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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:2238.)
© 2006 American Heart Association, Inc.

Vascular Biology

Effects of Granulocyte Colony Stimulating Factor on Functional Activities of Endothelial Progenitor Cells in Patients With Chronic Ischemic Heart Disease

Joerg Honold; Ralf Lehmann; Christopher Heeschen; Dirk H. Walter; Birgit Assmus; Ken-Ichiro Sasaki; Hans Martin; Judith Haendeler; Andreas M. Zeiher; Stefanie Dimmeler

From the Departments of Cardiology and Molecular Cardiology (J.H., R.L., C.H., D.H.W., B.A., K.-I.S., J.H., A.M.Z., S.D.), Internal Medicine III, and Department of Hematology (H.M.), Internal Medicine II, J.W. Goethe University of Frankfurt, Germany.

Correspondence to Stefanie Dimmeler, PhD, Department of Molecular Cardiology, Internal Medicine III, J.W. Goethe University of Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany. E-mail dimmeler{at}em.uni-frankfurt.de

Objective— Bone marrow–derived circulating endothelial progenitor cells (EPCs) may contribute to regeneration of infarcted myocardium and enhance neovascularization. Granulocyte colony-stimulating factor (G-CSF) is well-established to mobilize hematopoietic stem cells (HSCs) and might, thereby, also increase the pool of endogenously circulating EPC. Therefore, we investigated the effects of G-CSF administration on mobilization and functional activities of blood-derived EPC in patients with chronic ischemic heart disease (CIHD).

Methods and Results— Sixteen patients with CIHD received 10 µg/kg per day subcutaneous G-CSF injection for 5 days. Leukocyte counts, the number of HSCs and EPCs, and the migratory response to VEGF and SDF-1 were analyzed before and after G-CSF-therapy. At day 5 of G-CSF treatment, the number of circulating leukocytes, CD34⁺CD45⁺ and CD34⁺CD133⁺ cells was significantly increased. Likewise, G-CSF treatment augmented the numbers of colony forming units with endothelial cell morphology (EC-CFU). However, the functional activity of the EPC as assessed by the migratory response to VEGF and SDF-1 was significantly reduced after G-CSF treatment (P<0.01). Because G-CSF was previously shown to cleave the CXCR4 receptor, we determined the surface expression of the 6H8 epitope of the CXCR4 receptor by fluorescence-activated cell sorter (FACS) analysis. Consistent with the reduced migratory capacity, the surface expression of the functionally active CXCR4 receptor was significantly reduced. To test the functional activity of the cultivated EPCs in vivo, cells were intravenously infused in nude mice after hind limb ischemia. EPCs, which were cultivated before G-CSF administration, increased blood flow recovery and prevented limb necrosis. However, infusion of EPCs, which were isolated 5 days after G-CSF treatment from the same patient, showed a reduced capacity to augment blood flow recovery and to prevent necrosis by 27%.

Conclusion— G-CSF treatment effectively mobilizes HSCs and EPCs. However, the migratory response to SDF-1 and in vivo capacity of G-CSF-mobilized EPCs was significantly reduced.

Bone marrow–derived circulating endothelial progenitor cells (EPCs) may contribute to regeneration of infarcted myocardium and enhance neovascularization. Granulocyte colony-stimulating factor (G-CSF) is well-established to mobilize hematopoietic stem cells (HSCs) and might, thereby, also increase the pool of endogenously circulating EPC. Therefore, we investigated the effects of G-CSF administration on mobilization and functional activities of blood-derived EPC in patients with chronic ischemic heart disease (CIHD).

Key Words: chronic ischemic heart disease • endothelial progenitor cells • granulocyte colony stimulating factor

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