Human embryonic and induced pluripotent stem cell-derived cardiomyocytes exhibit beat rate variability and power-law behavior.
Human embryonic and induced pluripotent stem cell-derived cardiomyocytes exhibit beat rate variability and power-law behavior.
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DOI：
10.1161/circulationaha.111.045146
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发表时间：
2012-02-21
期刊：
影响因子：
37.8
通讯作者：
Binah O
中科院分区：
文献类型：
--
作者：
Mandel Y;Weissman A;Schick R;Barad L;Novak A;Meiry G;Goldberg S;Lorber A;Rosen MR;Itskovitz-Eldor J;Binah O
窦房结是心脏中产生冲动的主要组织。窦房结功能障碍引起的房室传导阻滞和心律失常在临床上很重要，通常使用电子起搏器治疗。虽然电子起搏器是一个很好的解决方案，但它也存在一些限制，这些限制刺激了对生物起搏的研究。为了评估潜在的生物起搏器的适用性，我们测试了以下假设：人胚胎干细胞衍生的心肌细胞（hESC-CM）和诱导多能干细胞衍生的心肌细胞（iPSC-CM）的自发电活动表现出与人窦房结相当的心率变异性和幂律行为。我们在稳定条件下记录了hESC-CM和iPSC-CM长达15天的细胞外电图。自发活动的节拍率时间序列进行了检查，其功率谱密度和其他方法来自非线性动力学。主要发现是hESC-CM和iPSC-CM的平均搏动率在整个15天随访期间是稳定的，并且在两种细胞类型中是相似的，hESC-CM和iPSC-CM表现出内在搏动率变异性和分形行为，并且异丙肾上腺素增加和氨甲酰胆碱降低hESC-CM和iPSC-CM中的搏动率。这是第一项证明hESC-CM和iPSC-CM表现出与人类相同的心率变异性和幂律行为的研究，从而支持这些细胞来源作为生物起搏器的潜在能力。我们能够从患者自己的头发中产生窦房相容的自发心肌细胞（通过角质形成细胞衍生的iPSC），从而消除了对免疫抑制的关键需求，使这些心肌细胞成为生物起搏器的有吸引力的细胞来源。
The sinoatrial node is the main impulse-generating tissue in the heart. Atrioventricular conduction block and arrhythmias caused by sinoatrial node dysfunction are clinically important and generally treated with electronic pacemakers. Although an excellent solution, electronic pacemakers incorporate limitations that have stimulated research on biological pacing. To assess the suitability of potential biological pacemakers, we tested the hypothesis that the spontaneous electric activity of human embryonic stem cell– derived cardiomyocytes (hESC-CMs) and induced pluripotent stem cell– derived cardiomyocytes (iPSC-CMs) exhibit beat rate variability and power-law behavior comparable to those of human sinoatrial node. We recorded extracellular electrograms from hESC-CMs and iPSC-CMs under stable conditions for up to 15 days. The beat rate time series of the spontaneous activity were examined in terms of their power spectral density and additional methods derived from nonlinear dynamics. The major findings were that the mean beat rate of hESC-CMs and iPSC-CMs was stable throughout the 15-day follow-up period and was similar in both cell types, that hESC-CMs and iPSC-CMs exhibited intrinsic beat rate variability and fractal behavior, and that isoproterenol increased and carbamylcholine decreased the beating rate in both hESC-CMs and iPSC-CMs. This is the first study demonstrating that hESC-CMs and iPSC-CMs exhibit beat rate variability and power-law behavior as in humans, thus supporting the potential capability of these cell sources to serve as biological pacemakers. Our ability to generate sinoatrial-compatible spontaneous cardiomyocytes from the patient’s own hair (via keratinocyte-derived iPSCs), thus eliminating the critical need for immunosuppression, renders these myocytes an attractive cell source as biological pacemakers.