CARDIAC STEM CELLS AND AGING OF THE HEART

该提案的长期目标是证明心脏是一个自我更新的器官，因此，心脏衰老是由功能胜任的心脏干细胞（CSC）的逐渐耗竭决定的。待检验的主要假设是，驻留CSC的池大小的减少依赖于富含G的单链抗体的积累。 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损伤与阻断细胞周期的基因产物的表达一起定义了老化的CSC。衰老的CSC获得永久的和不可逆的生物学状态，其包括在G 0-G1中的生长停滞。继承人 心脏中的分布和定位可能影响CSC老化。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中，例如左心室的基部和中部，然后发生在心房、心尖和右心室中，这些区域受到显著较低水平的血流动力学负荷。CSC老化对细胞产生负面影响 心脏的更新导致老年心肌细胞的积累和年轻的更有效和强大的细胞的慢性下降。这是因为CSC在旧心脏中对称或不对称分裂，产生谱系定向细胞而不保留CSC池大小。这些假设将在大鼠的生理老化过程中进行测试，并在小鼠中进行自发突变和c-kit受体失活。将采用大鼠模型来提供c-kit（POS）CSC的生物学行为的年龄依赖性变化与心脏衰老之间的关系的详细表征。这种可能性将通过在受辐射大鼠中进行消融和补充干预来证实。将研究具有非功能性c-kit受体的W/W v小鼠，以确定c-kit（POS）CSC在心肌老化演变中的实际作用。如果我们提出的心脏老化的概念具有一定的有效性，那么在W/W v小鼠中补充功能胜任的c-kit（POS）CSC可以预期逆转这些动物中心脏的过早老化。相反，主动脉结扎术造成的超负荷应加速失代偿性心脏病的发展。 由无应答c-kit（POS）CSC产生新肌细胞和血管结构的限制所决定的肌病。这应该能模拟衰老衰竭的心脏同样，用完整的c-kit（POS）CSC治疗可能会积极干扰肌病。总之，CSC功能的损失，强迫静止可能条件老化和衰老的哺乳动物心脏。

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.