Cardiac Stem Cells and Angiomyogenesis

描述（由申请人提供）：认识到成人心肌中存在心脏干细胞（CSC）库，提出了CSC是否负责胚胎、胎儿和出生后心脏中的心肌发生、调节成人器官中的肌细胞更新和调节心肌老化的问题。干细胞更新通过对称分裂发生，其产生两个子干细胞，或通过不对称分裂发生，其产生一个与母细胞相同的子细胞和具有不同命运的第二子细胞。这种干细胞生长的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的分裂中共分离旧的原始模板DNA链，从而继承旧DNA的子细胞保留干细胞特征，而获得新DNA的子细胞进入转运扩增池。如果这一假设是正确的，那么母体干细胞的数量可能在生命早期的某个时候由遗传决定，并且此后无法扩增。相反，这类“真正的”干细胞可能会随着年龄的增长而急剧减少，CSC的丢失可能是衰老性肌病发展的关键决定因素。在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，这些因素通常与生命过程和心肌老化有关，与疾病过程无关。对CSC的过度生长需求可能导致它们的耗尽，并且因此导致衰老的、收缩不良的、肥大的心肌细胞的积累。相反，保存携带母亲DNA的CSC库可以延迟衰老心脏表型的表现。因此，本申请的长期目标是确定内源性CSC在产前和产后心脏发育中的作用，以及它们在完全成熟器官中的功能和在衰老性肌病的起始和进展中的功能。

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.