Abstract 20660: Defective Trafficking of Senescent Human Cardiac Stem Cells: Role of EphrinA1/EphA2 Interaction.
Aging is the major independent risk factor for the development of chronic heart failure in humans. Based on animal studies it can be inferred that human cardiac stem cells (hCSCs) efficiently control organ homeostasis and have the ability to repair limited areas of damage in the adult young heart. However, aging results in a progressive deterioration of ventricular performance, suggesting that the regenerative capacity of hCSCs is decreased with age. Defective motility and migration of senescent hCSCs to the site of tissue injury may represent a critical aspect of myocardial aging. We report that hCSC trafficking in the heart is regulated by the interactions of the EphA2 receptor expressed on hCSCs with ephrin A1 ligand presented on the surface of cardiomyocytes. hCSCs in culture displayed the EphA2 receptor and were capable of synthesizing ephrin A1. EphA2 activation in hCSCs by ephrin A1 markedly increased the activity of the protein kinases of the Src family, resulting in actin bundling and enhanced cell motility. Moreover, exposure of hCSCs to the powerful chemoattractant hepatocyte growth factor/scatter factor (HGF) induced re-distribution of EphA2 to the leading edge and ephrin A1 to the trailing edge of the moving cells. This sub-cellular reorganization favored hCSC migration. To determine whether aging led to impairment in ephrin A1/EphA2 signaling system, we studied two models of cellular senescence in vitro: replicative senescence and oxidative stress-induced cellular aging. hCSCs at late passages or exposed to doxorubicin treatment expressed the senescence-associated protein p16INK4a. Old hCSCs continued to express the EphA2 receptor, but, at variance with young p16INK4a-negative hCSCs, presented negligible levels of ephrin A1. Additionally, senescent hCSCs failed to acquire polarized morphology spontaneously or in response to HGF stimulation. Collectively, our findings indicate that defects in the ephrin A1/EphA2 signaling occur with aging and account for the alterations in the migratory properties of old hCSCs.
- © 2010 by American Heart Association, Inc.