Abstract 12098: Heparin Disrupts the CXCR4 / SDF-1 Axis and Impairs the Functional Capacity of Bone Marrow-Derived Mononuclear Cells (BMC) Used for Cardiovascular Repair: Implications for the Heterogeneous Results of Clinical Cell Therapy Trials in AMI
The migratory capacity of BMC towards the chemokine SDF-1 plays a fundamental role for the functional activity and homing capacity of BMC and determines recovery of contractile function after intracoronary administration of BMC in patients with AMI. Since glycosaminoglycan species bind to chemokines, we hypothesized that heparin, a prototypic glycosaminoglycan, may bind to SDF-1 and competitively disrupt the CXCR4 receptor/SDF-1 axis. Therefore, we investigated whether heparin added to the BMC infusate to prevent clotting prior to intracoronary infusion interferes with the migratory capacity of BMC towards SDF-1.
Results: The addition of heparin to the BMC infusate profoundly and dose-dependently inhibited basal and SDF-1-induced BMC migration. In fact, the addition of 20 U/ml heparin to the BMC product for 30 min abrogated SDF-1-induced BMC invasion (16±8% of co., p<0.01). Heparin did not affect apoptosis or GM-CFU-capacity of isolated BMC (80±33% and 100±44% of co., respectively). The addition of heparin to the BMC product significantly reduced SDF-1-induced Akt phosphorylation to 57±10% of co, indicating disruption of the downstream CXCR4/SDF-1 signalling axis. Mechanistically, incubation of BMC with heparin significantly inhibited internalization of CXCR4 after SDF-1 stimulation, a process required for active CXCR4 signalling (co.: 517±204%; heparin: 150±148% increase in internalized CXCR4 after SDF-1 stim., p<0.05). In contrast to heparin, the clinically used anticoagulant bivalirudin did neither affect BMC invasion (91±32% of co.) nor CXCR4 signalling (Akt-phos. in response to SDF-1: 120±29% of co.) or receptor internalization. Finally, analysis of the published BMC therapy trials for AMI revealed that those trials reporting negative results (HEBE, ASTAMI) used high doses of heparin added to the BMC infusate prior to cell administration, whereas no heparin was used in the positive trials (REPAIR-AMI, REGENT, FinnCell, BONAMI and Janssen-trial).
Conclusion: Heparin added to the BMC infusate prior to intracoronary administration for AMI disrupts the CXCR4 / SDF-1 axis and profoundly impairs the functional capacity of BMC. These findings may importantly contribute to the reported heterogeneous results of BMC therapy trials in AMI.
- © 2011 by American Heart Association, Inc.