Induction of Cardiovascular Cells from hESCs by Embryonic Cues

用多能干细胞（PS）治疗性再生患病或受损的心肌取决于 在体外有效预分化PS细胞至冠状血管内的专门终点的能力 和心肌细胞谱系。本PPG的总体目标是阐明 心肌细胞和冠状血管细胞的同质群体可以以一种方式诱导， 与治疗性移植相容。这一目标将通过坚持一个压倒一切的原则来实现。 主题，基于胚胎发育过程中内胚层和中胚层谱系之间的相互作用， 特定的内胚层谱系诱导心肌源性和心外膜源性的分化， 冠状血管谱系。子项目1和4将重点研究内胚层分泌的生长因子 介导将hESC诱导为Nkx-2.5阳性和Islet 1阳性心肌细胞祖细胞，而 子项目2关注转录因子如何介导这些谱系决定。这将是 作为补充，子项目3将研究内胚层在规范 前心外膜及其后代，包括冠状动脉内皮和平滑肌冠状动脉血管 谱系，在多能胚胎干细胞中。这些相互作用的子项目所产生的协同作用将促进 的hESC衍生的心肌细胞和冠状血管细胞，其适合于移植到 动物模型的梗塞心脏。使用这些细胞的组合，赋予最佳的再生， 移植的改进，包括再灌注的影响，移植细胞的数量和时间， 移植将根据超声心动图评估的功能结果进行评价， 心室压力测量，以及移植目的的组织学结局 受损的心肌，具有血管化的、跳动的心肌细胞合胞体， 功能这些任务的成功完成将由行政（A）、环境、社会和文化事务部（E）和 细胞（B）、心血管生理学（C）和组织学与成像（D）核心

Therapeutic regeneration of diseased or damaged myocardium with pluripotent stem (PS) cells depends on the ability to efficiently pre-differentiate PS cells in vitro to specialized endpoints within the coronary vascular and cardiomyocyte lineages. The overall objective of this PPG is to elucidate mechanisms by which homogeneous populations of cardiomyogenic and coronary vascular cells can be induced in a fashion compatible with therapeutic transplantation. This objective will be approached by adhering to an over-riding theme, based on the interplay between endoderm and mesoderm lineages during embryonic development, that specific endodermal lineages induce differentiation of the cardiomyogenic and proepicardium-derived coronary vascular lineages. Subprojects 1 and 4 will focus on how endoderm-secreted growth factors mediate induction of hESCs into Nkx-2.5-positive and Islet 1-positive cardiomyocyte progenitors, while Subproject 2 focuses on how transcription factors mediate these lineage decisions. This will be complemented by Subproject 3 which will investigate endoderm's role during specification of the proepicardium and its progeny which includes coronary endothelial and smooth muscle coronary vascular lineages, in pluripotent ESCs. Synergy created by these interacting subprojects will facilitate the generation of hESC-derived cardiomyogenic and coronary vascular cells that are suitable for transplantation into infarcted hearts of animal models. Using a combination of these cells which confers optimal regeneration, transplantation refinements including effects of reperfusion, numbers of transplanted cells and timing of transplantation will be evaluated in terms of functional outcomes assessed by echocardiographic and ventricular pressure measurements, as well as by histological outcomes with the objective of engrafting damaged myocardium with a vascularized, beating syncytium of cardiomyocytes that restores cardiac function. Success achieving these tasks will be prmoted by synergy provided from Administrative (A), ES Cell (B), Cardiovascular Physiology (C) and Histology & Imaging (D) Cores