Induction of Cardiovascular Cells from hESCs by Embryonic Cues

描述（由申请人提供）：多能干细胞（PS）用于病变或受损心肌的治疗性再生依赖于体外将PS细胞有效地预分化到冠状血管和心肌细胞谱系内的特定终点的能力。本PPG的总体目标是阐明以一种与治疗性移植相容的方式诱导心肌细胞和冠状血管细胞的同质群体的机制。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了心源性和心外膜前源性冠状血管谱系的分化，从而达到了这一目标。亚项目1和4将专注于内胚层分泌的生长因子如何介导hESCs诱导成nkx -2.5阳性和胰岛1阳性心肌细胞祖细胞，而亚项目2则专注于转录因子如何介导这些谱系决定。子项目3将研究内胚层在多能ESCs中前心外膜及其后代（包括冠状动脉内皮和平滑肌冠状血管谱系）形成过程中的作用。这些相互作用的子项目产生的协同作用将促进hesc衍生的心肌细胞和冠状动脉血管细胞的产生，这些细胞适合移植到动物模型的梗死心脏中。利用这些细胞的最佳再生组合，移植改良包括再灌注效果、移植细胞数量和移植时间，将根据超声心动图和心室压测量评估的功能结果以及组织学结果进行评估，目的是将受损的心肌移植到血管化的、跳动的心肌细胞合胞体中，以恢复心脏功能。行政(A)、胚胎干细胞(B)、心血管生理(C)和组织学与成像(D)核心的协同作用将促进这些任务的成功实现

DESCRIPTION (provided by applicant): 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 promoted by synergy provided from Administrative (A), ES Cell (B), Cardiovascular Physiology (C) and Histology & Imaging (D) Cores