Aging and Homeostasis of Cardiac Stem Cell Niches

描述（由申请人提供）：心脏是一个自我更新的器官，其特征是驻留心脏干细胞（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心肌衰老发生的可能性，即尽管CSCs-ECCs细胞凋亡增加，但这些细胞永久退出细胞周期的数量不断增加。事实上，老年csc - eccs的积累速度可能大于其死亡速度，从而导致衰老生态位的形成和器官老化。旧的观点认为csc - eccs和心肌细胞的凋亡对心脏有害，这一观点受到了挑战，并提出了新的观点。非分裂的CSCs- ECCs和肥大的衰老肌细胞的凋亡被认为是一个有益的健康过程，可以保持心脏的年轻，从而保持其实质细胞的年轻。相反，对细胞凋亡的抵抗加速了心脏老化和心室功能障碍的发生。随着年龄的增长，聚集在壁龛中的csc - eccs可能变得更不容易发生凋亡，更不容易重新进入细胞周期，更不容易离开壁龛，生长和分化。因此，心肌细胞的生理周转受损，老化的效率较低的细胞积聚在心室。在年轻的心脏中，当需要时，单个CSC可以维持由心脏的高功能需求所决定的整个细胞的替换；这一机制符合克隆生长稳定性模型。这在老心脏中可能不是这样，在老心脏中，几个csc可能同时参与死亡细胞的替换；这一机制符合无性系生长演替模型。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、肌细胞和心力衰竭的早衰一致。W/WV小鼠c-kit受体突变，干细胞功能丧失，CSC-ECC加速，肌细胞老化。相比之下，超级p53小鼠细胞中野生型p53的表达增强；P53不是组成性激活的，但在刺激时，会导致P53反应的放大。Terc-/-小鼠和W/WV小鼠将使我们能够确定CSCs-ECCs生长缺陷（Terc-/-）和受损的CSC-ECC功能（W/WV）是否会导致壁龛内旧的非分裂原始细胞的积累和心室中衰老的肌细胞。生态位中抗凋亡CSCs-ECCs的数量预计会增加，导致衰老生态位的加速形成，以及从克隆稳定到克隆演替的心肌周转的早熟转变。相反，p53小鼠的CSCs-ECCs的周转可能会增加，因为它们的死亡时间会增加，克隆稳定性的保存时间比心肌生长的克隆继承时间更长。同样，由于细胞凋亡的增强，肌细胞再生的改善可能会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possibility that myocardial aging occurs as a result of a progressive increase in the number of CSCs-ECCs permanently withdrawn from the cell cycle in spite of an increase in apoptosis of these cells.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.