The ephrin A1-EphA2 system promotes cardiac stem cell migration after infarction

Polina Goichberg, Yingnan Bai, Domenico D'Amario, João Ferreira-Martins, Claudia Fiorini, Hanqiao Zheng, Sergio Signore, Federica Del Monte, Sergio Ottolenghi, David A. D'Alessandro, Robert E. Michler, Toru Hosoda, Piero Anversa, Jan Kajstura, Marcello Rota, Annarosa Leri

Research output: Contribution to journalArticle

52 Scopus citations

Abstract

Rationale: Understanding the mechanisms that regulate trafficking of human cardiac stem cells (hCSCs) may lead to development of new therapeutic approaches for the failing heart. Objective: We tested whether the motility of hCSCs in immunosuppressed infarcted animals is controlled by the guidance system that involves the interaction of Eph receptors with ephrin ligands. Methods and Results: Within the cardiac niches, cardiomyocytes expressed preferentially the ephrin A1 ligand, whereas hCSCs possessed the EphA2 receptor. Treatment of hCSCs with ephrin A1 resulted in the rapid internalization of the ephrin A1-EphA2 complex, posttranslational modifications of Src kinases, and morphological changes consistent with the acquisition of a motile cell phenotype. Ephrin A1 enhanced the motility of hCSCs in vitro, and their migration in vivo following acute myocardial infarction. At 2 weeks after infarction, the volume of the regenerated myocardium was 2-fold larger in animals injected with ephrin A1-activated hCSCs than in animals receiving control hCSCs; this difference was dictated by a greater number of newly formed cardiomyocytes and coronary vessels. The increased recovery in myocardial mass with ephrin A1-treated hCSCs was characterized by further restoration of cardiac function and by a reduction in arrhythmic events. Conclusions: Ephrin A1 promotes the motility of EphA2-positive hCSCs, facilitates their migration to the area of damage, and enhances cardiac repair. Thus, in situ stimulation of resident hCSCs with ephrin A1 or their ex vivo activation before myocardial delivery improves cell targeting to sites of injury, possibly providing a novel strategy for the management of the diseased heart.

Original languageEnglish (US)
Pages (from-to)1071-1083
Number of pages13
JournalCirculation research
Volume108
Issue number9
DOIs
StatePublished - Apr 29 2011

Keywords

  • cardiac stem cells
  • cell migration
  • ephrin
  • myocardial regeneration

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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    Goichberg, P., Bai, Y., D'Amario, D., Ferreira-Martins, J., Fiorini, C., Zheng, H., Signore, S., Del Monte, F., Ottolenghi, S., D'Alessandro, D. A., Michler, R. E., Hosoda, T., Anversa, P., Kajstura, J., Rota, M., & Leri, A. (2011). The ephrin A1-EphA2 system promotes cardiac stem cell migration after infarction. Circulation research, 108(9), 1071-1083. https://doi.org/10.1161/CIRCRESAHA.110.239459