Aging and Homeostasis of Cardiac Stem Cell Niches

心脏是一个自我更新的器官，其特征是驻留的心脏干细胞(CSCs)和早期承诺的细胞 (ECCS)储存在壁龛中。这种关于心脏的新观点增加了心肌老化发生的可能性 CSCs-ECC的数量逐渐增加，尽管增加了，但却永久退出了细胞周期 在这些细胞的凋亡中。事实上，旧的CSCs-ECC的积累速度可能大于其 死亡导致衰老的壁龛的形成和器官的老化。CSCs-ECCs凋亡的旧范式 心肌细胞对心脏有害，受到挑战，一种新的范式被引入。非分红CSCs的细胞凋亡- ECCS和肥大的衰老心肌细胞在这里被认为是一种有益的健康过程，可以保存年轻 心脏，因此，它的实质细胞的年轻。相反，对细胞凋亡的抵抗会加速心脏 衰老与心功能不全的发病。随着年龄的增长，聚集在壁龛中的CSCs-ECC可能会变少 易受细胞凋亡的影响，不易重新进入细胞周期，不太可能离开壁龛，生长和 差异化。因此，心肌细胞的生理性周转受损，老化的低效细胞积累。 脑室。在年轻的心脏中，当需要时，单个CSC可以维持整个细胞的替换 由心脏的高功能要求决定的；这一机制对应于克隆稳定性模型 关于成长的。这可能不是老心脏的情况，在旧心脏中，几个CSC可能同时参与 替换垂死的细胞；这一机制对应于克隆生长的连续模式。三只动物 将使用模型：端粒酶缺失(Terc“‘”)小鼠、W/WV小鼠和超级p53小鼠。Terc“‘” 小鼠的心脏表型与CSCs、心肌细胞和心力衰竭的早衰相一致。这个 W/WV小鼠c-kit受体突变，干细胞功能丧失，CSC-ECC和心肌细胞加速 衰老。相反，超级P53小鼠在细胞中野生型P53的表达增强；P53不是 结构性激活，但在刺激时，会导致放大的P53反应。《终结者》--《老鼠与波》 小鼠将允许我们确定CSCs-ECC(Terc“‘)和受损的CSC-ECC的生长缺陷 功能(W/WV)导致壁龛内陈旧的未分裂原始细胞积累并衰老 脑室的肌细胞。预计壁龛中抗凋亡的CSCs-ECCs的数量将会增加 导致衰老生态位的加速形成和从克隆稳定到克隆的早熟转变 连续的心肌周转。相反，p53小鼠可能具有CSCs-ECCs作为一种 心肌细胞克隆性稳定性与克隆性演替的结果比较 成长。同样，由于细胞凋亡的增强而导致的心肌细胞再生的改善可能会延缓 衰老细胞的积累，因此，心脏衰老和功能障碍的开始。最终，寿命可能是 在超级P53小鼠中增加。这项工作将促进我们对衰老和心力衰竭生物学的理解。

The heart is a self-renewing organ characterized by resident cardiac stem cells (CSCs) and early committed cells (ECCs) stored in niches. This novel view of the heart raises the possibilitythat myocardial aging occurs as a result of a progressive increase in the numberof CSCs-ECCs permanentlywithdrawn from the cell cycle in spite of an increase in apoptosis of these cells. In fact, the rate of accumulation of old CSCs-ECCs might be greater than the rate of their death leadingto the formation of senescent niches and organ aging. The old paradigm that apoptosis of CSCs-ECCs and myocytes is bad for the heart is challenged and a new paradigm is introduced. Apoptosis of non-dividingCSCs- ECCs and hypertrophied senescent myocytes is proposed here as a beneficial healthy process that preserves the youth of the heart and, thereby, the youth of its parenchymal cells. Conversely, resistance to apoptosis accelerates cardiac aging and the onset of ventricular dysfunction. With age, CSCs-ECCs clustered in the niches may become less susceptible to apoptosis, less prone to re-enter the cell cycle and less capable of leaving the niches, growing and differentiating. Therefore, the physiologic turnover of myocytes is impaired and old less efficient cells accumulatein the ventricle. In the young heart, a single CSC may sustain, when the need arises, the entire replacement of cells dictated by the high functional requirements of the heart; this mechanism corresponds to the model of clonalstability of growth. This may not be the case in the old heart in which several CSCs may be concurrently involved in the replacement of dying cells; this mechanism corresponds to the model of clonal succession of growth. Three animal models will be used: the telomerase null (Terc"'") mouse, the W/WV mouse and the super p53 mouse. The Terc"'" mouse has a cardiac phenotype that is consistent with precocious aging of CSCs, myocytes and heart failure. The W/WV mouse has a mutation of the c-kit receptor with loss of stem cell function, accelerated CSC-ECC and myocyte aging. In contrast, the super p53 mouse has an enhanced expression of wild-type p53 in the cells; p53 is not constitutively activated but, upon stimulation, leads to an amplified p53 response. The Terc." mouse and the WAV mouse will allow us to determine whether defects in the growth of CSCs-ECCs (Terc"'") and impaired CSC-ECC function (W/WV) result in the accumulation of old non-dividing primitive cells within the niches and senescent myocytes in the ventricles. The number of apoptosis-resistant CSCs-ECCs in the niches is anticipated to increase resulting in an accelerated formation of senescent niches and precocious shift from clonal stability to clonal succession of myocardial turnover. Conversely, the p53 mouse may have an enhanced turnover of CSCs-ECCs as a result of potentiation of their death and longer preservation of clonal stability versus clonal succession of myocardial growth. Similarly, the ameliorated regeneration of myocytes due to the enhanced apoptosis may delay the accumulation of senescent cells and, therefore, the onset of cardiac aging and dysfunction. Ultimately, lifespan may be increased in the super p53 mouse. This work will advance our understanding of the biology of aging and heart failure.