PDF(Pubmed)
Abstract：
Transplantation of pluripotent stem cell-derived cardiomyocytes is a novel promising cell-based therapeutic approach for patients with heart failure. However, engraftment arrhythmias are a predictable life-threatening complication and represent a major hurdle for clinical translation. Thus, we wanted to experimentally study whether impulse generation by transplanted cardiomyocytes can propagate to the host myocardium and overdrive the recipient rhythm. We transplanted human induced pluripotent stem cell-derived cardiomyocytes expressing the optogenetic actuator Bidirectional Pair of Opsins for Light-induced Excitation and Silencing (BiPOLES) in a guinea pig injury model. Eight weeks after transplantation ex vivo, Langendorff perfusion was used to assess electrical coupling. Pulsed photostimulation was applied to specifically activate the engrafted cardiomyocytes. Photostimulation resulted in ectopic pacemaking that propagated to the host myocardium, caused non-sustained arrhythmia, and stimulated the recipient heart with higher pacing frequency (4/9 hearts). Our study demonstrates that transplanted cardiomyocytes can (1) electrically couple to the host myocardium and (2) stimulate the recipient heart. Thus, our results provide experimental evidence for an important aspect of engraftment-induced arrhythmia induction and thereby support the current hypothesis that cardiomyocyte automaticity can serve as a trigger for ventricular arrhythmias.
摘要：
多能干细胞衍生的心肌细胞的移植是用于心力衰竭患者的新型有前景的基于细胞的治疗方法。然而,植入心律失常是一种可预测的危及生命的并发症,是临床转化的主要障碍.因此，我们希望通过实验研究移植的心肌细胞产生的冲动是否可以传播到宿主心肌并过度驱动受体节律。我们在豚鼠损伤模型中移植了表达光遗传学致动器双向视蛋白对的人诱导多能干细胞衍生的心肌细胞，用于光诱导的激发和沉默（BiPOLES）。离体移植后八周，Langendorff灌注用于评估电耦合。施加脉冲光刺激以特异性激活移植的心肌细胞。光刺激导致异位起搏传播到宿主心肌，引起非持续性心律失常，并以更高的起搏频率（4/9心脏）刺激受体心脏。我们的研究表明，移植的心肌细胞可以（1）电耦合到宿主心肌和（2）刺激受体心脏。因此，我们的结果为植入诱发心律失常的一个重要方面提供了实验证据,从而支持了目前的假设,即心肌细胞自律性可以作为室性心律失常的触发因素.
