title: Plasminogen regulates cardiac repair after myocardial infarction through its noncanonical function in stem cell homing to the infarcted heart.
abstract: OBJECTIVE
  The purpose of this study was to investigate the role of plasminogen (Plg) in stem cell-mediated cardiac repair and regeneration after myocardial infarction (MI).
  
  
  BACKGROUND
  An MI induces irreversible tissue damage, eventually leading to heart failure. Bone marrow (BM)-derived stem cells promote tissue repair and regeneration after MI. Thrombolytic treatment with Plg activators significantly improves the clinical outcome in MI by restoring cardiac perfusion. However, the role of Plg in stem cell-mediated cardiac repair remains unclear.
  
  
  METHODS
  An MI was induced in Plg-deficient (Plg(-/-)) and wild-type (Plg(+/+)) mice by ligation of the left anterior descending coronary artery. Stem cells were visualized by in vivo tracking of green fluorescent protein (GFP)-expressing BM cells after BM transplantation. Cardiac function, stem cell homing, and signaling pathways downstream of Plg were examined.
  
  
  RESULTS
  Granulocyte colony-stimulating factor, a stem cell mobilizer, significantly promoted BM-derived stem cell (GFP(+)c-kit(+) cell) recruitment into the infarcted heart and stem cell-mediated cardiac repair in Plg(+/+) mice. However, Plg deficiency markedly inhibited stem cell homing and cardiac repair, suggesting that Plg is critical for stem cell-mediated cardiac repair. Moreover, Plg regulated C-X-C chemokine receptor type 4 (CXCR4) expression in stem cells in vivo and in vitro through matrix metalloproteinase-9. Lentiviral reconstitution of CXCR4 expression in BM cells successfully rescued stem cell homing to the infarcted heart in Plg-deficient mice, indicating that CXCR4 has a critical role in Plg-mediated stem cell homing after MI.
  
  
  CONCLUSIONS
  These findings have identified a novel role for Plg in stem cell-mediated cardiac repair after MI. Thus, targeting Plg may offer a new therapeutic strategy for stem cell-mediated cardiac repair after MI.
authors.affiliation: Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Departments of Cardiovascular Medicine and Molecular Cardiology, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio; Division of Translational Medicine and Human Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania. Electronic address: gongy@mail.med.upenn.edu.
authors.forename: Yanqing
authors.initials: Y
authors.lastname: Gong
authors.affiliation: Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Departments of Cardiovascular Medicine and Molecular Cardiology, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio.
authors.forename: Yujing
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Departments of Cardiovascular Medicine and Molecular Cardiology, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio.
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Yi
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Departments of Cardiovascular Medicine and Molecular Cardiology, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio.
authors.forename: Jane
authors.initials: J
authors.lastname: Hoover-Plow
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation / Q000379:methods*; D004195:Disease Models, Animal; D005343:Fibrinolytic Agents / Q000627:therapeutic use; D006333:Heart Failure / Q000209:etiology* / Q000517:prevention & control; D019650:Hematopoietic Stem Cell Mobilization / Q000379:methods*; D051379:Mice; D009203:Myocardial Infarction / Q000150:complications / Q000503:physiopathology / Q000628:therapy*; D010958:Plasminogen / Q000627:therapeutic use*
chemical_list: D005343:Fibrinolytic Agents; D010958:Plasminogen
keywords: BM-derived stem cells; CXCR4; myocardial infarction; plasminogen