Abstract 406: Plasminogen Regulates Mesenchymal Stem Cell-mediated Tissue Repair After Ischemia Through Cry61

Abstract

Objective: Stem cell transplantation has emerged as a promising strategy for improving post-ischemic tissue repair. However, the poor survival and persistence of the transplanted cells including mesenchymal stem cells (MSCs) in the hostile ischemic microenvironments represents a major therapeutic barrier. Previous work shows that plasminogen (Plg) promotes post-injury tissue repair by mobilizing hematopoietic stem cell from bone marrow to circulation. Here our studies aim to define the role of Plg in microenvironment-dependent, MSC-mediated tissue repair after hindlimb ischemia. Approach and Results: Our studies show that Plg stimulates MSC proliferation and migration under normoxia and promotes MSC survival under hypoxia. Hindlimb ischemia was induced in Plg-deficient (Plg -/- ) and wild-type (Plg +/+ ) mice by ligation of femoral artery, followed by injection with fLuc/tdTomato + MSCs into the ischemic limbs. Our data show that Plg deficiency abolishes MSC survival, migration, and proliferation in the ischemic limbs, and abrogates MSC-mediated blood reperfusion, neovascularization and tissue repair after ischemia, suggesting that Plg is critical for MSC-mediated tissue repair. Furthermore, multiplex cytokine array analysis identifies Cyr61, a pro-angiogenic factor, as a downstream target of Plg in MSCs. Plg cleaves and activates Cyr61, which is required for Plg-stimulated MSC survival and migration. Finally, Plg-mediated Cry61 cleavage further promotes EC migration and neovascularization in vitro and in vivo. Conclusions: Our study suggests that Plg promotes MSC survival and persistence in ischemic limbs and improves tissue repair. We identify an underlying mechanism, by which Plg induces Cyr61 cleavage and activation in MSCs, enhancing MSC survival and migration and promoting EC migration and neovascularization. Thus, targeting Plg/Cyr61 may offer exciting therapeutic opportunities for strengthening MSC therapy in ischemic diseases.