Abstract 20671: Ephrin A1/EphA2 Signaling Promotes Mobilization of Human Cardiac Stem Cells in the Infarcted Heart
Understanding the mechanisms that regulate trafficking of human cardiac stem cells (hCSCs) in the normal and diseased myocardium may lead to the development of new therapeutic approaches for the failing heart. The objective of this work was to identify novel pathways that control hCSC migration enhancing tissue regeneration following ischemic injury. We report that the motility of hCSCs in the infarcted mouse heart is controlled by the cell guidance system involving ephrin ligands and their receptors (Eph). In the adult human myocardium, cardiomyocytes were found to express preferentially the ephrin A1 ligand, while hCSCs possessed the EphA2 receptor. In the cardiac niches, the differential distribution of ligand and receptor may trigger a cross-talk between hCSCs and cardiomyocytes favoring the egress of primitive cells towards areas of injury. This possibility was supported by a significant increase in the expression of ephrin A1 in human myocytes obtained from failing hearts and in the border zone of acutely infarcted mice. Moreover, intramyocardial administration of ephrin A1 to infarcted hearts shortly after coronary artery ligation resulted in an augmented mobilization and translocation of endogenous mouse CSCs to the site of ischemic injury. Treatment of hCSCs with recombinant ephrin A1 prior to transplantation to the acutely infarcted myocardium enhanced their adhesion, chemotaxis and speed of locomotion in the border zone and necrotic region at 48 hours. Moreover, at two weeks after infarction, hCSCs exposed to ephrin A1 showed a more efficient regenerative response with restoration of large areas of scarred myocardium. Importantly, the ephrinA1/EphA2 pathway was found to be impaired with cellular aging, suggesting that defective motility may explain, at least in part, the reduced regenerative ability of old hCSCs with short telomeres. Collectively, our data indicate that ephrin A1/EphA2 signaling favors hCSC migration, facilitating cell mobilization to the area of damage and, ultimately, cardiac repair. Thus, in situ activation of resident hCSCs with ephrin A1 or their ex vivo manipulation may improve hCSC targeting to the site of tissue injury, providing a novel strategy for the management of the diseased heart.
- © 2010 by American Heart Association, Inc.