Granulocyte colony-stimulating factor mobilizes functional endothelial progenitor cells in patients with coronary artery disease.
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.


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.
Powell
Tiffany M
TM
Cardiovascular Branch, National Heart, Lung, and Blood Institute and the Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892-1650, USA.
Paul
Jonathan D
JD
Hill
Jonathan M
JM
Thompson
Michael
M
Benjamin
Moshe
M
Rodrigo
Maria
M
McCoy
J Philip
JP
Read
Elizabeth J
EJ
Khuu
Hanh M
HM
Leitman
Susan F
SF
Finkel
Toren
T
Cannon
Richard O
RO
D000071916:AC133 Antigen; D000328:Adult; D000368:Aged; D000818:Animals; D015703:Antigens, CD; D018952:Antigens, CD34 / Q000097:blood; D015415:Biomarkers; D002454:Cell Differentiation; D019070:Cell Lineage; D002478:Cells, Cultured / Q000187:drug effects; D003114:Colony-Forming Units Assay; D003327:Coronary Disease / Q000097:blood / Q000628:therapy*; D042783:Endothelial Cells / Q000737:chemistry / Q000166:cytology; D004730:Endothelium, Vascular / Q000473:pathology; D005260:Female; D000069585:Filgrastim; D006023:Glycoproteins / Q000097:blood*; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D019650:Hematopoietic Stem Cell Mobilization; D006412:Hematopoietic Stem Cells / Q000737:chemistry; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D010455:Peptides / Q000097:blood*; D019718:Receptors, CXCR4 / Q000032:analysis; D011994:Recombinant Proteins; D012307:Risk Factors; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000097:blood
D000071916:AC133 Antigen; D015703:Antigens, CD; D018952:Antigens, CD34; D015415:Biomarkers; D006023:Glycoproteins; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; D019718:Receptors, CXCR4; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D040301:Vascular Endothelial Growth Factor Receptor-2; D000069585:Filgrastim