Aging is the major independent risk factor for chronic heart failure. Despite the presence of cardiac stem cells (CSCs), the old human heart undergoes progressive deterioration in ventricular performance, coupled with scattered foci of fibrosis and accumulation of poorly contracting myocytes. We raised the possibility that defects in the translocation of senescent human CSCs (hCSCs) to the sites of damage constitute a key determinant in the manifestation of the aging myopathy. We report that ephrin A1-EphA2 receptor signaling is a critical modulator of hCSC motility. Ephrin A1, a membrane-anchored protein, is expressed on the myocyte sarcolemma and acts as a ligand for the EphA2 receptor on neighboring hCSCs, facilitating their migration. Pre-treatment of young hCSCs with ephrin A1 resulted in enhanced movement of the transplanted cells to the necrotic tissue, with formation of new myocardium and improvement in cardiac function. Whether senescent hCSCs promote a comparable regenerative response remained to be established. Surprisingly, the expression of EphA2 did not differ in young and old hCSCs. With respect to young cells, senescent hCSCs showed a 2-fold increase in intracellular ROS levels. Oxidative stress led to post-translational modifications and functional alterations of the EphA2 receptor. Specifically, the ability of ephrin A1 to induce phosphorylation of the EphA2 receptor was markedly attenuated in senescent hCSCs, resulting in inadequate activation of Src family proteins. As a consequence, the phosphorylation and activity of caveolin-1, a substrate of Src kinases, was reduced. These molecular alterations led to impaired endocytosis of the ligand-receptor complex, a cellular process essential for ephrin A1-EphA2 signaling. Lack of endocytosis precluded rearrangement of the actin cytoskeleton and cell migration. Importantly, ephrin A1-stimulated senescent hCSCs delivered to infarcted rats accumulated in proximity of the site of injection and did not translocate to the ischemic area. Thus, oxidative stress interferes with EphA2 signaling in aging hCSCs, negatively affecting their migration. Restoration of the EphA2 function in old hCSCs may enhance their mobilization and improve cell targeting to the injured area.
3D-model of adult cardiac stem cells promotes cardiac differentiation and resistance to oxidative stress
