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, Pia Ragno

Research output: Contribution to journalArticlepeer-review

Abstract

We investigated the involvement of the urokinase-type plasminogen-activator receptor (uPAR) in granulocyte-colony-stimulating factor (G-CSF)-mduced 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 (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.

Original languageEnglish
Pages (from-to)2198-2205
Number of pages8
JournalBlood
Volume105
Issue number5
DOIs
Publication statusPublished - Mar 1 2005

ASJC Scopus subject areas

  • Hematology

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