Stem Cells in the Developing Heart

发育中的心脏中的干细胞

• 批准号: 8249041
• 负责人: Marcello Rota
• 金额: $ 41.81万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8249041
• 关键词: 1,2-diacylglycerol; Abbreviations; Actinin; Actins; Address; Adult; Affect; Age; Angiotensin II; Anterior; Antigens; Biological Models; Birth; Calcium; Calcium Channel; Calcium Oscillations; Calcium-Sensing Receptors; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cell Differentiation process; Cell Proliferation; Cell division; Cell physiology; Cells; Cellular Structures; Complement; Connexin 43; Contractile Proteins; Coupled; Data; Development; Differentiation and Growth; Diglycerides; Discrimination; Elements; Embryo; Embryonic Heart; Endoplasmic Reticulum; Equation; Event; Fluorescence; Gap Junctions; Generations; Goals; Growth; Heart; Heart Atrium; Homeostasis; Human; Hypertrophy; ITPR1 gene; In Vitro; Inositol; Insulin-Like Growth Factor I; Laboratories; Lead; Life; Mechanics; Mediating; Mesoderm; Methodology; Mitotic; Mitotic spindle; Modeling; Morphogenesis; Mus; Muscle Cells; Muscle Contraction; Myocardial; Myosin Heavy Chains; Organ; Pattern; Peptidyl-Dipeptidase A; Phenotype; Physiological; Population; Process; Proliferating; Property; Proteins; Proto-Oncogene Protein c-kit; Published Comment; Renin-Angiotensin System; Research; Role; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum; Scheme; Spatial Distribution; Staging; Stem cells; Stretching; System; Time; Transgenic Mice; Ventricular; Work; Workload; abstracting; attenuation; base; calcium metabolism; cell growth; design; fetal; immunocytochemistry; in vivo; mechanical behavior; migration; mouse model; postnatal; prenatal; primitive cell; progenitor; promoter; receptor; regenerative; repaired; response; transcription factor; tripolyphosphate; young adult

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.

06. 项目总结/摘要 该应用提出了胚胎、胎儿和产后肌细胞室的可能性 心脏是由一组常驻 c-kit 阳性心脏祖细胞的激活和谱系定型产生的 细胞（CPC）聚集在原始心脏内的壁龛中。心脏形态发生可能是介导的 通过 CPC 内的自发钙振荡导致细胞生长和肌细胞的获得 表型。提出了这样一种可能性：CPC 的命运受到细胞内瞬时变化的调节。 钙是构成这些原始细胞对称和不对称分裂的基本元素。 类似地，钙振荡调节 CPC 分化为有功能的肌细胞， 变得可电和机械兴奋。为了解决这些基本问题，两只转基因小鼠 已开发出模型：其中 EGFP 受 c-kit 启动子（c-kit-EGFP 小鼠）和第二个，其中 EGFP 表达受心脏特异性 ¿-肌球蛋白重链调节 启动子（¿MHC-EGFP 小鼠）。 c-kit-EGFP 小鼠应该允许我们识别胚胎阶段 哪些 c-kit 阳性 EGFP 阳性 CPC 出现在正在形成的心脏中，它们的解剖分布和 产前和产后生活的发育变化。 MHC-EGFP 小鼠将允许我们定义 出生后形成的心肌细胞的定位和空间分布，这些信息将得到补充 以及在 c-kit-EGFP 小鼠中获得的数据。对于这两个模型，之间的关系 肌细胞的生成以及 CPC 的激活、定型和分化将被建立。这些 研究将与电生理学、机械和钙处理的分析相结合 CPC 和线性相关细胞的特性及其生长和分化模式。最终， 以钙为主要调节系统的细胞生理学和生长的相互依赖性将是 决定。因此，心内祖细胞在发育中的心脏中的作用将是 特征，并且该信息可能对心肌对缺血的适应具有重要意义 以及晚年的非缺血性损伤。