Stem Cell Mobilization As Therapy For Myocardial Ischemi

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Circulating endothelial progenitor cells (EPCs) may function to repair cardiovascular injury, but are reduced in patients with coronary artery disease. Granulocyte-colony stimulating factor (G-CSF) mobilizes CD34+ hematopoietic progenitor cells, which may include cells of EPC lineage identified by the markers CD133 and VEGFR-2. We show that G-CSF 10 ig/kg administered daily for 5 days to 12 patients with chronic myocardial ischemia increased circulating CD34+/CD133+ cells to approximately 60 cells/il blood, a 200-fold increase from basal levels. Also mobilized by G-CSF were cells with CD133/VEGFR-2 surface markers consistent with EPC phenotype, although the absolute number in blood was small (approximately 6 cells/il). CD133+ cells coexpressed the chemokine receptor CXCR4, which may be important for homing of EPCs to ischemic tissue expressing its cognate ligand, stromal-derived factor. One week following completion of G-CSF treatment, levels of cells with CD133/CXCR4 surface markers returned towards baseline values. At this time-point, however, mononuclear cells showed increased expression of markers found on mature endothelial cells [CD144 (VE-cadherin), CD31 (PECAM), CD51/61 (avaIII integrin)]. In order to determine functional properties of EPCs in coronary artery disease, mononuclear cells from 6 patients were plated on fibronectin with EPC growth media for one week, and assayed for colonies with out-growth of mature endothelial cells (confirmed by uptake of fluorescent DiI-acetylated LDL). Pre-treatment EPC colony-forming units were lower than in healthy controls. Following G-CSF administration, however, patients showed an almost 30-fold increase in EPC colony-forming units. These findings establish that G-CSF administration to patients with coronary artery disease increases numbers of circulating CD34+/CD133+ cells, which includes the EPC sub-set. Additionally, colony-forming capacity, a functional measure of EPC viability, is stimulated in patients receiving G-CSF. Chemokine receptor expression is also increased, in addition to sustained increase in cells expressing mature endothelial markers at one week following treatment. Whether EPCs mobilized into the circulation and activated by G-CSF will be sufficient in number and homing efficiency to initiate vasculogenesis and myocyte repair in patients with chronic ischemic heart disease must be tested in clinical trials.