Induction of Cardiovascular Cells from hESCs by Embryonic Cues

描述(由申请人提供)：使用多能干细胞(PS)对病变或受损心肌进行治疗性再生取决于在体外有效地将PS细胞预分化为冠状动脉血管和心肌细胞谱系中的特定终点的能力。PPG的总体目标是阐明以与治疗性移植兼容的方式诱导同种心肌和冠脉血管细胞群的机制。这一目标将通过坚持一个压倒一切的主题，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冠状动脉血管谱系的分化来实现。子项目1和子项目4将重点研究内胚层分泌的生长因子如何介导hESCs向Nkx-2.5阳性和胰岛1阳性的心肌祖细胞诱导，而子项目2重点研究转录因子如何介导这些谱系决定。子项目3将对此进行补充，该项目将研究内胚层在多能ESCs的心前膜及其后代(包括冠状动脉内皮细胞和平滑肌冠状血管谱系)的规范过程中的作用。这些相互作用的子项目产生的协同作用将促进hESC来源的心肌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塞心脏中。利用这些能够提供最佳再生的细胞组合，将根据超声心动图和室压测量评估的功能结果以及组织学结果来评估移植改进，包括再灌注效果、移植细胞数量和移植时机，目的是将受损心肌移植到恢复心脏功能的血管化、跳动的心肌细胞合胞体中。行政(A)、胚胎干细胞(B)、心血管生理学(C)和组织与成像(D)核心提供的协同作用将促进成功完成这些任务

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