Stem Cells in the Developing Heart

发育中的心脏中的干细胞

• 批准号: 7782732
• 负责人: Marcello Rota
• 金额: $ 42.12万
• 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/7782732
• 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; Insulin-Like-Growth Factor I Receptor; 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; Ryanodine Receptors; Sarcoplasmic Reticulum; Scheme; Spatial Distribution; Staging; Stem cells; Stretching; System; Time; Transgenic Mice; Ventricular; Work; Workload; attenuation; base; calcium metabolism; cell growth; design; fetal; immunocytochemistry; in vivo; mechanical behavior; migration; mouse model; postnatal; prenatal; primitive cell; progenitor; promoter; public health relevance; receptor; regenerative; repaired; response; transcription factor; tripolyphosphate; young adult

DESCRIPTION (provided by applicant): 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 1-myosin heavy chain promoter (1MHC-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 1MHC-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. PUBLIC HEALTH RELEVANCE: Determining whether a selective class of stem cells is implicated in cardiac development has consequences on our understanding of the formation of the heart and the mechanisms that regulate muscle contraction. This information is critical for the identification of the regenerative potential of the adult heart and its ability to react and repair in response to cardiovascular disease.

描述（由申请人提供）：本申请提出了这样一种可能性：胚胎、胎儿和产后心脏的肌细胞区室是通过聚集在原始心脏内的壁龛中的常驻c-kit阳性心脏祖细胞（CPC）池的激活和谱系定型而产生的。心脏形态发生可能由 CPC 内的自发钙振荡介导，导致细胞生长和肌细胞表型的获得。 CPC 的命运可能受到细胞内钙的瞬时变化的调节，而细胞内钙构成了这些原始细胞对称和不对称分裂的基本要素。类似地，钙振荡调节 CPC 分化为功能健全的肌细胞，使肌细胞变得具有电和机械兴奋性。为了解决这些基本问题，开发了两种转基因小鼠模型：一种是 EGFP 受 c-kit 启动子（c-kit-EGFP 小鼠）控制，另一种是 EGFP 表达受心脏特异性 1-肌球蛋白重链启动子（1MHC-EGFP 小鼠）调节。 c-kit-EGFP 小鼠应该允许我们识别 c-kit 阳性 EGFP 阳性 CPC 在形成心脏中出现的胚胎阶段、它们的解剖分布以及产前和产后生活中的发育变化。 1MHC-EGFP 小鼠将允许我们定义出生后形成的肌细胞的定位和空间分布，并且该信息将与 c-kit-EGFP 小鼠中获得的数据相补充。通过这两个模型，将建立肌细胞的生成与CPC的激活、定型和分化之间的关系。这些研究将与 CPC 和线性相关细胞的电生理、机械和钙处理特性及其生长和分化模式的分析相结合。最终，细胞生理学和生长与钙作为主要调节系统的相互依赖性将被确定。因此，心内祖细胞在发育中的心脏中的作用将得到表征，并且该信息可能对心肌在以后的生活中适应缺血性和非缺血性损伤具有重要意义。公共健康相关性：确定特定类别的干细胞是否与心脏发育有关，对我们对心脏形成和调节肌肉收缩机制的理解产生影响。这些信息对于识别成人心脏的再生潜力及其对心血管疾病的反应和修复能力至关重要。