STEM CELLS AND CARDIOVASCULAR REPAIR

描述(由申请人提供)： 干细胞和心血管修复：我们提出了一个使用成人和多能人类干细胞修复心肌梗死的综合计划，重点是临床前的翻译。有3个项目和3个核心。项目1(Murry，Schwartz，MaHony)专注于血管形成，首先移植临床相关来源的人心肌细胞、内皮细胞和间充质干细胞。接下来，他们从胚胎干细胞移植了一种多能的人类心血管前体细胞，能够产生心肌细胞、内皮细胞和平滑肌，在梗死区产生血管化的心肌。最后，他们探索了移植物诱导宿主冠脉侧支动脉化的机制。项目2(Laflamme，Santana)研究人类心肌细胞的电生理学，使用遗传选择来产生起搏器细胞与工作型细胞。他们将确定将hESC来源的心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不同影响。项目3(Torok-Storb，Bowen-Pope)在狗身上开发了一种心脏修复的临床前模型。他们将建立一个系统，从他们最近产生的犬类诱导多能干细胞(IPSCs)中可扩展地生产心肌细胞。接下来，他们研究MSCs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MSCs是否诱导第三方对同种异体心肌细胞的耐受。最后，他们用犬IPSC来源的心肌细胞和MSCs进行移植研究，在狗身上创建了一个临床相关的心脏干细胞治疗模型。项目得到干细胞核心(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；Out-Come核心(B)提供组织学服务，这是心肌梗死动物模型、细胞移植和生理评估的主要专业知识来源；以及行政核心(C)，协调会议、研讨会系列、提供财政支持和计划年度PPG撤退。

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.