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-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 (uPAR84-95). uPAR84-95 induced CD34+ KG1 and CD34+ HSC migration by activating the high-affinity fMet-Leu-Phe (fMLP) receptor (FPR). In addition, uPAR84-95 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, uPAR84-95 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.
Selleri
Carmine
C
Division of Hematology, Istituto di Endocrinologia ed Oncologia Sperimentale (IEOS), Consiglio Nazionale delle Ricerche, Via Pansini 5, I-80131, Naples, Italy.
Montuori
Nunzia
N
Ricci
Patrizia
P
Visconte
Valeria
V
Carriero
Maria Vincenza
MV
Sidenius
Nicolai
N
Serio
Bianca
B
Blasi
Francesco
F
Rotoli
Bruno
B
Rossi
Guido
G
Ragno
Pia
P
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D002465:Cell Movement; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage / Q000494:pharmacology; D019650:Hematopoietic Stem Cell Mobilization; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000502:physiology*; D006801:Humans; D018950:Lipopolysaccharide Receptors; D011956:Receptors, Cell Surface / Q000235:genetics / Q000502:physiology*; D044042:Receptors, Formyl Peptide; D055293:Receptors, Urokinase Plasminogen Activator; D063268:Sialic Acid Binding Ig-like Lectin 3; D014019:Tissue Donors; D015854:Up-Regulation / Q000187:drug effects
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; C571163:CD33 protein, human; D018950:Lipopolysaccharide Receptors; C524898:PLAUR protein, human; D011956:Receptors, Cell Surface; D044042:Receptors, Formyl Peptide; D055293:Receptors, Urokinase Plasminogen Activator; D063268:Sialic Acid Binding Ig-like Lectin 3; D016179:Granulocyte Colony-Stimulating Factor