title: 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.
  
  
  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. Overexpression 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.
authors.affiliation: Departments of Anesthesia and Medicine, and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (P.G., R.K., M.C., Y.B., F.S., A.S., S.S., J.K., M.R., PA., A.L.); and the Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China (Y.B.).
authors.forename: Polina
authors.initials: P
authors.lastname: Goichberg
authors.forename: Ramaswamy
authors.initials: R
authors.lastname: Kannappan
authors.forename: Maria
authors.initials: M
authors.lastname: Cimini
authors.forename: Yingnan
authors.initials: Y
authors.lastname: Bai
authors.forename: Fumihiro
authors.initials: F
authors.lastname: Sanada
authors.forename: Andrea
authors.initials: A
authors.lastname: Sorrentino
authors.forename: Sergio
authors.initials: S
authors.lastname: Signore
authors.forename: Jan
authors.initials: J
authors.lastname: Kajstura
authors.forename: Marcello
authors.initials: M
authors.lastname: Rota
authors.forename: Piero
authors.initials: P
authors.lastname: Anversa
authors.forename: Annarosa
authors.initials: A
authors.lastname: Leri
mesh_terms: D000328:Adult; D053687:Adult Stem Cells / Q000166:cytology / Q000502:physiology*; D000368:Aged; D000375:Aging / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D004705:Endocytosis / Q000502:physiology; D036382:Ephrin-A1 / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000166:cytology*; D036104:Receptor, EphA2 / Q000235:genetics / Q000378:metabolism*; D012038:Regeneration / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D014168:Transferrin / Q000378:metabolism
chemical_list: D036382:Ephrin-A1; D014168:Transferrin; D036104:Receptor, EphA2
keywords: aging; cell movement; receptor, EphA2; stem cells