Cardiac Stem Cell Growth, Aging and Death

心脏干细胞的生长、衰老和死亡

• 批准号: 6717523
• 负责人: JAN KAJSTURA
• 金额: $ 38.97万
• 依托单位: NEW YORK MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6717523
• 关键词: cardiac myocytes; cell age; cell cycle; cell growth regulation; cell population study; cell senescence; free radical oxygen; growth factor receptors; hepatocyte growth factor; insulinlike growth factor; laboratory mouse; laboratory rat; renin angiotensin system; stem cells; surface antigens

DESCRIPTION (provided by applicant): This project has three principal goals: 1. The recognition of the role that stem cell surface antigens have in conditioning the growth and differentiation of cardiac stem cells (CSCs) in myocardial cell lineages; 2. The demonstration that age leads to a downregulation of the hepatocyte growth factor (HGF)-cMet and insulin-like growth factor-1 (IGF-1)-IGF-1 receptor (IGF-1R) systems, and to an upregulation of the renin-angiotensin system (RAS) in CSCs and early committed cells; and 3. The identification of an age-dependent increase in the local RAS, which mediates the formation of reactive oxygen species (ROS), triggering apoptotic and necrotic death of CSCs, progenitors and precursors. Point 1 aims at the characterization of the classes of CSCs regulating the physiologic turnover of myocardial cells in the adult normal heart. This information is considered critical for the elucidation of the potential mechanisms of cardiac repair in disease states. Point 2 raises the possibility that attenuation of the HGF-c-Met system with age negatively interferes with the migration of CSCs from the storage areas to the injured sites of ventricular myocardium, limiting their activation and growth. Reduction of cell turnover results in accumulation of old cardiac cells with defective function. Similarly, the IGF-I-IGF-I R system might be downregulated in aging CSCs and this could affect cell replication, differentiation and survival, contributing to the development of the aging myopathy. Point 3 emphasizes the effects of oxidative damage induced by an upregulation of the local RAS not adequately counteracted by the IGF-I-IGF-1R system in the old heart. Low levels of oxidative challenge initiate apoptosis and high levels promote necrosis. Death of CSCs and early committed cells may result in the loss of the growth reserve of the aging myocardium. Senescent myocytes, coronary arterioles and capillary structures could die and the architecture of the ventricular wall may assume pathologic characteristics. These might include mural thinning, cavitary dilation, poor tissue perfusion, cardiac dysfunction and, ultimately, terminal failure and death. Thus, the hypothesis is advanced that CSC aging occurs and involves downregulation of growth factor receptor systems favoring locomotion, growth and differentiation. Conversely, inhibitors of the cell cycle and marker of cellular senescence increase in combination with oxidative DNA damage, potentiating the endogenous cell death pathway.

描述（由申请人提供）：该项目具有三个主要目标：1。对干细胞表面抗原在调节心肌细胞谱系中心脏干细胞（CSC）的作用的识别； 2。证明年龄导致肝细胞生长因子（HGF）-CMET和胰岛素样生长因子-1（IGF-1）-IGF-1受体（IGF-1R）系统的下调，以及CSC和早期合作细胞中肾素 - 血管紧张素系统（RAS）的上调；和3。鉴定局部RA的年龄依赖性增加，局部RA介导了活性氧（ROS）的形成，触发CSC，祖细胞和前体的凋亡和坏死死亡。点1的目的是表征CSC的类别，该类别调节成人正常心脏中心肌细胞的生理周转。该信息对于阐明疾病状态中心脏修复的潜在机制至关重要。点2提高了HGF-C-MET系统随着年龄的衰减而衰减的可能性，使CSC从存储区域迁移到心室心肌受伤部位的迁移，从而限制了它们的激活和生长。细胞更新的减少导致功能有缺陷的旧心细胞的积累。同样，IGF-I-IGF-I R系统可能在老化的CSC中被下调，这可能会影响细胞的复制，分化和生存，这有助于衰老肌病的发展。第3点强调了由旧心脏中IGF-I-IGF-1R系统对局部RA的上调所引起的氧化损伤的影响。低水平的氧化挑战会引发凋亡，高水平促进坏死。 CSC的死亡和早期所承诺的细胞可能导致衰老心肌的生长储备丧失。衰老的肌细胞，冠状动脉和毛细血管结构可能会死亡，并且心室壁的结构可能具有病理特征。这些可能包括壁画变薄，空洞扩张，组织灌注不良，心脏功能障碍以及最终的终末失败和死亡。因此，假设CSC衰老发生并涉及有利于运动，生长和分化的生长因子受体系统的下调。相反，细胞周期的抑制剂和细胞衰老的标志物与氧化DNA损伤的结合增加，增强了内源性细胞死亡途径。