Embryonic stem cell immunogenicity increases upon differentiation after transplantation into ischemic myocardium.
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.
Swijnenburg
Rutger-Jan
RJ
Department of Surgery, Leiden University School of Medicine, The Netherlands. rjswijnenburg@hotmail.com
Tanaka
Masashi
M
Vogel
Hannes
H
Baker
Jeanette
J
Kofidis
Theo
T
Gunawan
Feny
F
Lebl
Darren R
DR
Caffarelli
Anthony D
AD
de Bruin
Jorg L
JL
Fedoseyeva
Eugenia V
EV
Robbins
Robert C
RC
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