Aging and Homeostasis of Cardiac Stem Cell Niches

描述(申请人提供)：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)和储存在壁龛中的早期承诺细胞(ECCs)。这种关于心脏的新观点提出了一种可能性，即心肌老化的发生是由于CSCs-ECC的数量逐渐增加，这些细胞永久退出细胞周期，尽管这些细胞的凋亡率增加。事实上，陈旧的CSCs-ECCs的积累速度可能大于它们的死亡速度，从而导致衰老生态位的形成和器官老化。对CSCs-ECCs和心肌细胞凋亡对心脏有害的旧范式提出了挑战，并引入了一种新的范式。未分裂的CSCs-ECCs和肥大的衰老心肌细胞的凋亡在这里被认为是一种有益的健康过程，可以保存心脏的年轻，从而保持其实质细胞的年轻。相反，对凋亡的抵抗会加速心脏衰老和心功能不全的发生。随着年龄的增长，聚集在壁龛中的CSCs-ECC可能变得不太容易凋亡，不太容易重新进入细胞周期，也不太能离开壁龛、生长和分化。因此，心肌细胞的生理性周转受损，陈旧的低效细胞在脑室积聚。在年轻的心脏中，当需要时，单个CSC可以维持心脏高功能要求所决定的整个细胞的替换；这一机制与克隆生长稳定模型相对应。在老年心脏中，这可能不是这样的情况，在这种情况下，几个CSC可能同时参与死亡细胞的替换；这种机制对应于克隆生长继承模型。将使用三种动物模型：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。W/WV小鼠具有c-kit受体突变，干细胞功能丧失，CSC-ECC加速，心肌细胞老化。相比之下，超级P53小鼠在细胞中野生型P53的表达增强；P53不是结构性激活的，但在刺激时，会导致放大的P53反应。Terc-/-小鼠和W/WV小鼠将使我们能够确定CSCs-ECC生长缺陷(Terc-/-)和CSC-ECC功能受损(W/WV)是否会导致壁龛中陈旧的未分裂原始细胞和脑室中衰老的心肌细胞积累。预计壁龛中抗凋亡的CSCs-ECCs的数量将增加，导致衰老壁龛的加速形成，并导致心肌更新从克隆稳定到克隆连续的早熟转变。相反，与心肌生长的克隆继承相比，P53小鼠可能具有CSCs-ECC的更新换代增强的结果，其结果是CSCs-ECC的死亡增强，克隆稳定性保持更长时间。同样，由于细胞凋亡增强而改善的心肌细胞再生可能延缓衰老细胞的积累，从而延缓心脏衰老和功能障碍的发生。最终，超级p53小鼠的寿命可能会延长。这项工作将促进我们对衰老和心力衰竭生物学的理解。

DESCRIPTION (provided by applicant): 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 possibility that myocardial aging occurs as a result of a progressive increase in the number of CSCs-ECCs permanently withdrawn from the cell cycle in spite of an increase in apoptosis of these cells.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 leading to 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-dividing CSCs- 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 accumulate in 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 clonal stability 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 W/WV 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.