Induction of Cardiovascular Cells from hESCs by Embryonic Cues

通过胚胎线索从 hESC 诱导心血管细胞

• 批准号: 7904883
• 负责人: John W Lough
• 金额: $ 167.41万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7904883
• 关键词: Induction; Cardiovascular; Cells; hESCs; Embryonic

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

描述（由申请人提供）：患病或损坏的心肌的治疗性再生具有多能茎（PS）细胞取决于有效地在冠状血管和心脏索细胞谱系中有效预分化PS细胞的能力。该PPG的总体目的是阐明机制，通过这种机制，可以以与治疗性移植兼容的方式诱导心肌和冠状动脉血管细胞的均质种群。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，该目标将通过遵守过度骑行的主题来实现，该特定的内胚层诱导了心肌生成性和前胸膜衍生的冠状动脉血管谱系的分化。次要注射1和4将集中于内胚层分泌的生长因子如何介导HESC诱导到NKX-2.5阳性和ISLET和ISLET 1阳性心肌细胞祖细胞中，而Subproject 2的重点是转录因子如何介导这些谱系决策。这将由副标题3补充，该第3次将研究内胚层在预胸膜及其后代的规范中的作用，其中包括冠状动脉内皮和平滑肌冠状动脉血管谱系，在多能ESC中。这些相互作用的次体产生的协同作用将促进适合于移植到动物模型梗塞心脏的hESC衍生的心肌和冠状动脉血管细胞的产生。将使用这些细胞的组合来赋予最佳再生，移植精炼，包括再灌注的影响，移植细胞的数量和移植的时间，将根据超声心动图和心室压力测量以及通过组织学的构造，由造成的综合构成的造影量来评估。恢复心脏功能的心肌细胞。完成这些任务的成功将由行政（a），ES细胞（b），心血管生理学（C）和组织学和成像（D）核心提供的协同作用。