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Blood, 1 March 2005, Vol. 105, No. 5, pp. 2198-2205.
Prepublished online as a Blood First Edition Paper on October 19, 2004; DOI 10.1182/blood-2004-06-2424.
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TRANSPLANTATION
Involvement of the urokinase-type plasminogen activator receptor in hematopoietic stem cell mobilization
Carmine Selleri,
Nunzia Montuori,
Patrizia Ricci,
Valeria Visconte,
Maria Vincenza Carriero,
Nicolai Sidenius,
Bianca Serio,
Francesco Blasi,
Bruno Rotoli,
Guido Rossi, and
Pia Ragno
From the Division of Hematology, the Institute of Experimental Endocrinology and Oncology (National Research Council) and the Department of Cellular and Molecular Biology and Pathology, "Federico II" University, Naples; the Department of Experimental Oncology, National Cancer Institute, Naples; and the Molecular Genetics Unit, Department of Cell Biology and Functional Genomics, University "Vita-Salute San Raffaele" and IFOM (Firc Institute of Molecular Oncology), Milan, Italy.
We investigated the involvement of the urokinase-type plasminogen-activator receptor (uPAR) in granulocyte–colony-stimulating factor (G-CSF)–induced mobilization of CD34+ hematopoietic stem cells (HSCs) from 16 healthy donors. Analysis of peripheral blood mononuclear cells (PBMNCs) showed an increased uPAR expression after G-CSF treatment in CD33+ myeloid and CD14+ monocytic cells, whereas mobilized CD34+ HSCs remained uPAR negative. G-CSF treatment also induced an increase in serum levels of soluble uPAR (suPAR). Cleaved forms of suPAR (c-suPAR) were released in vitro by PBMNCs and were also detected in the serum of G-CSF–treated donors. c-suPAR was able to chemoattract CD34+ KG1 leukemia cells and CD34+ HSCs, as documented by their in vitro migratory response to a chemotactic suPAR-derived peptide (uPAR84-95). uPAR84-95 induced CD34+ KG1 and CD34+ HSC migration by activating the high-affinity fMet-Leu-Phe (fMLP) receptor (FPR). In addition, uPAR84-95 inhibited CD34+ KG1 and CD34+ HSC in vitro migration toward the stromal-derived factor 1 (SDF1), thus suggesting the heterologous desensitization of its receptor, CXCR4. Finally, uPAR84-95 treatment significantly increased the output of clonogenic progenitors from long-term cultures of CD34+ HSCs. Our findings demonstrate that G-CSF–induced upregulation of uPAR on circulating CD33+ and CD14+ cells is associated with increased uPAR shedding, which leads to the appearance of serum c-suPAR. c-suPAR could contribute to the mobilization of HSCs by promoting their FPR-mediated migration and by inducing CXCR4 desensitization.
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