title: The ephrin A1-EphA2 system promotes cardiac stem cell migration after infarction.
abstract: BACKGROUND
  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.
  
  
  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.
authors.affiliation: Department of Anesthesia, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.
authors.forename: Polina
authors.initials: P
authors.lastname: Goichberg
authors.forename: Yingnan
authors.initials: Y
authors.lastname: Bai
authors.forename: Domenico
authors.initials: D
authors.lastname: D'Amario
authors.forename: João
authors.initials: J
authors.lastname: Ferreira-Martins
authors.forename: Claudia
authors.initials: C
authors.lastname: Fiorini
authors.forename: Hanqiao
authors.initials: H
authors.lastname: Zheng
authors.forename: Sergio
authors.initials: S
authors.lastname: Signore
authors.forename: Federica
authors.initials: F
authors.lastname: del Monte
authors.forename: Sergio
authors.initials: S
authors.lastname: Ottolenghi
authors.forename: David A
authors.initials: DA
authors.lastname: D'Alessandro
authors.forename: Robert E
authors.initials: RE
authors.lastname: Michler
authors.forename: Toru
authors.initials: T
authors.lastname: Hosoda
authors.forename: Piero
authors.initials: P
authors.lastname: Anversa
authors.forename: Jan
authors.initials: J
authors.lastname: Kajstura
authors.forename: Marcello
authors.initials: M
authors.lastname: Rota
authors.forename: Annarosa
authors.initials: A
authors.lastname: Leri
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology; D003593:Cytoplasm / Q000378:metabolism; D036382:Ephrin-A1 / Q000235:genetics* / Q000378:metabolism; D036383:Ephrin-A2 / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology* / Q000628:therapy; D032383:Myocytes, Cardiac / Q000166:cytology*; D051381:Rats; D011916:Rats, Inbred F344; D017180:Tachycardia, Ventricular / Q000473:pathology / Q000503:physiopathology / Q000628:therapy
chemical_list: D036382:Ephrin-A1; D036383:Ephrin-A2; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins