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Original Research

Heparin Disrupts the CXCR4 / SDF-1 Axis and Impairs the Functional Capacity of Bone Marrow–Derived Mononuclear Cells Used for Cardiovascular Repair

Florian H. Seeger, Tina Rasper, Ariane Fischer, Marion Muhly-Reinholz, Eduard Hergenreider, David M. Leistner, Katharina Sommer, Yosif Manavski, Reinhard Henschler, Emmanouil Chavakis, Birgit Assmus, Andreas M. Zeiher, Stefanie Dimmeler
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https://doi.org/10.1161/CIRCRESAHA.112.265678
Circulation Research. 2012;CIRCRESAHA.112.265678
Originally published July 19, 2012
Florian H. Seeger
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Tina Rasper
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Ariane Fischer
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Marion Muhly-Reinholz
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Eduard Hergenreider
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David M. Leistner
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Katharina Sommer
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Yosif Manavski
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Reinhard Henschler
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Emmanouil Chavakis
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Birgit Assmus
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Andreas M. Zeiher
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Stefanie Dimmeler
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Abstract

Rationale: 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 anti-coagulants. However, a comprehensive analysis of the effects of anti-coagulants 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.

Methods and Results: Heparin, but not bivalirudin, profoundly and dose-dependently inhibited basal- and SDF-1-induced BMC migration. Incubation of BMC with 20U/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). Pre-treatment of BMC 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 BMC. Mechanistically, heparin binds to both, the chemoattractant SDF-1 and its receptor 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, and, thereby interfering with migration and homing of BMC. In contrast, the thrombin inhibitor bivalirudin did not interfere with BMC-homing and SDF-1/CXCR4 signaling. These findings suggest that bivalirudin but not heparin might be recommended as anti-coagulant for intracoronary infusion of BMC for cell therapy after cardiac ischemia.

  • Cell transplantation
  • Migration
  • BMC
  • acute myocardial infarction
  • bivalirudin
  • cell therapy
  • heparin
  • Received January 25, 2012.
  • Accepted July 18, 2012.
  • Copyright © 2012, American Heart Association
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    Heparin Disrupts the CXCR4 / SDF-1 Axis and Impairs the Functional Capacity of Bone Marrow–Derived Mononuclear Cells Used for Cardiovascular Repair
    Florian H. Seeger, Tina Rasper, Ariane Fischer, Marion Muhly-Reinholz, Eduard Hergenreider, David M. Leistner, Katharina Sommer, Yosif Manavski, Reinhard Henschler, Emmanouil Chavakis, Birgit Assmus, Andreas M. Zeiher and Stefanie Dimmeler
    Circulation Research. 2012;CIRCRESAHA.112.265678, originally published July 19, 2012
    https://doi.org/10.1161/CIRCRESAHA.112.265678

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    Heparin Disrupts the CXCR4 / SDF-1 Axis and Impairs the Functional Capacity of Bone Marrow–Derived Mononuclear Cells Used for Cardiovascular Repair
    Florian H. Seeger, Tina Rasper, Ariane Fischer, Marion Muhly-Reinholz, Eduard Hergenreider, David M. Leistner, Katharina Sommer, Yosif Manavski, Reinhard Henschler, Emmanouil Chavakis, Birgit Assmus, Andreas M. Zeiher and Stefanie Dimmeler
    Circulation Research. 2012;CIRCRESAHA.112.265678, originally published July 19, 2012
    https://doi.org/10.1161/CIRCRESAHA.112.265678
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