title: Adenosine stimulates the migration of human endothelial progenitor cells. Role of CXCR4 and microRNA-150.
abstract: BACKGROUND
  Administration of endothelial progenitor cells (EPC) represents a promising option to regenerate the heart after myocardial infarction, but is limited because of low recruitment and engraftment in the myocardium. Mobilization and migration of EPC are mainly controlled by stromal cell-derived factor 1α (SDF-1α) and its receptor CXCR4. We hypothesized that adenosine, a cardioprotective molecule, may improve the recruitment of EPC to the heart.
  
  
  METHODS
  EPC were obtained from peripheral blood mononuclear cells of healthy volunteers. Expression of chemokines and their receptors was evaluated using microarrays, quantitative PCR, and flow cytometry. A Boyden chamber assay was used to assess chemotaxis. Recruitment of EPC to the infarcted heart was evaluated in rats after permanent occlusion of the left anterior descending coronary artery.
  
  
  RESULTS
  Microarray analysis revealed that adenosine modulates the expression of several members of the chemokine family in EPC. Among these, CXCR4 was up-regulated by adenosine, and this result was confirmed by quantitative PCR (3-fold increase, P<0.001). CXCR4 expression at the cell surface was also increased. This effect involved the A(2B) receptor. Pretreatment of EPC with adenosine amplified their migration towards recombinant SDF-1α or conditioned medium from cardiac fibroblasts. Both effects were abolished by CXCR4 blocking antibodies. Adenosine also increased CXCR4 under ischemic conditions, and decreased miR-150 expression. Binding of miR-150 to the 3' untranslated region of CXCR4 was verified by luciferase assay. Addition of pre-miR-150 blunted the effect of adenosine on CXCR4. Administration of adenosine to rats after induction of myocardial infarction stimulated EPC recruitment to the heart and enhanced angiogenesis.
  
  
  CONCLUSIONS
  Adenosine increases the migration of EPC. The mechanism involves A(2B) receptor activation, decreased expression of miR-150 and increased expression of CXCR4. These results suggest that adenosine may be used to enhance the capacity of EPC to revascularize the ischemic heart.
authors: Laboratory of Cardiovascular Research, Public Research Centre-Health (CRP-Santé), Luxembourg, Luxembourg.
authors: Magali
authors: M
authors: Rolland-Turner
authors: Emeline
authors: E
authors: Goretti
authors: Mélanie
authors: M
authors: Bousquenaud
authors: Frédérique
authors: F
authors: Léonard
authors: Christelle
authors: C
authors: Nicolas
authors: Lu
authors: L
authors: Zhang
authors: Fatiha
authors: F
authors: Maskali
authors: Pierre-Yves
authors: PY
authors: Marie
authors: Yvan
authors: Y
authors: Devaux
authors: Daniel
authors: D
authors: Wagner
mesh_terms: D000241:Adenosine / Q000008:administration & dosage* / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D064987:Cell- and Tissue-Based Therapy; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007963:Leukocytes, Mononuclear; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D009203:Myocardial Infarction / Q000235:genetics / Q000628:therapy; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism; D012038:Regeneration / Q000235:genetics; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000241:Adenosine; D035683:MicroRNAs; D019718:Receptors, CXCR4; C527276:CXCR4 protein, human; C533097:MIR150, human