title: Preserving prostaglandin E2 level prevents rejection of implanted allogeneic mesenchymal stem cells and restores postinfarction ventricular function.
abstract: BACKGROUND
  Allogeneic mesenchymal stem cells (MSCs) were immunoprivileged early after cardiac implantation and improved heart function in preclinical and clinical studies. However, long-term preclinical studies demonstrated that allogeneic MSCs lost their immunoprivilege and were rejected in the injured myocardium, resulting in recurrent ventricular dysfunction. This study identifies some of the mechanisms responsible for the immune switch in MSCs and suggests a new treatment to maintain immunoprivilege and preserve heart function.
  
  
  RESULTS
  Rat MSC immunoprivilege was mediated by prostaglandin E2 (PGE2)-induced secretion of 2 critical chemokines, CCL12 and CCL5. These chemokines stimulated the chemoattraction of T cells toward MSCs, suppressed cytotoxic T-cell proliferation, and induced the production of T regulatory cells. MSCs treated with 5-azacytidine for 24 hours differentiated into myogenic cells after 2 weeks, which was associated with decreased PGE2 and chemokine production and the loss of immunoprivilege. Treatment of differentiated MSCs with PGE2 restored chemokine levels and preserved MSC immunoprivilege. In a rat myocardial infarction model, allogeneic MSCs (3 × 10(6) cells/rat) were injected into the infarct region with or without a biodegradable hydrogel that slowly released PGE2. Five weeks later, the transplanted MSCs expressed myogenic lineage markers and were rejected in the control group, but in the PGE2-treated group, the transplanted cells survived and heart function improved.
  
  
  CONCLUSIONS
  Allogeneic MSCs maintained immunoprivilege by PGE2-induced secretion of chemokines CCL12 and CCL5. Differentiation of MSCs decreased PGE2 levels, and immunoprivilege was lost. Maintaining PGE2 levels preserved immunoprivilege after differentiation, prevented rejection of implanted MSCs, and restored cardiac function.
authors.affiliation: Division of Cardiovascular Surgery and Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada (S.D., X.-P.H., J.G., J.W., A.M., S.-H.L., W.-F.Z., D.S., R.D.W., R.-K.L.); Department of Surgery, University of Toronto, Toronto, Ontario, Canada (S.D., X.-P.H., J.G., J.W., A.M., S.-H.L., W.-F.Z., D.S., R.D.W., R.-K.L.); Institute of Cardiovascular Sciences, St. Boniface Research Centre, Faculty of Medicine, University of Manitoba, Winnipeg, Canada (S.D., P.K.S.); and Department of Cardiac Surgery, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (P.L.).
authors.forename: Sanjiv
authors.initials: S
authors.lastname: Dhingra
authors.forename: Peng
authors.initials: P
authors.lastname: Li
authors.forename: Xi-Ping
authors.initials: XP
authors.lastname: Huang
authors.forename: Jian
authors.initials: J
authors.lastname: Guo
authors.forename: Jun
authors.initials: J
authors.lastname: Wu
authors.forename: Anton
authors.initials: A
authors.lastname: Mihic
authors.forename: Shu-Hong
authors.initials: SH
authors.lastname: Li
authors.forename: Wang-Fu
authors.initials: WF
authors.lastname: Zang
authors.forename: Daniel
authors.initials: D
authors.lastname: Shen
authors.forename: Richard D
authors.initials: RD
authors.lastname: Weisel
authors.forename: Pawan K
authors.initials: PK
authors.lastname: Singal
authors.forename: Ren-Ke
authors.initials: RK
authors.lastname: Li
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D018920:Coculture Techniques; D015232:Dinoprostone / Q000378:metabolism* / Q000502:physiology / Q000627:therapeutic use; D005260:Female; D006084:Graft Rejection / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D011897:Random Allocation; D051381:Rats; D011917:Rats, Inbred Lew; D017208:Rats, Wistar; D014184:Transplantation, Homologous; D016276:Ventricular Function / Q000187:drug effects / Q000502:physiology*
chemical_list: D015232:Dinoprostone
keywords: immunoprivilege; myocardial infarction; stem cells; transplantation