Plasminogen Regulates Stromal Cell–Derived Factor-1/CXCR4–Mediated Hematopoietic Stem Cell Mobilization by Activation of Matrix Metalloproteinase-9

Abstract

Granulocyte colony-stimulating factor (G-CSF) is a widespread therapeutic agent for stimulation of hematopoietic progenitor and stem cell (HPSC) mobilization from bone marrow (BM). Plasminogen (Plg) has been shown to be critical for HPSC mobilization. Here, we investigated the role of Plg in G-CSF-induced HPSC mobilization and the underlying mechanism. By using gene-targeted mice, our data show that Plg is required for G-CSF-induced HPSC egress to sinusoidal capillaries in BM and subsequent mobilization to peripheral circulation. G-CSF induced Plg-dependent activation of matrix metalloproteinase-9 (MMP-9) in BM, and MMP-9 neutralization or deficiency suppressed HPSC migration and mobilization. Reconstitution of MMP-9 activity by BM transplantation after lentiviral overexpression rescued HPSC mobilization in Plg-deficient mice, indicating that MMP-9 activation is required for Plg-mediated HPSC mobilization. Interestingly, after G-CSF simulation, Plg downregulated stromal cell-derived factor-1 in BM and spatiotemporally regulated the expression of C-X-C chemokine receptor type 4 (CXCR4) on mobilized HPSCs, and reconstitution of MMP-9 activity in Plg-deficient mice reversed CXCR4 expression on HPSCs in plasma and BM, suggesting that CXCR4 serves as a new downstream signal of Plg/MMP-9 in HPSC mobilization. Our data elucidated a novel mechanism that Plg regulates MMP-9-dependent CXCR4 expression to facilitate HPSC mobilization in response to G-CSF.