DESCRIPTION (provided by applicant): Our central hypothesis is that myocardial aging alone or together with cardiac pathology is dictated by depletion of human cardiac stem cells (hCSCs) with loss of growth reserve for organ homeostasis and repair. The identification of a class of hCSCs with enhanced ability for myocyte and vessel regeneration would have significant implications in delaying or reversing myocardial aging with restoration of the youth of the organ. The possibility that non-random chromatid segregation regulates stem cell division would prevent the acquisition of genomic mutations and telomere attrition during DNA replication. These processes cannot be avoided with random DNA template segregation, in which the old and new DNA strands are acquired by the daughter cell. The growth potential of stem cells possessing the old DNA is theoretically superior to that of stem cells inheriting only the newly synthesized DNA. However, whether this is an all-or-none phenomenon that applies to all organs and the heart in particular is unknown. Several critical issues have to be addressed, concerning the notion of asymmetric segregation of chromatids during stem cell division. They include: a) the actual primitive state of cells carrying the immortal DNA; b) the real length of telomere in cells with the "mother" DNA; c) the lack of quantitative estimates of the fraction of cells dividing by symmetric versus asymmetric chromatid segregation; and d) the molecular basis determining the enhanced growth reserve of hCSCs with the old DNA. These variables impose a reevaluation of the strategies implemented in the identification of hCSCs. Importantly, the etiology of the aging myopathy is unknown and defects in hCSCs may condition the senescent cardiac phenotype, which together with cardiac diseases, may lead to severe ventricular decompensation. On this premise, the role of symmetric stem cell division and fate, i.e., random DNA template segregation, and asymmetric stem cell division and fate, i.e., non-random DNA template segregation, will have to be determined to characterize the contribution of hCSC growth and differentiation to the development of the old failing heart.

This research aims at the identification of the most powerful resident cardiac stem cell present in the human heart. If successful, novel strategies for the treatment of the senescent failing heart will be identified. Additionally, the aging myopathy might be reversed with restoration of the youth of the organ.