Ephrin A1/EphA2 Signaling and Myocardial Aging

描述(申请人提供)：本申请的中心假设是，心肌老化是由c-kit阳性的心脏干细胞(CSCs)的运动性随时间变化而决定的。CSCs的有缺陷的迁移可能会阻碍它们从壁龛出口和移位到旧心脏的损伤部位。调节干细胞迁移的引导系统涉及Eph受体酪氨酸激酶家族，该家族与表达ephin配体的邻近细胞相互作用。EphA2受体优先定位于CSCs的表面，而相应的配体ephin A1分布在心肌细胞膜上，心肌细胞在壁龛内充当支持细胞。EphA2被EPhin A1激活导致CSCs定向迁移，促进其向损伤部位募集，而EphA2通路的阻断则取消了CSCs的运动性反应。EPhin A1/EphA2信号的异常可能会干扰老化心脏中陈旧的CSCs的移位。CSCs在老年心肌中的迁移受损可能与以下因素有关：a)衰老心肌细胞合成Ephin A1减少；b)CSCs中EphA2表达减少；和/或c)EphA2及其下游效应物在翻译或翻译后水平发生改变。这些可能性将被测试，以确定旨在恢复衰老心肌中陈旧CSCs治疗效果的靶点。在老年CSCs中恢复EphA2信号可能会延缓、预防或逆转老化的心脏表型的表现。此外，我们还开发了一种从旧心脏中识别和选择性分离具有完整再生潜力的CSCs的策略。随着年龄的增长，衰老的CSCs在心肌中积累；然而，具有高生长储备的“年轻”细胞池在一生中持续存在。这些细胞有望保留ePhin A1/EphA2信号转导能力和迁移特性。基于年轻和老年CSCs激活EPhin A1途径的不同能力，可以收集和实施具有功能功能的CSCs池，以使衰老的心脏重新填充机械效率高的心肌细胞。最终，对旧心脏的深刻重组可能会延长人类的健康和寿命。

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.