ABSTRACT
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.
Subject(s)
Antigens, CD34/metabolism , Apoptosis/physiology , Myocardial Infarction/pathology , Neovascularization, Physiologic/physiology , Receptors, CCR3/metabolism , Receptors, CXCR4/metabolism , Animals , Antigens, CD34/immunology , Apoptosis/drug effects , Biopsy, Needle , Cell Movement/drug effects , Cell Movement/physiology , Chemokine CCL5/metabolism , Chemokine CXCL12/pharmacology , Chemotaxis/drug effects , Chemotaxis/physiology , Disease Models, Animal , Hematopoietic Stem Cells , Humans , Immunohistochemistry , Myocytes, Cardiac/cytology , Myocytes, Cardiac/physiology , Neovascularization, Physiologic/drug effects , Probability , RNA, Messenger/analysis , Random Allocation , Rats , Rats, Nude , Receptors, CCR3/immunology , Receptors, CXCR4/immunology , Sensitivity and Specificity , Tissue Culture TechniquesABSTRACT
In the adult, new blood vessel formation can occur either through angiogenesis from pre-existing mature endothelium or vasculogenesis mediated by bone marrow-derived endothelial precursors. We recently isolated endothelial progenitor cells, or angioblasts, in human adult bone marrow which have selective migratory properties for ischemic tissues, including myocardium, to where they home and induce vasculogenesis. Here we show that myocardial production of the IL-8/Gro-alpha CXC chemokine family is significantly increased after acute ischemia, and that this provides a chemoattractant gradient for bone marrow-derived endothelial progenitors, or angioblasts. This chemokine-mediated homing of bone marrow angioblasts to the ischemic heart regulates their ability to induce myocardial neovascularization, protection against cardiomyocyte apoptosis, and functional cardiac recovery. Together, our results indicate that CXC chemokines play a central role in regulating vasculogenesis in the adult, and suggest that manipulation of interactions between chemokines and their receptors on autologous human bone marrow-derived angioblasts could augment neovascularization of ischemic myocardial tissue.
