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

ABSTRACT We investigated the involvement of the urokinase-type plasminogen-activator receptor (uPAR) in G-CSF-induced mobilization of CD34+ hematopoietic stem cells (HSC) from 16 healthy donors. The analysis of peripheral blood mononuclear cells (PBMNC) showed an increased uPAR expression after G-CSF treatment in CD33+ myeloid and CD14+ monocytic cells, whereas mobilized CD34+ HSC 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 PBMNC and were also detected in the serum of G-CSF-treated donors. c-suPAR was able to chemoattract CD34+ KG1 leukemia cells and CD34+ HSC, 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 fMLP receptor (FPR). In addition, uPAR84-95 inhibited CD34+ KG1 and CD34+ HSC migration toward the stromal derived factor 1 (SDF1), thus suggesting the heterologous desensitation of its receptor, CXCR4. Finally, uPAR84-95 treatment significantly increased the output of clonogenic progenitors from long-term cultures of CD34+ HSC. Our findings demonstrate that G-CSF-induced up-regulation 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 HSC mobilization by promoting their FPR-mediated migration and by inducing CXCR4 desensitation.