Involvement of the urokinase-type plasminogen activator receptor in hematopoietic stem cell mobilization

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-CSIF treatment in CD33(+) myeloid and CD14(+) monocytic cells, whereas mobilized CD34(+) HSCs remained uPAR negative. G-CSIF 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 (uPAR(84-95)). uPAR(84-95) induced CD34(+) KG1 and CD34(+) HSC migration by activating the high-affinity fMet-Leu-Phe (fMLP) receptor (FPR). In addition, uPAR(84-95) 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, uPAR(84-95) 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. (C) 2005 by The American Society of Hematology