干细胞衍生的心肌细胞表现出心律失常的潜力

Y. Zhang, C. Hartzell, Michael Narlow, S. Dudley
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引用次数: 122

摘要

背景:来自多能胚胎干细胞(ESCs)和胚胎癌细胞(ECCs)的心肌细胞(CMs)具有成人心肌细胞的一些特征,但不是全部特征。ESCs已经显示出在心肌损伤区域移植的能力,这表明它们可以用于心肌病的细胞移植治疗。我们研究了小鼠ESCs和ECCs分化的CMs的致心律失常特性。方法与结果:采用全细胞膜片钳模式对体外来源的cms进行研究。两种来源的CMs均表现出动作电位(AP)形态的异质性,最大上冲程速度(dV/dt)降低,AP持续时间延长。CMs在培养中表现出长时间的自发电活动。在有或没有药物增强的情况下,观察到频繁的触发活性。Cs+取代[K+]i后,Bay K8644 +四乙基氯化铵(TEA)和[TEA]o分别可诱发2期和3期早期后去极化。心动过缓刺激、低钾血症和奎尼丁联合作用导致早期后去极化。高钙血症或异丙肾上腺素可容易且可逆地诱导延迟后去极化。结论:escs或ECCs分化为至少3种AP表型。CMs具有自发性活动,低dV/dt, AP持续时间延长,易诱发心律失常。这些发现提高了在细胞移植治疗中使用全能性ESCs的谨慎性,因为它们可能从3种经典机制(再入、自动性或触发性活动)中的任何一种中作为意外的心律失常源。
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Stem Cell-Derived Cardiomyocytes Demonstrate Arrhythmic Potential
Background—Cardiomyocytes (CMs) derived from pluripotent embryonic stem cells (ESCs) and embryonal carcinoma cells (ECCs) have some but not all characteristics of adult myocytes. ESCs have shown the ability to engraft in areas of myocardial damage, which suggests their use in cell transplantation therapy for cardiomyopathy. We studied the arrhythmogenic properties of CMs differentiated from mouse ESCs and ECCs. Methods and Results—CMs derived in vitro were studied in the whole-cell patch-clamp mode. CMs from both sources showed action potential (AP) morphology heterogeneity, with reduced maximum upstroke velocities (dV/dt) and prolonged AP durations. CMs demonstrated prolonged, spontaneous electrical activity in culture. Frequent triggered activity was observed with and without pharmacological enhancement. Phase 2 or 3 early afterdepolarizations could be induced easily by Bay K8644 plus tetraethylammonium chloride (TEA) or [TEA]o after Cs+ replacement for [K+]i, respectively. A combination of bradycardic stimulation, hypokalemia, and quinidine resulted in early afterdepolarizations. Delayed afterdepolarizations could be induced easily and reversibly by hypercalcemia or isoproterenol. Conclusions—ESCs or ECCs differentiated into at least 3 AP phenotypes. CMs showed spontaneous activity, low dV/dt, prolonged AP duration, and easily inducible triggered arrhythmias. These findings raise caution about the use of totipotent ESCs in cell transplantation therapy, because they may act as an unanticipated arrhythmogenic source from any of the 3 classic mechanisms (reentry, automaticity, or triggered activity).
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