CCR3- and CXCR4-mediated interactions regulate migration of CD34+ human bone marrow progenitors to ischemic
N Bonaros1, H Sondermeijer, H Sondermejer
1Department of Cardiac Surgery, Innsbruck Medical University, Innsburck, Austria. nikolaos.bonaros@i-med.ac.at
Insights
Hematopoietic progenitor cell migration to ischemic heart tissue is regulated by CC chemokine receptor 3 (CCR3). Targeting CXC chemokine receptor 4 (CXCR4) can improve cell therapy effectiveness for heart failure.
Area of Science:
- Cardiovascular Research
- Stem Cell Biology
- Immunology
Background:
- Hematopoietic progenitor cells (HPCs) promote neovascularization and survival in ischemic hearts.
- HPCs express CC chemokine receptor 3 (CCR3) and CXC chemokine receptor 4 (CXCR4), but their roles in cardiac homing are unclear.
Purpose of the Study:
- To investigate the role of CCR3 and CXCR4 in the migration of CD34+ progenitor cells to ischemic myocardium.
- To determine the impact of chemokine receptor manipulation on cell therapy efficacy for myocardial infarction.
Main Methods:
- Myocardial infarction was induced in rats, followed by injection of human bone marrow-derived CD34+ cells.
- In vitro chemotaxis assays were performed with or without chemokine stimulation.
- Cell migration, apoptosis, and capillary density were assessed using immunohistochemistry and morphologic analysis.
- Blocking antibodies for CCR3 and CXCR4, and stromal cell-derived factor-1 (SDF-1) were used to probe receptor function.
Main Results:
- Ischemic myocardium showed increased mRNA for CCR3 ligands (eotaxin, RANTES, MCP-3) but not CXCR4 ligand (SDF-1).
- Anti-CCR3 antibody inhibited migration to ischemic tissue, while anti-CXCR4 antibody inhibited migration to bone marrow.
- Intramyocardial SDF-1 injection enhanced angioblast migration to the heart, improving neovascularization, cardiomyocyte survival, and cardiac function.
Conclusions:
- CCR3-dependent chemokines guide CD34+ progenitor cell migration to ischemic, but not normal, myocardium.
- Modulating CXCR4 interactions holds potential for enhancing cell therapy outcomes post-myocardial infarction.
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.
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