Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, USA.
Center for Cardiovascular Biology, University of Washington, Seattle, Washington, USA.
Nat Biotechnol. 2018 Aug;36(7):597-605. doi: 10.1038/nbt.4162. Epub 2018 Jul 2.
Pluripotent stem cell-derived cardiomyocyte grafts can remuscularize substantial amounts of infarcted myocardium and beat in synchrony with the heart, but in some settings cause ventricular arrhythmias. It is unknown whether human cardiomyocytes can restore cardiac function in a physiologically relevant large animal model. Here we show that transplantation of ∼750 million cryopreserved human embryonic stem cell-derived cardiomyocytes (hESC-CMs) enhances cardiac function in macaque monkeys with large myocardial infarctions. One month after hESC-CM transplantation, global left ventricular ejection fraction improved 10.6 ± 0.9% vs. 2.5 ± 0.8% in controls, and by 3 months there was an additional 12.4% improvement in treated vs. a 3.5% decline in controls. Grafts averaged 11.6% of infarct size, formed electromechanical junctions with the host heart, and by 3 months contained ∼99% ventricular myocytes. A subset of animals experienced graft-associated ventricular arrhythmias, shown by electrical mapping to originate from a point-source acting as an ectopic pacemaker. Our data demonstrate that remuscularization of the infarcted macaque heart with human myocardium provides durable improvement in left ventricular function.
多能干细胞衍生的心肌细胞移植物可以使大量梗死的心肌重新肌肉化，并与心脏同步跳动，但在某些情况下会引起室性心律失常。目前尚不清楚人类心肌细胞是否可以在生理相关的大型动物模型中恢复心脏功能。在这里，我们展示了约 7.5 亿个冷冻保存的人类胚胎干细胞衍生的心肌细胞（hESC-CMs）的移植可以增强患有大面积心肌梗死的猕猴的心脏功能。hESC-CM 移植后 1 个月，与对照组的 2.5 ± 0.8%相比，整体左心室射血分数提高了 10.6 ± 0.9%，3 个月时，治疗组的左心室射血分数又提高了 12.4%，而对照组则下降了 3.5%。移植物平均占梗死面积的 11.6%，与宿主心脏形成电机械连接，并且在 3 个月时包含约 99%的心室肌细胞。一部分动物经历了与移植物相关的室性心律失常，通过电描记图显示，这些心律失常起源于一个作为异位起搏器的点源。我们的数据表明，用人类心肌细胞重塑梗死的猕猴心脏，可以提供持久的左心室功能改善。
