Stem Cells in the Developing Heart

06.项目摘要/摘要 这一应用增加了胚胎、胎儿和出生后的肌细胞隔间的可能性 心脏是由一群常驻的c-kit阳性心脏祖细胞的激活和谱系承诺而产生的。 在原始心脏内聚集在壁龛中的细胞(CP)。心脏形态发生可能是由 通过CPC内自发的钙振荡导致细胞生长和获得心肌细胞 表型。提出了CPC的命运受细胞内瞬时变化影响的可能性 构成这些原始细胞对称和不对称分裂的基本元素的钙。 类似地，钙振荡调节CPC分化为具有功能的肌细胞， 变得电性和机械性可兴奋。为了解决这些根本问题，两只转基因小鼠 已经开发了模型：其中EGFP受c-kit-启动子(c-kit-EGFP)的控制 小鼠)和第二种受心脏特异性肌球蛋白重链调控的绿色荧光蛋白表达 启动子(MHC-EGFP小鼠)。C-kit-egfp小鼠应该可以让我们在 哪些c-kit阳性-EGFP阳性的CPC出现在形成的心脏中，它们的解剖分布和 出生前和出生后生活的发育变化。MHC-EGFP鼠标将允许我们定义 出生后形成心肌细胞的定位和空间分布，这一信息将得到补充 数据将在c-kit-EGFP小鼠中获得。在这两个模型中， 将建立心肌细胞的生成和CPC的激活、承诺和分化。这些 研究将与电生理、机械和钙处理的分析相结合 CPC和线性相关细胞的特性以及它们的生长和分化模式。最终， 以钙为主要调节系统的细胞生理和生长的相互依存关系将是 下定决心。因此，心内祖细胞在心脏发育中的作用将是 这一信息可能对心肌对缺血的适应有重要意义。 以及晚年的非缺血性损害。

06. Project Summary/Abstract This application raises the possibility that the myocyte compartment of the embryonic, fetal and post-natal heart is generated by activation and lineage commitment of a pool of resident c-kit-positive cardiac progenitor cells (CPCs) which are clustered in niches within the primitive heart. Cardiac morphogenesis may be mediated by spontaneous calcium oscillations within CPCs which lead to cell growth and the acquisition of the myocyte phenotype. The possibility is raised that the fate of CPCs is regulated by transient changes in intracellular calcium which constitute the essential element of symmetric and asymmetric division of these primitive cells. Similarly, calcium oscillations condition the differentiation of CPCs into functionally competent myocytes which become electrically and mechanically excitable. To address these fundamental issues, two transgenic mouse models have been developed: one in which EGFP is under the control of the c-kit-promoter (c-kit-EGFP mouse) and the second in which EGFP expression is regulated by the cardiac specific ¿-myosin heavy chain promoter (¿MHC-EGFP mouse). The c-kit-EGFP mouse should allow us to identify the embryonic stages at which c-kit-positive-EGFP-positive CPCs appear in the forming heart, their anatomical distribution and developmental changes in prenatal and postnatal life. The ¿MHC-EGFP mouse will permit us to define the localization and spatial distribution of forming myocytes postnatally and this information will be complemented with the data to be obtained in the c-kit-EGFP mouse. With these two models, the relationship between the generation of myocytes and the activation, commitment and differentiation of CPCs will be established. These studies will be integrated with the analysis of the electrophysiological, mechanical and calcium handling properties of CPCs and linearly related cells together with their pattern of growth and differentiation. Ultimately, the interdependence of cellular physiology and growth with calcium being the master regulatory system will be determined. Therefore, the role that intracardiac progenitor cells have in the developing heart will be characterized and this information may have important implications in the myocardial adaptations to ischemic and non-ischemic damage later in life.