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(Circulation. 2005;112:I-166 – I-172.)
© 2005 American Heart Association, Inc.

Cell Transplantation and Tissue Engineering

Embryonic Stem Cell Immunogenicity Increases Upon Differentiation After Transplantation Into Ischemic Myocardium

Rutger-Jan Swijnenburg, MS; Masashi Tanaka, MD; Hannes Vogel, MD; Jeanette Baker, PhD; Theo Kofidis, MD; Feny Gunawan, BS; Darren R. Lebl, MS; Anthony D. Caffarelli, MD; Jorg L. de Bruin, MD; Eugenia V. Fedoseyeva, PhD; Robert C. Robbins, MD

From the Department of Surgery, Leiden University School of Medicine, The Netherlands (R.J.S.); Departments of Cardiothoracic Surgery (R.J.S., M.T., T.K., F.G., D.R.L., A.D.C., J.L.d.B., E.V.F., R.C.R.), Pathology (H.V.), and Medicine (J.B.), Stanford University School of Medicine, Stanford, Calif.

Correspondence to Rutger-Jan Swijnenburg, MS, Department of Cardiothoracic Surgery, Stanford University School of Medicine, Falk Cardiovascular Research Center, 300 Pasteur Dr, Stanford, CA 94303-95407. E-mail rjswijnenburg{at}hotmail.com

Background— We investigated whether differentiation of embryonic stem cells (ESCs) in ischemic myocardium enhances their immunogenicity, thereby increasing their chance for rejection.

Methods and Results— In one series, 129/SvJ-derived mouse ESCs (ES-D3 line) were transplanted by direct myocardial injection (1x10⁶ 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.

Conclusion— 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.

Key Words: cells • transplantation • myocardium • immunology