Ephrin A1/EphA2 Signaling and Myocardial Aging

描述（由申请人提供）：本申请的中心假设是心肌老化由c-kit阳性心脏干细胞（CSC）运动性的时间依赖性变化决定。CSC的迁移缺陷可能会阻碍它们从龛位中流出并易位到旧心脏中的损伤部位。调节干细胞迁移的引导系统涉及Eph受体酪氨酸激酶家族，其与表达肝配蛋白配体的邻近细胞相互作用。EphA 2受体优先位于CSC的表面上，而相应的配体肝配蛋白A1分布在心肌细胞的膜上，心肌细胞充当小生境内的支持细胞。通过肝配蛋白A1激活EphA 2导致CSC的定向迁移，促进它们向损伤部位的募集，而阻断EphA 2途径消除CSC的运动反应。Ephrin A1/EphA 2信号通路的缺失可能会干扰衰老心脏中陈旧CSC的易位。陈旧心肌中CSC迁移受损可能由以下因素决定：a）衰老心肌细胞肝配蛋白A1的合成减少; B）CSC中EphA 2的表达减少;和/或c）EphA 2及其下游效应物的翻译或翻译后水平的改变。这些可能性将被测试，以确定旨在恢复衰老心肌中的老CSC的治疗效果的目标。在老年CSC中EphA 2信号传导的恢复可以延迟、预防或逆转衰老心脏表型的表现。此外，我们已经开发了一种策略，用于识别和选择性分离具有完整再生潜力的CSCs。随着年龄的增长，衰老的CSC在心肌中积累;然而，具有高生长储备的“年轻”细胞池在整个生命中持续存在。预期这些细胞保留ephrin A1/EphA 2信号传导能力和迁移特性。基于年轻和年老的CSC激活肝配蛋白A1通路的不同能力，可以收获功能上有能力的CSC库并实施以用机械有效的心肌细胞重新填充衰老的心脏。最终，老年心脏的深刻重组可能会延长人类的健康寿命和寿命。

DESCRIPTION (provided by applicant): The central hypothesis of this application is that myocardial aging is dictated by time-dependent changes in the motility of c-kit-positive cardiac stem cells (CSCs). Defective migration of CSCs may oppose their egress from the niches and translocation to the sites of damage in the old heart. A guidance system that regulates stem cell migration involves the family of Eph receptor tyrosine kinases, which interact with the neighboring cells expressing the ephrin ligands. EphA2 receptors are preferentially located on the surface of CSCs, while the corresponding ligand, ephrin A1, is distributed on the membrane of cardiomyocytes, which act as supporting cells within the niches. Activation of EphA2 by ephrin A1 results in directional migration of CSCs, promoting their recruitment to the site of injury, while blockade of the EphA2 pathway abrogates the motile response of CSCs. Abnormalities in ephrin A1/EphA2 signaling may interfere with the translocation of old CSCs in the aging heart. The impaired migration of CSCs in old myocardium may be dictated by: a) reduced synthesis of ephrin A1 by senescent cardiomyocytes; b) decreased expression of EphA2 in CSCs; and/or c) alterations at the translational or post-translational level of EphA2 and its downstream effectors. These possibilities will be tested to identify targets aiming at the recovery of the therapeutic efficacy of old CSCs in the senescent myocardium. Restoration of EphA2 signaling in old CSCs may delay, prevent, or reverse the manifestations of the aging cardiac phenotype. Additionally, we have developed a strategy for the recognition and selective isolation of CSCs with intact regenerative potential from the old heart. With aging, senescent CSCs accumulate in the myocardium; however, a pool of "young" cells with high growth reserve persists throughout life. These cells are expected to retain ephrin A1/EphA2 signaling capacity and migratory properties. Based on the differential ability of young and old CSCs to activate the ephrin A1 pathway, the pool of functionally-competent CSCs may be harvested and implemented to repopulate the senescent heart with mechanically efficient cardiomyocytes. Ultimately, the profound restructuring of the old heart may prolong the health span and lifespan in humans.