heart tissue.

ABSTRACT: Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have wide potential application in basic research, drug discovery, and regenerative medicine, but functional maturation remains challenging. Here, we present a method whereby maturation of hiPSC-CMs can be accelerated by simultaneous application of physiological Ca²⁺ and frequency-ramped electrical pacing in culture. This combination produces positive force-frequency behavior, physiological twitch kinetics, robust β-adrenergic response, improved Ca²⁺ handling, and cardiac troponin I expression within 25 days. This study provides insights into the role of Ca²⁺ in hiPSC-CM maturation and offers a scalable platform for translational and clinical research.

SUBMITTER: Shen S

PROVIDER: S-EPMC9481907 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Physiological calcium combined with electrical pacing accelerates maturation of human engineered heart tissue.

Shen Shi S Sewanan Lorenzo R LR Shao Stephanie S Halder Saiti S SS Stankey Paul P Li Xia X Campbell Stuart G SG

Stem cell reports 20220804 9

Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have wide potential application in basic research, drug discovery, and regenerative medicine, but functional maturation remains challenging. Here, we present a method whereby maturation of hiPSC-CMs can be accelerated by simultaneous application of physiological Ca<sup>2+</sup> and frequency-ramped electrical pacing in culture. This combination produces positive force-frequency behavior, physiological twitch kinetics, robust ...[more]

PMID: 35931080

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Project description:The pulmonary vein, which returns oxygenated blood to the left atrium, is ensheathed by a population of unique, myocyte-like cells called pulmonary vein sleeve cells (PVCs). These cells autonomously generate action potentials that propagate into the left atrial chamber and cause arrhythmias resulting in atrial fibrillation; the most common, often sustained, form of cardiac arrhythmia. In mice, PVCs extend along the pulmonary vein into the lungs, and are accessible in a lung slice preparation. We exploited this model to study how aberrant Ca(2+) signaling alters the ability of PVC networks to follow electrical pacing. Cellular responses were investigated using real-time 2-photon imaging of lung slices loaded with a Ca(2+)-sensitive fluorescent indicator (Ca(2+) measurements) and phase contrast microscopy (contraction measurements). PVCs displayed global Ca(2+) signals and coordinated contraction in response to electrical field stimulation (EFS). The effects of EFS relied on both Ca(2+) influx and Ca(2+) release, and could be inhibited by nifedipine, ryanodine or caffeine. Moreover, PVCs had a high propensity to show spontaneous Ca(2+) signals that arose via stochastic activation of ryanodine receptors (RyRs). The ability of electrical pacing to entrain Ca(2+) signals and contractile responses was dramatically influenced by inherent spontaneous Ca(2+) activity. In PVCs with relatively low spontaneous Ca(2+) activity (<1 Hz), entrainment with electrical pacing was good. However, in PVCs with higher frequencies of spontaneous Ca(2+) activity (>1.5 Hz), electrical pacing was less effective; PVCs became unpaced, only partially-paced or displayed alternans. Because spontaneous Ca(2+) activity varied between cells, neighboring PVCs often had different responses to electrical pacing. Our data indicate that the ability of PVCs to respond to electrical stimulation depends on their intrinsic Ca(2+) cycling properties. Heterogeneous spontaneous Ca(2+) activity arising from stochastic RyR opening can disengage them from sinus rhythm and lead to autonomous, pro-arrhythmic activity.

Dataset Information

Physiological calcium combined with electrical pacing accelerates maturation of human engineered heart tissue.

Publications

Physiological calcium combined with electrical pacing accelerates maturation of human engineered heart tissue.

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