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In vivo Activity of the Cleaved Form of Soluble Urokinase Receptor: A New Hematopoietic Stem/Progenitor Cell Mobilizer

¹ Department of Biochemistry and Medical Biotechnology, ² Institute of Experimental Endocrinology and Oncology (National Research Council), ³ Department of Cellular and Molecular Biology and Pathology, and ⁴ Veterinary Service Center, "Federico II" University; and ⁵ Department of Experimental Oncology, National Cancer Institute, Naples, Italy

Requests for reprints: Pia Ragno, Istituto di Endocrinologia ed Oncologia Sperimentale, Consiglio Nazionale delle Ricerche, Via Pansini 5, I-80131, Naples, Italy. Phone: 39-081-746-3309; Fax: 39-081-770-1016; E-mail: ragno{at}unina.it.

Cleaved forms of soluble urokinase receptor (c-suPAR) have been detected in body fluids from patients affected by various tumors. We recently reported increased c-suPAR levels in sera of healthy donors during granulocyte colony-stimulating factor (G-CSF)–induced mobilization of CD34⁺ hematopoietic stem cells (HSC). In vitro, c-suPAR or its derived chemotactic peptide (uPAR_84-95) stimulated migration of human CD34⁺ HSCs and inactivated CXCR4, the chemokine receptor primarily responsible for HSC retention in bone marrow. These results suggested that c-suPAR could potentially contribute to regulate HSC trafficking from and to bone marrow. Therefore, we investigated uPAR_84-95 effects on mobilization of mouse CD34⁺ hematopoietic stem/progenitor cells (HSC/HPC). We first showed that uPAR_84-95 stimulated in vitro dose-dependent migration of mouse CD34⁺ M1 leukemia cells and inactivated murine CXCR4. uPAR_84-95 capability to induce mouse HSC/HPC release from bone marrow and migration into the circulation was then investigated in vivo. uPAR_84-95 i.p. administration induced rapid leukocytosis, which was associated with an increase in peripheral blood CD34⁺ HSCs/HPCs. In vitro colony assays confirmed that uPAR_84-95 mobilized hematopoietic progenitors, showing an absolute increase in circulating colony-forming cells. uPAR_84-95 mobilizing activity was comparable to that of G-CSF; however, neither synergistic nor additive effect was observed in combining the two molecules. These findings show for the first time in vivo biological effects of c-suPAR. Its capability to mobilize HSCs suggests potential clinical applications in HSC transplantation. (Cancer Res 2006; 66(22): 10885-90)

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