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J Thorac Cardiovasc Surg 2008;136:1044-1053
© 2008 The American Association for Thoracic Surgery

Cardiopulmonary Support and Physiology

CCR3- and CXCR4-mediated interactions regulate migration of CD34+ human bone marrow progenitors to ischemic myocardium and subsequent tissue repair

N. Bonaros, MDa,*,*, H. Sondermejer, MDb,*, M. Schuster, PhDb, R. Rauf, MDa, S.F. Wang, MDb, T. Seki, PhDb, D. Skerrett, MDb, S. Itescu, MDb, A.A. Kocher, MDa,b

a Department of Cardiac Surgery Innsbruck Medical University, Innsburck, Austria
b Departments of Medicine, Surgery, and Pathology, Columbia University, New York, NY

Received for publication October 5, 2007; revisions received December 6, 2007; accepted for publication December 24, 2007.

* Address for reprints: Nikolaos Bonaros, MD, Department of Cardiac Surgery, Innsbruck Medical University, Anichstrasse 35, A-6020, Innsbruck, Austria. (Email: nikolaos.bonaros{at}i-med.ac.at).

Objective: Hematopoietic progenitor cells are able to induce neovascularization of ischemic myocardium, inhibit apoptosis, and prevent heart failure. They express functional CC chemokine-binding receptor 3 (CCR3) and CXC chemokine-binding receptor 4 (CXCR4); however, the role of those receptors in migration of progenitor cells into the ischemic myocardium is unknown.

Methods: Myocardial infarction was surgically induced in athymic nude rats, and human bone marrow–derived CD34+ cells or saline was injected into the tail vein. Cell chemotaxis was studied in vitro using chemotaxis chambers with or without concomitant stimulation with eotaxin or stromal cell–derived factor-1. Cell migration into ischemic myocardium was evaluated by immunohistochemistry. CCR3 and CXCR4 antibodies or local injections of stromal cell–derived factor-1 were used to investigate the role of chemokine expression in the migration capacity of the injected cells. Morphologic analysis included evaluation of apoptosis and capillary density in the ischemic myocardium.

Results: Ischemic rat myocardium demonstrated induced messenger RNA expression for the CCR3-binding chemokines eotaxin, RANTES (regulated on activation, normal T expressed and secreted), and monocyte chemotactic protein-3, but not the CXCR4-binding chemokine stromal cell–derived factor-1. Migration of human angioblasts to ischemic rat myocardium was inhibited by a blocking anti-CCR3 monoclonal antibody, but not by a blocking anti-CXCR4 monoclonal antibody, which instead inhibited migration to bone marrow. Finally, intramyocardial injection of stromal cell–derived factor-1 redirected migration of human angioblasts to ischemic rat hearts, resulting in augmented neovascularization, enhanced cardiomyocyte survival, and functional cardiac recovery.

Conclusions: CCR3-dependent chemokine interactions regulate endogenous migration of CD34+ progenitors from bone marrow to ischemic but not to normal myocardium. Manipulating CXCR4-dependent interactions could enhance the efficacy of cell therapy after myocardial infarction.

Abbreviations and Acronyms CCR3 = CC chemokine-binding receptor 3; CXCR4 = CXC chemokine-binding receptor 4; FDG = 18F-fluoro-2-deoxy-D-glucose; G-CSF = granulocyte-colony stimulating factor; LAD = left anterior descending coronary artery; mAb = monoclonal antibody; MCP-3 = monocyte chemotactic protein-3; MHC = major histocompatibility complex; RANTES = regulated on activation, normal T expressed and secreted; RPL32 = ribosomal protein L32; SCF = stem cell factor; SDF-1 = stromal cell–derived factor-1; VCAM-1 = vascular cell adhesion molecule; VEGF = vascular endothelial growth factor; VEGFR-2 = vascular endothelial growth factor receptor-2






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