In vivo activity of the cleaved form of soluble urokinase receptor: a new hematopoietic stem/progenitor cell mobilizer.
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.
Selleri
Carmine
C
Department of Biochemistry and Medical Biotechnology, Institute of Experimental Endocrinology and Oncology (National Research Council), Naples, Italy.
Montuori
Nunzia
N
Ricci
Patrizia
P
Visconte
Valeria
V
Baiano
Antonio
A
Carriero
Maria Vincenza
MV
Rotoli
Bruno
B
Rossi
Guido
G
Ragno
Pia
P
D000818:Animals; D018952:Antigens, CD34 / Q000096:biosynthesis; D002465:Cell Movement / Q000187:drug effects*; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D019650:Hematopoietic Stem Cell Mobilization / Q000379:methods*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D007938:Leukemia / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects; D010446:Peptide Fragments / Q000494:pharmacology*; D019718:Receptors, CXCR4 / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000378:metabolism*; D055293:Receptors, Urokinase Plasminogen Activator; D011994:Recombinant Proteins / Q000494:pharmacology
D018952:Antigens, CD34; C514936:CXCR4 protein, mouse; C524898:PLAUR protein, human; D010446:Peptide Fragments; C524899:Plaur protein, mouse; D019718:Receptors, CXCR4; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor