Abstract 245: Plasminogen Augments Cxcl12/cxcr4-regulated Stem Cell Homing And Contributes To Cardiac Repair After Myocardial Infarction.
Myocardial infarction (MI) is a leading cause of morbidity and mortality worldwide. Bone marrow (BM)-derived stem cells promote tissue repair and regeneration after MI. Thrombolytic treatment with plasminogen (Plg) activators significantly improves the clinical outcome in MI by restoration of cardiac perfusion. In addition to its canonical function, Plg is critical for cardiac repair, wound healing and liver injury, however, the mechanism for Plg-regulated tissue repair remains unclear. Here, we show a novel role of Plg in stem cell-mediated neovascularization and cardiac repair after MI. Our data show that Granulocyte colony-stimulating factor (G-CSF), a stem cell mobilizer, significantly increased neovascularization and decreased infarct size in the infarct area, and improved ejection fraction and LV internal diameter by echocardiogram in wild-type mice. No improvement in tissue repair and heart function was observed in Plg deficient (Plg-/-) mice indicating that Plg is required for stem cell-regulated cardiac repair after MI. In vivo tracking of GFP-expressing BM cells after BM transplantation revealed that in Plg-/- mice, recruitment of BM-derived stem cells (GFP+c-kit+ cells) to the infarcted heart and stem cell-derived vessels and arteries are dramatically decreased (by 11 fold) suggesting that Plg may regulate stem cell homing to the lesion sites and subsequently contribute stem cell-mediated tissue regeneration. Mechanistic studies show that Plg up-regulated CXCR4 expression on stem cell in vivo and in vitro, suggesting Plg may promotes stem cell homing by induction of CXCR4 expression in stem cells. Stem cell migration was enhanced by endogenous Plg in vitro, however, AMD3100, a CXCR4 antagonist, significantly inhibited Plg-regulated stem cell migration. Furthermore, lentiviral reconstitution of CXCR4 expression in BM cells rescued stem cell homing to the infarcted heart in Plg-/- mice, indicating that Plg mediates stem cell homing through regulating CXCR4 expression. These findings identified a novel role of Plg in cardiac repair by promoting stem cell homing to the injured heart after MI. Thus, targeting Plg may offer a new therapeutic strategy for strengthening stem cell-mediated cardiac repair and regeneration after MI.
Author Disclosures: Y. Gong: None Y. Zhao: None Y. Fan: None J. Hoover-Plow: None.
This research has received full or partial funding support from the American Heart Association, National Center.
- © 2014 by American Heart Association, Inc.