Circulating bone marrow-derived endothelial progenitor cells (EPCs) promote vascular reparative processes and neoangiogenesis, and their number in peripheral blood correlates with endothelial function and cardiovascular risk. We tested the hypothesis that the cytokine erythropoietin (EPO) stimulates EPCs in humans. We studied 11 patients with renal anemia and 4 healthy subjects who received standard doses of recombinant human EPO (rhEPO). Treatment with rhEPO caused a significant mobilization of CD34 ؉ /CD45 ؉ circulating progenitor cells in peripheral blood (measured by flow cytometry), and increased the number of functionally active EPCs (measured by in vitro assay) in patients (week 2, 312% ؎ 31%; week 8, 308% ؎ 40%; both P < .01 versus baseline) as well as in healthy subjects (week 8, 194% ؎ 15%; P < .05 versus baseline). IntroductionStem cell therapy emerges as a promising approach in cardiovascular medicine. Current research focuses on bone marrow-derived endothelial progenitor cells (EPCs), which promote vascular reparative processes. [1][2][3] EPCs are considered to originate from CD34-positive (CD34 ϩ ) stem cells. 3 These cells differentiate via separate pathways into erythrocytes, thrombocytes, various lineages of leukocytes, and also endothelial cells. EPCs are found mainly in the bone marrow, but may also circulate in the vasculature where they home and incorporate into sites of active neovascularization. 1,[4][5][6][7] In experimental studies, increased neovascularization by these cells improves cardiac function after myocardial ischemia. [8][9][10] In patients with myocardial infarction, the clinical outcome is strongly correlated to the number of mobilized EPCs from the bone marrow. 11 Thus, the search for substances that modulate the number and/or function of EPCs is a matter of considerable interest. For example, vascular endothelial growth factor (VEGF) has been shown to regulate EPC proliferation and differentiation. 12 Erythropoietin (EPO) is a cytokine stimulating erythrocyte differentiation. It is produced mainly in the renal interstitium in response to hypoxic stimuli. Currently the main indication for use of recombinant human EPO (rhEPO) is treatment of anemia due to EPO deficiency in patients with chronic renal failure. EPO also appears to have direct biologic effects on endothelial cells. 13,14 Furthermore, both VEGF and EPO share important activities with respect to neoangiogenesis. 12,15 The main target of both cytokines seems to be the vasculature. 16 Thus, EPO could affect EPC proliferation and differentiation as well.We tested the hypothesis that EPO modulates the number of functionally active EPCs in humans. For this purpose, we assessed circulating CD34 ϩ cells in whole blood using flow cytometry, and the number of functionally active EPCs in an in vitro assay during 8 weeks of treatment with standard rhEPO doses in 11 patients with renal anemia and in 4 healthy subjects. Patients and methods Study participants and protocolThe study protocols were approved by the Hannover Medic...