Age-Associated Defects in EphA2 Signaling Impair the Migration of Human Cardiac Progenitor Cells

Abstract

Background Aging negatively impacts on the function of resident human cardiac progenitor cells (hCPCs). Effective regeneration of the injured heart requires mobilization of hCPCs to the sites of damage. In the young heart, signaling by the guidance receptor EphA2 in response to the ephrin A1 ligand promotes hCPC motility and improves cardiac recovery after infarction. Methods and Results We report that old hCPCs are characterized by cell-autonomous inhibition of their migratory ability ex vivo and impaired translocation in vivo in the damaged heart. EphA2 expression was not decreased in old hCPCs; however, the elevated level of reactive oxygen species in aged cells induced post-translational modifications of the EphA2 protein. EphA2 oxidation interfered with ephrin A1-stimulated receptor auto-phosphorylation, activation of Src family kinases, and caveolin-1-mediated internalization of the receptor. Cellular aging altered the EphA2 endocytic route, affecting the maturation of EphA2-containing endosomes and causing premature signal termination. Over-expression of functionally intact EphA2 in old hCPCs corrected the defects in endocytosis and downstream signaling, enhancing cell motility. Based on the ability of phenotypically young hCPCs to respond efficiently to ephrin A1, we developed a novel methodology for the prospective isolation of live hCPCs with preserved migratory capacity and growth reserve. Conclusions Our data demonstrate that the ephrin A1/EphA2 pathway may serve as a target to facilitate trafficking of hCPCs in the senescent myocardium. Importantly, EphA2 receptor function can be implemented for the selection of hCPCs with high therapeutic potential, a clinically relevant strategy that does not require genetic manipulation of stem cells.

miR‐204 downregulates EphB2 in aging mouse hippocampal neurons

“…In fully matured primary cultured hippocampal neurons (DIV24), we found that increased miR‐204 or decreased EphB2 was accompanied by increase in senescence markers such as SA‐β‐gal and p16. Loss of EphA3, one of the Eph family, was reported to be involved in inducing senescent phenotypes in nontransformed cells (Lahtela et al ., 2013) and defects of EphA2, another member of Eph family, also induce senescence in cardiac progenitor cells (Goichberg et al ., 2013). Our results indicate that reduced EphB2 expression in aged hippocampal neurons promotes senescence‐like phenotype.…”

Aging Effects on Cardiac Progenitor Cell Physiology

“…Senescent cells adopt a flattened morphology and show enlarged nuclei (118). A necessary but insufficient sign of senescence is the lack of expression of cell cycle proteins indicative of growth arrest (see Fig.…”

Accumulation of Mitochondrial DNA Mutations Disrupts Cardiac Progenitor Cell Function and Reduces Survival

“…Although our studies suggest that accumulation of mtDNA damage is an important contributor to the functional decline of CPCs, additional factors will also contribute to the aging phenotype. For instance, reduced levels of the nucleolar protein nucleostemin contribute to senescence in CPCs (12), and defects in EphA2 signaling in aged CPCs impair their migration (13). Increased knowledge of the molecular basis for CPC function can be used to select for the most optimal autologous CPCs to be transplanted back into a patient to ensure maximal myocardial regeneration and repair.…”

“…More importantly, utilization of autologous CPCs in patients with ischemic cardiomyopathy in the SCIPIO clinical trial is showing promising results (9,10). Studies have found that CPC function is reduced with age, which reduces their regenerative capacity (11)(12)(13). Because stem cell therapies for cardiovascular disease primarily target geriatric patients, the autologous CPCs might have reduced regenerative capacity once they are transplanted back into the patient's heart.…”