Granulocyte colony-stimulating factor mobilizes functional endothelial progenitor cells in patients with coronary
Tiffany M Powell1, Jonathan D Paul, Jonathan M Hill
1Cardiovascular Branch, National Heart, Lung, and Blood Institute and the Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892-1650, USA.
Insights
Granulocyte colony-stimulating factor (G-CSF) increased endothelial progenitor cells (EPCs) in coronary artery disease (CAD) patients. This G-CSF therapy may enhance vascular repair in CAD by boosting EPC number and function.
Area of Science:
- Cardiovascular Research
- Stem Cell Biology
- Hematology
Background:
- Endothelial progenitor cells (EPCs) are crucial for vascular repair but are reduced in patients with coronary artery disease (CAD).
- The number and function of EPCs may be improved by granulocyte colony-stimulating factor (G-CSF), a known mobilizer of hematopoietic progenitor cells.
Purpose of the Study:
- To investigate the effect of G-CSF on EPCs in patients with CAD.
- To assess if G-CSF can increase the number and functional capacity of EPCs in CAD patients.
Main Methods:
- Compared EPC markers (CD34+/CD133+, CD133+/VEGFR-2+) and endothelial cell-forming capacity in CAD patients versus healthy controls.
- Administered G-CSF (10 microg/kg/day for 5 days) to CAD patients and measured changes in EPC markers, including CXCR4 expression.
- Assessed the in-vitro endothelial cell-forming clusters after G-CSF treatment.
Main Results:
- CAD patients exhibited significantly lower levels of CD34+/CD133+ and CD133+/VEGFR-2+ cells compared to healthy controls.
- G-CSF treatment markedly increased circulating CD34+/CD133+ and CD133+/VEGFR-2+ cells, as well as CD133+ cells expressing the homing receptor CXCR4.
- Following G-CSF administration, CAD patients showed a significant increase in endothelial cell-forming clusters in culture, which decreased two weeks post-treatment.
Conclusions:
- Coronary artery disease patients have reduced EPCs, but G-CSF administration effectively increases EPC number and homing receptor expression.
- G-CSF treatment enhances the functional capacity of EPCs, evidenced by increased endothelial cell outgrowth in vitro.
- Clinical trials are warranted to determine the efficacy of G-CSF-mobilized EPCs for vascular repair and myocyte regeneration in CAD patients.
Objective:
Endothelial progenitor cells (EPCs) that may repair vascular injury are reduced in patients with coronary artery disease (CAD). We reasoned that EPC number and function may be increased by granulocyte colony-stimulating factor (G-CSF) used to mobilize hematopoietic progenitor cells in healthy donors.
Methods And Results:
Sixteen CAD patients had reduced CD34(+)/CD133(+) (0.0224+/-0.0063% versus 0.121+/-0.038% mononuclear cells [MNCs], P<0.01) and CD133(+)/VEGFR-2(+) cells, consistent with EPC phenotype (0.00033+/-0.00015% versus 0.0017+/-0.0006% MNCs, P<0.01), compared with 7 healthy controls. Patients also had fewer clusters of cells in culture, with out-growth consistent with mature endothelial phenotype (2+/-1/well) compared with 16 healthy subjects at high risk (13+/-4/well, P<0.05) or 14 at low risk (22+/-3/well, P<0.001) for CAD. G-CSF 10 microg/kg per day for 5 days increased CD34(+)/CD133(+) cells from 0.5+/-0.2/microL to 59.5+/-10.6/microL and CD133(+)/ VEGFR-2(+) cells from 0.007+/-0.004/microL to 1.9+/-0.6/microL (both P<0.001). Also increased were CD133(+) cells that coexpressed the homing receptor CXCR4 (30.4+/-8.3/microL, P<0.05). Endothelial cell-forming clusters in 10 patients increased to 27+/-9/well after treatment (P<0.05), with a decline to 9+/-4/well at 2 weeks (P=0.06).
Conclusions:
Despite reduced EPCs compared with healthy controls, patients with CAD respond to G-CSF with increases in EPC number and homing receptor expression in the circulation and endothelial out-growth in culture. Endothelial progenitor cells (EPCs) are reduced in coronary artery disease. Granulocyte colony-stimulating factor (CSF) administered to patients increased: (1) CD133+/VEGFR-2+ cells consistent with EPC phenotype; (2) CD133+ cells coexpressing the chemokine receptor CXCR4, important for homing of EPCs to ischemic tissue; and (3) endothelial cell-forming clusters in culture. Whether EPCs mobilized into the circulation will be useful for the purpose of initiating vascular growth and myocyte repair in coronary artery disease patients must be tested in clinical trials.
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