Integration and Arrhythmia Suppression with hESC-Derived Cardiomyocyte Grafts

描述（由申请人提供）：由于其巨大的体外扩增能力和分化成表型明确的心肌细胞的能力，多能人胚胎干细胞（hESC）是基于细胞的心脏治疗的有吸引力的来源。我们的研究小组有令人兴奋的新数据表明，hESC衍生的心肌细胞（hESC-CM）可以与宿主心肌细胞在豚鼠心脏移植后偶联，但它们在受损心脏中的整合是不完美的。我们还发现hESC-CM移植显著降低自发性和诱导性心律失常的发生率。本申请建立在这些观察结果的基础上，并且具有两个总体目标：第一，确定这种心肌抑制作用的机制基础，第二，测试进一步增强hESC-CM在受损心脏中的机电整合的新方法。在目的1中，我们将检验hESC-CM移植对电稳定性的有益作用与其功能掺入相关的假设。在目标2中，我们将检验以下假设：在豚鼠梗死模型中，用间隙连接修饰剂处理将改善hESC-CM移植后的宿主-移植物偶联。最后，在目标3中，我们将使用体外模型来开发Wnt 5a介导的趋化性作为改善hESC-CM移植物整合的补充策略。

DESCRIPTION (provided by applicant): Because of their tremendous capacity for in vitro expansion and ability to differentiate into phenotypically unambiguous cardiomyocytes, pluripotent human embryonic stem cells (hESCs) are an attractive source for cell-based cardiac therapies. Our group has exciting new data indicating that hESC-derived cardiomyocytes (hESC-CMs) can couple with host myocardium following transplantation in guinea pig hearts, but their integration is imperfect in injured hearts. We have also found that hESC-CM transplantation significantly decreases the incidence of both spontaneous and induced arrhythmias. The present application builds on these observations and has two overall goals: first, to determine the mechanistic basis for this arrhythmia-suppressive effect and, second, to test novel approaches to further enhance the electromechanical integration of hESC-CMs in injured hearts. In Aim 1, we will test the hypothesis that the beneficial effects of hESC-CM transplantation on electrical stability correlates with their functional incorporation. In Aim 2, w will test the hypothesis that treatment with gap-junction modifiers will improve host-graft coupling following hESC-CM transplantation in a guinea pig infarct model. Finally, in Aim 3, we will use in vitro models to develop Wnt5a-mediated chemotaxis as a complementary strategy to improve the integration of hESC-CM grafts.