title: Heparin disrupts the CXCR4/SDF-1 axis and impairs the functional capacity of bone marrow-derived mononuclear cells used for cardiovascular repair.
abstract: BACKGROUND
  Cell therapy is a promising option for the treatment of acute or chronic myocardial ischemia. The intracoronary infusion of cells imposes the potential risk of cell clotting, which may be prevented by the addition of anticoagulants. However, a comprehensive analysis of the effects of anticoagulants on the function of the cells is missing.
  
  
  OBJECTIVE
  Here, we investigated the effects of heparin and the thrombin inhibitor bivalirudin on bone marrow-derived mononuclear cell (BMC) functional activity and homing capacity.
  
  
  RESULTS
  Heparin, but not bivalirudin profoundly and dose-dependently inhibited basal and stromal cell-derived factor 1 (SDF-1)-induced BMC migration. Incubation of BMCs with 20 U/mL heparin for 30 minutes abrogated SDF-1-induced BMC invasion (16±8% of control; P<0.01), whereas no effects on apoptosis or colony formation were observed (80±33% and 100±44% of control, respectively). Pretreatment of BMCs with heparin significantly reduced the homing of the injected cells in a mouse ear-wound model (69±10% of control; P<0.05). In contrast, bivalirudin did not inhibit in vivo homing of BMCs. Mechanistically, heparin binds to both, the chemoattractant SDF-1 and its receptor, chemokine receptor 4 (CXCR4), blocking CXCR4 internalization as well as SDF-1/CXCR4 signaling after SDF-1 stimulation.
  
  
  CONCLUSIONS
  Heparin blocks SDF-1/CXCR4 signaling by binding to the ligand as well as the receptor, thereby interfering with migration and homing of BMCs. In contrast, the thrombin inhibitor bivalirudin did not interfere with BMC homing or SDF-1/CXCR4 signaling. These findings suggest that bivalirudin but not heparin might be recommended as an anticoagulant for intracoronary infusion of BMCs for cell therapy after cardiac ischemia.
authors: Institute for Cardiovascular Regeneration, Centre of Molecular Medicine, Goethe University, Haus 25, 4. Stock, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
authors: Florian H
authors: FH
authors: Seeger
authors: Tina
authors: T
authors: Rasper
authors: Ariane
authors: A
authors: Fischer
authors: Marion
authors: M
authors: Muhly-Reinholz
authors: Eduard
authors: E
authors: Hergenreider
authors: David M
authors: DM
authors: Leistner
authors: Katharina
authors: K
authors: Sommer
authors: Yosif
authors: Y
authors: Manavski
authors: Reinhard
authors: R
authors: Henschler
authors: Emmanouil
authors: E
authors: Chavakis
authors: Birgit
authors: B
authors: Assmus
authors: Andreas M
authors: AM
authors: Zeiher
authors: Stefanie
authors: S
authors: Dimmeler
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology; D000991:Antithrombins / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000166:cytology*; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D064987:Cell- and Tissue-Based Therapy; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000187:drug effects* / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D006493:Heparin / Q000494:pharmacology*; D006629:Hirudins / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008815:Mice, Inbred Strains; D009203:Myocardial Infarction / Q000628:therapy*; D010446:Peptide Fragments / Q000494:pharmacology; D019718:Receptors, CXCR4 / Q000187:drug effects* / Q000502:physiology; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology
chemical_list: D000925:Anticoagulants; D000991:Antithrombins; C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D006629:Hirudins; D010446:Peptide Fragments; D019718:Receptors, CXCR4; D011994:Recombinant Proteins; D006493:Heparin; C074619:bivalirudin