Cardiac Stem Cells and Angiomyogenesis

描述（由申请人提供）：在成人心肌中存在心脏干细胞（CSCs）的认识提出了一个问题，即CSCs是否负责胚胎、胎儿和出生后心脏的心肌形成，调节成人器官中的心肌细胞更新和心肌衰老。干细胞的更新是通过对称分裂产生两个子干细胞，或者通过不对称分裂产生一个与母细胞相同的子细胞和另一个具有不同命运的子细胞。干细胞生长的这个概念最近被一个旧理论的复活所扰乱，该理论认为干细胞能够在连续分裂中将旧的原始模板DNA链聚集在一起，因此继承旧DNA的子细胞保留了干细胞的特征，而获得新DNA的子细胞则进入了转运扩增池。如果这一假设是正确的，那么母干细胞的数量可能是在生命早期的某个时候由基因决定的，此后就无法扩大。相反，这类“真正的”干细胞可能随着年龄的增长而急剧减少，CSCs的丢失可能是衰老性肌病发展的关键决定因素。干细胞分裂过程中对旧DNA的保护不能防止氧化应激和环境因素的后果，这些因素通常存在于生命过程和心肌衰老中，独立于疾病过程。对CSCs的过度生长需求可能导致其耗竭，从而导致衰老、收缩不良、肥大的心肌细胞的积累。相反，保存携带母体DNA的CSCs可能会延缓衰老心脏表型的表现。因此，这项应用的长期目标是确定内源性CSCs在出生前和出生后心脏发育中的作用，以及它们在完全成熟的器官和衰老性肌病的发生和进展中的功能。

DESCRIPTION (provided by applicant): The recognition that a pool of cardiac stem cells (CSCs) is present in the adult myocardium poses the question whether CSCs are responsible for cardiomyogenesis in the embryonic, fetal and postnatal heart, regulate myocyte renewal in the adult organ and condition myocardial aging. Stem cell renewal occurs by symmetric division, which generates two daughter stem cells, or by asymmetric division, which generates one daughter cell that is identical to the mother cell and a second daughter cell which has a separate fate. This notion of stem cell growth has recently been perturbed by the resurrection of an old theory, suggesting that stem cells are capable of cosegregating the old original template DNA strands in consecutive divisions so that the daughter cell that inherits the old DNA retains stem cell features while the daughter cell that acquires the new DNA enters the transit amplifying pool. If this hypothesis is correct, the number of mother stem cells may be genetically determined sometime early in life and cannot be expanded thereafter. Conversely, this class of "true" stem cells may decrease dramatically as a function of age and loss of CSCs may be a critical determinant of the development of the aging myopathy. Protection of the old DNA during stem cell division cannot prevent the consequences of oxidative stress and environmental factors commonly present with the course of life and myocardial aging, independently from disease processes. Excessive growth demands on CSCs may lead to their depletion and, as a consequence, to accumulation of senescent, poorly contracting, hypertrophied cardiomyocytes. Conversely, preservation of the pool of CSCs carrying the mother DNA may delay the manifestations of the senescent cardiac phenotype. Thus, the long-term objective of this application is to establish the role of endogenous CSCs in the development of the heart prenatally and postnatally, and their function in the fully mature organ and in the initiation and progression of the aging myopathy.