uPAR and Proteases in Mobilization of Hematopoietic Stem Cells

Abstract

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.