title: Differentiation of allogeneic mesenchymal stem cells induces immunogenicity and limits their long-term benefits for myocardial repair.
abstract: BACKGROUND
  Cardiac cell therapy for older patients who experience a myocardial infarction may require highly regenerative cells from young, healthy (allogeneic) donors. Bone marrow mesenchymal stem cells (MSCs) are currently under clinical investigation because they can induce cardiac repair and may also be immunoprivileged (suitable for allogeneic applications). However, it is unclear whether allogeneic MSCs retain their immunoprivilege or functional efficacy late after myocardial implantation. We evaluated the effects of MSC differentiation on the immune characteristics of cells in vitro and in vivo and monitored cardiac function for 6 months after post-myocardial infarction MSC therapy.
  
  
  RESULTS
  In the in vitro experiments, inducing MSCs to acquire myogenic, endothelial, or smooth muscle characteristics (via 5-azacytidine or cytokine treatment) increased major histocompatibility complex-Ia and -II (immunogenic) expression and reduced major histocompatibility complex-Ib (immunosuppressive) expression, in association with increased cytotoxicity in coculture with allogeneic leukocytes. In the in vivo experiments, we implanted allogeneic or syngeneic MSCs into infarcted rat myocardia. We measured cell differentiation and survival (immunohistochemistry, real-time polymerase chain reaction) and cardiac function (echocardiography, pressure-volume catheter) for 6 months. MSCs (versus media) significantly improved ventricular function for at least 3 months after implantation. Allogeneic (but not syngeneic) cells were eliminated from the heart by 5 weeks after implantation, and their functional benefits were lost within 5 months.
  
  
  CONCLUSIONS
  The long-term ability of allogeneic MSCs to preserve function in the infarcted heart is limited by a biphasic immune response whereby they transition from an immunoprivileged to an immunogenic state after differentiation, which is associated with an alteration in major histocompatibility complex-immune antigen profile.
authors.affiliation: Department of Surgery, Division of Cardiovascular Surgery, University of Toronto and University Health Network, Toronto, Ontario, Canada.
authors.forename: Xi-Ping
authors.initials: XP
authors.lastname: Huang
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Sun
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Miyagi
authors.forename: Heather
authors.initials: H
authors.lastname: McDonald Kinkaid
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Richard D
authors.initials: RD
authors.lastname: Weisel
authors.forename: Ren-Ke
authors.initials: RK
authors.lastname: Li
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000276:immunology*; D005260:Female; D007519:Isoantigens / Q000008:administration & dosage* / Q000009:adverse effects*; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000009:adverse effects* / Q000379:methods; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000276:immunology* / Q000473:pathology; D009203:Myocardial Infarction / Q000276:immunology* / Q000473:pathology / Q000601:surgery; D051381:Rats; D011917:Rats, Inbred Lew; D017208:Rats, Wistar; D013997:Time Factors; D014184:Transplantation, Homologous / Q000009:adverse effects* / Q000276:immunology* / Q000473:pathology
chemical_list: D007519:Isoantigens