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衰老是由c-kit阳性心脏干细胞（CSCs）运动的时间依赖性变化决定的。CSCs有缺陷的迁移可能会反对它们从壁龛的出口和易位到旧心脏的损伤部位。调控干细胞迁移的一个引导系统涉及Eph受体酪氨酸激酶家族，它与表达ephrin配体的邻近细胞相互作用。EphA2受体优先位于CSCs的表面，而相应的配体ephrin A1分布在心肌细胞的膜上，在壁龛内起到支持细胞的作用。ephrin A1激活EphA2可导致CSCs定向迁移，促进其向损伤部位募集，而阻断EphA2通路则可消除CSCs的运动反应。ephrin A1/EphA2信号的异常可能干扰老化心脏中老年CSCs的易位。老龄心肌中CSCs迁移功能受损可能是由于：a)衰老心肌细胞ephrin A1合成减少；b) EphA2在CSCs中的表达降低；和/或c) EphA2及其下游效应物在翻译或翻译后水平的改变。这些可能性将进行测试，以确定旨在恢复衰老心肌中旧CSCs治疗功效的靶点。衰老CSCs中EphA2信号的恢复可能延缓、预防或逆转老化心脏表型的表现。此外，我们还开发了一种识别和选择性分离具有完整再生潜力的旧心脏CSCs的策略。随着年龄的增长，衰老的CSCs在心肌中积累；然而，一群具有高增长储备的“年轻”细胞在整个生命中持续存在。这些细胞有望保留ephrin A1/EphA2信号传导能力和迁移特性。基于年轻和年老的CSCs激活ephrin A1通路的不同能力，可以收集并使用具有功能能力的CSCs库，用机械效率高的心肌细胞重新填充衰老的心脏。最终，旧心脏的深刻重组可能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.