title: Cultured human bone marrow-derived CD31(+) cells are effective for cardiac and vascular repair through enhanced angiogenic, adhesion, and anti-inflammatory effects.
abstract: BACKGROUND
  Cell therapy for cardiovascular disease has been limited by low engraftment of administered cells and modest therapeutic effects. Bone marrow (BM) -derived CD31(+) cells are a promising cell source owing to their high angiovasculogenic and paracrine activities.
  
  
  OBJECTIVE
  This study sought to identify culture conditions that could augment the cell adhesion, angiogenic, and anti-inflammatory activities of BM-derived CD31(+) cells, and to determine whether these cultured CD31(+) cells are effective for cardiac and vascular repair.
  
  
  METHODS
  CD31(+) cells were isolated from human BM by magnetic-activated cell sorting and cultured for 10 days under hematopoietic stem cell, mesenchymal stem cell, or endothelial cell culture conditions. These cells were characterized by adhesion, angiogenesis, and inflammatory assays. The best of the cultured cells were implanted into myocardial infarction (MI) and hindlimb ischemia (HLI) models to determine therapeutic effects and underlying mechanisms.
  
  
  RESULTS
  The CD31(+) cells cultured in endothelial cell medium (EC-CD31(+) cells) showed the highest adhesion and angiogenic activities and lowest inflammatory properties in vitro compared with uncultured or other cultured CD31(+) cells. When implanted into mouse MI or HLI models, EC-CD31(+) cells improved cardiac function and repaired limb ischemia to a greater extent than uncultured CD31(+) cells. Histologically, injected EC-CD31(+) cells exhibited higher retention, neovascularization, and cardiomyocyte proliferation. Importantly, cell retention and endothelial transdifferentiation was sustained up to 1 year.
  
  
  CONCLUSIONS
  Short-term cultured EC-CD31(+) cells have higher cell engraftment, vessel-formation, cardiomyocyte proliferation, and anti-inflammatory potential, are highly effective for both cardiac and peripheral vascular repair, and enhance survival of mice with heart failure. These cultured CD31(+) cells may be a promising source for treating ischemic cardiovascular diseases.
authors.affiliation: Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia; Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Incheon, South Korea; International St. Mary's Hospital, Incheon, South Korea; Department of Anatomy and Cell Biology and Mitochondria Hub Regulation Center, College of Medicine, Dong-A University, Busan, South Korea; Department of Cardiology, The Fourth Hospital of Harbin Medical University, Harbin, China.
authors.forename: Sung-Whan
authors.initials: SW
authors.lastname: Kim
authors.affiliation: Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia.
authors.forename: Mackenzie
authors.initials: M
authors.lastname: Houge
authors.affiliation: Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia; Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, Georgia.
authors.forename: Milton
authors.initials: M
authors.lastname: Brown
authors.affiliation: Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia; Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, Georgia.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Davis
authors.affiliation: Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia; Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, Georgia. Electronic address: yyoon5@emory.edu.
authors.forename: Young-Sup
authors.initials: YS
authors.lastname: Yoon
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000502:physiology; D016026:Bone Marrow Transplantation / Q000379:methods*; D002448:Cell Adhesion / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology*; D002478:Cells, Cultured; D005260:Female; D006614:Hindlimb / Q000098:blood supply / Q000502:physiology; D006801:Humans; D018836:Inflammation Mediators / Q000502:physiology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D017202:Myocardial Ischemia / Q000473:pathology / Q000628:therapy*; D032383:Myocytes, Cardiac / Q000502:physiology; D018919:Neovascularization, Physiologic / Q000502:physiology*; D038081:Organogenesis / Q000502:physiology; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000502:physiology*; D011897:Random Allocation; D016896:Treatment Outcome
chemical_list: D018836:Inflammation Mediators; D019408:Platelet Endothelial Cell Adhesion Molecule-1
keywords: CD31; angiogenesis; engraftment; inflammation; myocardial infarction; peripheral vascular disease