Induction of Cardiovascular Cells from hESCs by Embryonic Cues

多能干细胞对病变或受损心肌的治疗再生依赖于 体外有效地将PS细胞预分化为冠状动脉血管内的特殊终点的能力 和心肌细胞谱系。这个PPG的总体目标是阐明通过什么机制 均一群体的心肌和冠脉血管细胞可以通过一种方式被诱导 与治疗性移植相容。这一目标的实现将通过坚持凌驾于 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来源的分化 冠状动脉血管谱系。子项目1和4将集中于内胚层如何分泌生长因子 介导hESCs向Nkx-2.5阳性和胰岛1阳性心肌祖细胞的诱导，而 子项目2的重点是转录因子如何调节这些血统决定。这将是 子项目3将调查内胚层在规范 心前膜及其子代，包括冠脉内皮细胞和血管平滑肌 血统，在多能胚胎干细胞中。这些相互作用的子项目产生的协同效应将促进 人胚胎干细胞来源的心肌和冠脉血管细胞适合移植到 心肌梗死动物模型。使用这些细胞的组合可以实现最佳再生， 移植的改进，包括再灌注的影响，移植细胞的数量和移植的时机 移植将根据超声心动图评估的功能结果和 心脏压力测量，以及植入目的的组织学结果 受损的心肌，有血管的，跳动的心肌细胞合胞体，恢复心脏 功能。成功完成这些任务将由行政(A)、经济顾问(ES)提供的协同作用推动 细胞(B)、心血管生理学(C)和组织学与影像(D)

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