STEM CELLS AND CARDIOVASCULAR REPAIR

描述（由申请人提供）： 干细胞和心血管修复：我们提出了一个关于心肌梗死修复的综合计划，使用成人和多能人类干细胞，重点是临床前转化。有三个项目和三个核心。项目1（Murry，Schwartz，Mahoney）专注于血管化，从临床相关来源的人心肌细胞，内皮细胞和MSC的移植开始。接下来，他们移植了一种来自ESC的多能人类心血管祖细胞，能够产生心肌细胞，内皮细胞和平滑肌，以在梗死部位产生血管化心肌。最后，他们探讨了移植物诱导宿主冠状动脉侧支动脉化的机制。项目2（Laflamme，桑塔纳）研究人类心肌细胞的电生理学，利用遗传选择产生起搏细胞与工作型细胞。他们将鉴定将hESC衍生的肌细胞指定为工作型与起搏器表型的信号通路，目的是确定起搏器细胞是工作型细胞的前体还是单独的稳定分支。最后，他们使用细胞移植来评估不同肌细胞亚型与宿主心肌细胞偶联的能力，并测试它们对电稳定性的差异影响。项目3（Torok-Storb，Bowen-Pope）开发了犬心脏修复的临床前模型。他们将从最近产生的犬诱导多能干细胞（iPSC）中产生一种可规模化生产心肌细胞的系统。接下来，他们研究MSC是否可以促进内源性细胞和外源性心肌细胞的修复，包括测试MSC是否诱导第三方对同种异体心肌细胞的耐受性。最后，他们用犬iPSC衍生的心肌细胞和MSC进行移植研究，在犬中建立了心脏干细胞治疗的临床相关模型。项目得到了干细胞核心（A）的支持，该核心培训研究人员使用hESC并提供分化细胞，即，心肌细胞;成果核心（B）提供组织学服务，是心肌梗死动物模型、细胞移植和生理学评估的核心专业知识来源;行政核心（C）协调会议、研讨会系列、提供财政支持和计划年度PPG务虚会。

DESCRIPTION (provided by applicant): Stem Cells and Cardiovascular Repair: We propose a comprehensive program on myocardial infarct repair using adult and pluripotent human stem cells, with an emphasis on pre-clinical translation. There are 3 projects and 3 cores. Project 1 (Murry, Schwartz, Mahoney) focuses on vascularization, beginning with transplants of clinically relevant sources of human cardiomyocytes, endothelium and MSCs. Next, they transplant a multipotent human cardiovascular progenitor from ESCs, capable of generating cardiomyocytes, endothelium and smooth muscle, to generate vascularized myocardium in the infarct. Finally, they explore mechanisms through which grafts induce collateral arterialization from the host coronaries. Project 2 (Laflamme, Santana) studies the electro-physiology of human cardiomyocytes, using genetic selection to generate pacemaker vs. working-type cells. They will identify signaling pathways that specify hESC-derived myocytes into working-type vs. pacemaker phenotypes, with a goal of determining if pacemaker cells are precursors of the working-type cells or a separate stable branch. Lastly, they use cell transplantation to assess the ability of the different myocyte subtypes to couple with host cardiomyocytes and test their differential effects on electrical stability. Project 3 (Torok-Storb, Bowen-Pope) develops a pre-clinical model in the dog for cardiac repair. They will generate a system for scalable production of cardiomyocytes from their recently generated canine induced pluripotent stem cells (iPSCs). Next, they investigate if MSCs can pro-mote repair by endogenous cells and exogenous cardio-myocytes, including testing if MSCs induce third-party tolerance to allogeneic cardiomyocytes. Finally, they perform transplantation studies with canine iPSC-derived cardiomyocytes and MSCs, creating a clinically relevant model of cardiac stem cell therapy in the dog. Projects are supported by a Stem Cell Core (A) that trains investigators in hESC use and provides differentiated cells i.e., cardiomyocytes; an Out-comes Core (B) provides histology services, a central source of expertise in animal models of myocardial infarction, cell transplantation and physiological assessment; and an Administrative Core (C) to coordinate meetings, seminar series, provide fiscal support and plan the annual PPG retreat.