Figure 1: Plasmin-dependent and -independent mechanisms for HPSC mobilization from the BM to circulation. (a) Plasmin-mediated proteolysis induces HPSC mobilization. uPA converts Plg into protease-active plasmin that activates pro-MMP-9. Active MMP-9 cleaves KitL and upregulates CXCR4, and MMP-9 and plasmin degrade ECM, both of which release HPSC from the BM, leading to HPSC egress to circulation. (b) Plasmin-independent proteolysis and chemotaxis induce HPSC mobilization. uPAR is cleaved to chemotactic suPAR that drives HPSC migration to circulation. Cleavage of membrane uPAR also directly disrupts the interaction between uPAR and VLA-4, degrades vitronectin, and desensitizes the CXCR4 signal, which leads to HPSC mobilization.