title: Embryonic stem cell immunogenicity increases upon differentiation after transplantation into ischemic myocardium.
abstract: BACKGROUND
  We investigated whether differentiation of embryonic stem cells (ESCs) in ischemic myocardium enhances their immunogenicity, thereby increasing their chance for rejection.
  
  
  RESULTS
  In one series, 129/SvJ-derived mouse ESCs (ES-D3 line) were transplanted by direct myocardial injection (1 x 10(6) cells) into murine hearts of both allogeneic (BALB/c, n=20) and syngeneic (129/SvJ, n=12) recipients after left anterior artery ligation. Hearts were procured at 1, 2, 4, and 8 weeks after ESC transplantation and analyzed by immunohistochemistry to assess immune cell infiltration (CD3, CD4, CD8, B220, CD11c, Mac-1, and Gr-1) and ESC differentiation (hematoxylin and eosin). In a second series (allogeneic n=5, sham n=3), ESC transplantation was performed similarly; however after 2 weeks, left anterior descending artery-ligated and ESC-injected hearts were heterotopically transplanted into naive BALB/c recipients. After an additional 2 weeks, donor hearts were procured and analyzed by immunohistochemistry. In the first series, the size of all ESC grafts remained stable and there was no evidence of ESC differentiation 2 weeks after transplantation; however, after 4 weeks, both allogeneic and syngeneic ESC grafts showed the presence of teratoma. By 8 weeks, surviving ESCs could be detected in the syngeneic but not in the allogeneic group. Mild inflammatory cellular infiltrates were found in allogeneic recipients at 1 and 2 weeks after transplantation, progressing into vigorous infiltration at 4 and 8 weeks. The second series demonstrated similar vigorous infiltration of immune cells as early as 2 weeks after heterotopic transplantation.
  
  
  CONCLUSIONS
  In vivo differentiated ESCs elicit an accelerated immune response as compared with undifferentiated ESCs. These data imply that clinical transplantation of allogeneic ESCs or ESC derivatives for treatment of cardiac failure might require immunosuppressive therapy.
authors.affiliation: Department of Surgery, Leiden University School of Medicine, The Netherlands. rjswijnenburg@hotmail.com
authors.forename: Rutger-Jan
authors.initials: RJ
authors.lastname: Swijnenburg
authors.forename: Masashi
authors.initials: M
authors.lastname: Tanaka
authors.forename: Hannes
authors.initials: H
authors.lastname: Vogel
authors.forename: Jeanette
authors.initials: J
authors.lastname: Baker
authors.forename: Theo
authors.initials: T
authors.lastname: Kofidis
authors.forename: Feny
authors.initials: F
authors.lastname: Gunawan
authors.forename: Darren R
authors.initials: DR
authors.lastname: Lebl
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Caffarelli
authors.forename: Jorg L
authors.initials: JL
authors.lastname: de Bruin
authors.forename: Eugenia V
authors.initials: EV
authors.lastname: Fedoseyeva
authors.forename: Robert C
authors.initials: RC
authors.lastname: Robbins
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology*; D002460:Cell Line / Q000276:immunology / Q000637:transplantation; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D016332:Fetal Tissue Transplantation / Q000276:immunology*; D006084:Graft Rejection / Q000276:immunology*; D006098:Granulocytes / Q000276:immunology; D006338:Heart Neoplasms / Q000209:etiology* / Q000473:pathology; D016027:Heart Transplantation / Q000276:immunology; D007273:Injections, Intramuscular; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D017202:Myocardial Ischemia / Q000601:surgery*; D009206:Myocardium / Q000276:immunology* / Q000473:pathology; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000276:immunology / Q000637:transplantation*; D011183:Postoperative Complications / Q000209:etiology* / Q000473:pathology; D033581:Stem Cell Transplantation / Q000009:adverse effects; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013724:Teratoma / Q000209:etiology* / Q000473:pathology; D016042:Transplantation, Heterotopic / Q000276:immunology; D014184:Transplantation, Homologous / Q000276:immunology; D014185:Transplantation, Isogeneic / Q000276:immunology