title: Allogeneic Mesenchymal Stromal Cells Transplanted Onto the Heart Surface Achieve Therapeutic Myocardial Repair Despite Immunologic Responses in Rats.
abstract: BACKGROUND
  Transplantation of allogeneic mesenchymal stromal cells (MSCs) is a promising treatment for heart failure. We have shown that epicardial placement of cell sheets markedly increases donor cell survival and augments therapeutic effects compared with the current methods. Although immune rejection of intramyocardially injected allogeneic MSCs have been suggested, allogeneic MSCs transplanted on the heart surface (virtual space) may undergo different courses. This study aimed to elucidate immunologic response against epicardially placed allogeneic MSCs, rejection or acceptance of these cells, and their therapeutic effects for heart failure.
  
  
  RESULTS
  At 4 weeks after coronary artery ligation, Lewis rats underwent epicardial placement of MSC sheets from syngeneic Lewis or allogeneic Fischer 344 rats or sham treatment. At days 3 and 10 after treatment, similar ratios (≈50% and 30%, respectively) of grafted MSCs survived on the heart surface in both MSC sheet groups. By day 28, survival of syngeneic MSCs was substantially reduced (8.9%); survival of allogeneic MSCs was more extensively reduced (0.2%), suggesting allorejection. Correspondingly, allogeneic MSCs were found to have evoked an immunologic response, albeit low level, as characterized by accumulation of CD4(+) T cells and upregulation of interleukin 6. Despite this alloimmune response, the allogeneic MSC sheet achieved myocardial upregulation of reparative factors, enhanced repair of the failing myocardium, and improved cardiac function to the equivalent degree observed for the syngeneic MSC sheet.
  
  
  CONCLUSIONS
  Allogeneic MSCs placed on the heart surface evoked an immunologic response; however, this allowed sufficient early phase donor cell survival to induce equivalent therapeutic benefits to syngeneic MSCs. Further development of this approach toward clinical application is warranted.
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom.
authors.forename: Nobuko
authors.initials: N
authors.lastname: Tano
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kaneko
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Ichihara
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom.
authors.forename: Chiho
authors.initials: C
authors.lastname: Ikebe
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Coppen
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom.
authors.forename: Manabu
authors.initials: M
authors.lastname: Shiraishi
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Shintani
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom.
authors.forename: Kenta
authors.initials: K
authors.lastname: Yashiro
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom.
authors.forename: Anthony
authors.initials: A
authors.lastname: Warrens
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom ken.suzuki@qmul.ac.uk.
authors.forename: Ken
authors.initials: K
authors.lastname: Suzuki
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002470:Cell Survival; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006084:Graft Rejection / Q000276:immunology; D006085:Graft Survival; D006333:Heart Failure / Q000276:immunology / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D015850:Interleukin-6 / Q000276:immunology; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000276:immunology*; D009203:Myocardial Infarction / Q000276:immunology / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D009206:Myocardium / Q000276:immunology* / Q000473:pathology; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D020127:Recovery of Function; D012038:Regeneration; D013318:Stroke Volume; D013997:Time Factors; D014184:Transplantation, Homologous; D016277:Ventricular Function, Left
chemical_list: D015850:Interleukin-6
keywords: allotransplantation; cell transplantation; heart failure; immunologic response; mesenchymal stem cell