CARDIAC STEM CELLS AND AGING OF THE HEART

这一建议的长期目标是证明心脏是一个自我更新的器官，因此，心脏衰老是由功能正常的心脏干细胞(CSCs)的逐渐枯竭决定的。需要检验的主要假设是，常驻CSCs池大小的减少取决于富含G的单链的积累 片段，端粒相关蛋白的下调，染色质后期桥的形成和端粒缩短。这些形式的DNA损伤与阻止细胞周期的基因产物的表达一起定义了衰老的CSCs。衰老的CSCs获得了一种永久的、不可逆的生物学状态，包括生长停滞在G0-G1期。T继承人 CSC在心脏的分布和定位可能影响CSC的衰老。CSC老化可能首先发生在暴露于高血流动力学应力的解剖区域，如左心室底部和中部，然后发生在承受明显较低血流动力学负荷水平的心房、心尖部和右室。CSC老化对细胞有负面影响 心脏的周转导致陈旧的心肌细胞的积累和年轻的、更有效和强大的细胞的慢性衰退。这是因为CSC在旧心脏中对称或不对称地分裂，在不保持CSC池大小的情况下产生有血统的细胞。这些假说将在大鼠的生理衰老过程中以及c-kit受体自发突变和失活的小鼠中得到验证。大鼠模型将被用来提供c-kit(POS)CSCs生物学行为的年龄依赖变化与心脏老化之间的关系的详细表征。这种可能性将通过对受辐射的大鼠进行消融和补充干预来证实。为了确定c-kit(POS)CSCs在心肌衰老进化中的实际作用，将对带有非功能性c-kit受体的W/W v小鼠进行研究。如果我们提出的心脏老化的概念有一定的正确性，那么在W/W v小鼠中补充功能正常的c-kit(POS)CSCs有望逆转这些动物心脏的过早衰老。相反，通过主动脉环扎术施加的超负荷应该加速失代偿的发展。 肌病是由无反应的c-kit(POS)CSCs在产生新的心肌细胞和血管结构方面的局限性所决定的。这应该模仿衰老衰竭的心脏。同样，使用完整的c-kit(POS)CSCs治疗可能会对肌病产生积极的干扰作用。总之，强迫静息导致的CSC功能丧失可能导致哺乳动物心脏的衰老和衰老。

The long-term objective of this proposal is to demonstrate that the heart is a self-renewing organ and, therefore, cardiac aging is determined by the progressive depletion of functionally competent cardiac stem cells (CSCs). The major hypothesis to be tested is that the reduction in the pool size of resident CSCs is dependent on the accumulation of G-rich single stranded fragments, downregulation of telomere related proteins, formation of chromatin anaphase bridges and telomeric shortening. These forms of DNA damage together with the expression of gene products blocking the cell cycle define aged CSCs. Senescent CSCs acquire a permanent and irreversible biological status, which consists of growth arrest i n G0-G1. T heir distribution and localization in the heart may influence CSC aging. CSC aging could occur first in anatomical regions exposed to high hemodynamic stress, such as the base and mid-portion of the left ventricle, and later in the atria, apex and right ventricle, which are subjected to significantly lower levels of hemodynamic loads. CSC aging negatively affects the cell turnover of the heart resulting in the accumulation of old myocytes and a chronic decline in young more efficient and powerful cells. This is because CSCs divide symmetrically or asymmetrically in the old heart, giving rise to lineage committed cells without preserving the CSC pool size. These hypotheses will be tested during physiological aging in rats, and in mice with spontaneous mutation and inactivation of the c-kit receptor. The rat model will be employed to provide a detailed characterization of the relationship between the age-dependent changes in the biological behavior of c-kit(POS) CSCs and heart aging. This possibility will be confirmed by ablation and replenishment interventions in irradiated rats. The W/W v mouse with a non-functional c-kit receptor will be studied in order to define the actual role of c-kit(POS) CSCs in the evolution of myocardial aging. If the notion of heart aging we have suggested has some validity, replenishment of functionally competent c-kit(POS) CSCs in W/W v mice can be expected to reverse premature aging of the heart in these animals. Conversely, the imposition of an overload by aortic banding should accelerate the development of a decompensated myopathy dictated by limitations in the generation of new myocytes and vascular structures by the non-responding c-kit (POS) CSCs. This should mimic the senescent failing heart. Again, treatment with intact c-kit(POS) CSCs might positively interfere with the myopathy. In conclusion, loss of CSC function by forced quiescence may condition aging and senescence of the mammalian heart.