uPAR and Proteases in Mobilization of Hematopoietic Stem Cells
The specific cell-surface receptor for the urokinase-type plasminogen activator (uPA) was identified in 1985; since then, a large body of evidence showed that urokinase-type plasminogen activator receptor (uPAR) was not only the receptor for a proteolytic enzyme but also a multifunctional signaling molecule capable of various interactions and activities. In fact, uPAR is implicated in several biological events, such as cell adhesion, migration, proliferation, and survival. Cell-surface uPAR can be cleaved by neutrophil proteases, matrix metalloproteases, plasmin, and uPA itself. Both full-length and cleaved uPAR can be shed from the cell surface, generating full-length and cleaved forms of soluble uPAR (suPAR and c-suPAR). suPAR retains most of uPAR activities which are lost by c-suPAR. However, c-suPAR becomes a potent chemoattractant for cells expressing receptors of the FPR (fMLP: formyl-methionine-leucine-proline) family.
Very recently, uPAR involvement has been reported in the trafficking of human and mouse hematopoietic stem cells (HSCs) from and to bone marrow (BM). In humans, c-suPAR levels are strongly increased during HSC mobilization induced by the granulocyte-colony-stimulating factor (G-CSF). Increased c-suPAR could contribute to HSC migration into the circulation both directly, by inducing HSC migration, and indirectly, by inactivating CXCR4, a key receptor in HSC retention in BM. In vivo, a specific c-suPAR-derived peptide induces mobilization of mouse CD34+ HSCs to the same extent as G-CSF. In mice, uPAR is expressed on HSCs and seems to act as a retention signal in BM, likely by interacting with the VLA-4 integrin. uPAR shedding from the cell surface induces HSC release from BM and mobilization into the circulation. Proteases, which are largely produced in BM during G-CSF-induced mobilization, and, in particular, plasmin are strongly involved in these events and play an important role in HSC trafficking.
KeywordsHematopoietic Stem Cell Urokinase Receptor Bone Marrow Stroma Human Vascular Smooth Muscle Cell uPAR Expression
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