Induced pluripotent stem cells (iPSCs), reprogrammed from somatic cells with defined factors, hold great promise for regenerative medicine as the renewable source of autologous cells1,2,3,4,5. Whereas it has been generally assumed that these autologous cells should be immune-tolerated by the recipient from whom the iPSCs are derived, their immunogenicity has not been vigorously examined. We show here that, whereas embryonic stem cells (ESCs) derived from inbred C57BL/6 (B6) mice can efficiently form teratomas in B6 mice without any evident immune rejection, the allogeneic ESCs from 129/SvJ mice fail to form teratomas in B6 mice due to rapid rejection by recipients. B6 mouse embryonic fibroblasts (MEFs) were reprogrammed into iPSCs by either retroviral approach (ViPSCs) or a novel episomal approach (EiPSCs) that causes no genomic integration. In contrast to B6 ESCs, teratomas formed by B6 ViPSCs were mostly immune-rejected by B6 recipients. In addition, the majority of teratomas formed by B6 EiPSCs were immunogenic in B6 mice with T cell infiltration, and apparent tissue damage and regression were observed in a small fraction of teratomas. Global gene expression analysis of teratomas formed by B6 ESCs and EiPSCs revealed a number of genes frequently overexpressed in teratomas derived from EiPSCs, and several such gene products were shown to contribute directly to the immunogenicity of the B6 EiPSC-derived cells in B6 mice. These findings indicate that, in contrast to derivatives of ESCs, abnormal gene expression in some cells differentiated from iPSCs can induce T-cell-dependent immune response in syngeneic recipients. Therefore, the immunogenicity of therapeutically valuable cells derived from patient-specific iPSCs should be evaluated before any clinic application of these autologous cells into the patients.
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Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676 (2006)
Takahashi, K. et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861–872 (2007)
Yu, J. et al. Induced pluripotent stem cell lines derived from human somatic cells. Science 318, 1917–1920 (2007)
Park, I.-H. et al. Reprogramming of human somatic cells to pluripotency with defined factors. Nature 451, 141–146 (2008)
Lowry, W. E. et al. Generation of human induced pluripotent stem cells from dermal fibroblasts. Proc. Natl Acad. Sci. USA 105, 2883–2888 (2008)
Dhodapkar, K. M. et al. Natural immunity to pluripotency antigen OCT4 in humans. Proc. Natl Acad. Sci. USA 107, 8718–8723 (2010)
Jincho, Y. et al. Generation of genome integration-free induced pluripotent stem cells from fibroblasts of C57BL/6 mice without c-Myc transduction. J. Biol. Chem. 285, 26384–26389 (2010)
Chen, Y. T. et al. Identification of CT46/HORMAD1, an immunogenic cancer/testis antigen encoding a putative meiosis-related protein. Cancer Immun. 5, 9 (2005)
Kont, V. et al. Modulation of Aire regulates the expression of tissue-restricted antigens. Mol. Immunol. 45, 25–33 (2008)
Guermonprez, P., Valladeau, J., Zitvogel, L., Théry, C. & Amigorena, S. Antigen presentation and T cell stimulation by dendritic cells. Annu. Rev. Immunol. 20, 621–667 (2002)
Stadtfeld, M., Nagaya, M., Utikal, J., Weir, G. & Hochedlinger, K. Induced pluripotent stem cells generated without viral integration. Science 322, 945–949 (2008)
Zhou, H. et al. Generation of induced pluripotent stem cells using recombinant proteins. Cell Stem Cell 4, 381–384 (2009)
Chin, M. H. et al. Induced pluripotent stem cells and embryonic stem cells are distinguished by gene expression signatures. Cell Stem Cell 5, 111–123 (2009)
Liu, L. et al. Activation of the imprinted Dlk1-Dio3 region correlates with pluripotency levels of mouse stem cells. J. Biol. Chem. 285, 19483–19490 (2010)
Stadtfeld, M. et al. Aberrant silencing of imprinted genes on chromosome 12qF1 in mouse induced pluripotent stem cells. Nature 465, 175–181 (2010)
Doi, A. et al. Differential methylation of tissue- and cancer-specific CpG island shores distinguishes human induced pluripotent stem cells, embryonic stem cells and fibroblasts. Nature Genet. 41, 1350–1353 (2009)
Kim, K. et al. Epigenetic memory in induced pluripotent stem cells. Nature 467, 285–290 (2010)
Polo, J. M. et al. Cell type of origin influences the molecular and functional properties of mouse induced pluripotent stem cells. Nature Biotechnol. 28, 848–855 (2010)
Lister, R. et al. Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells. Nature 471, 68–73 (2011)
Zhao, T. & Xu, Y. p53 and stem cells: new developments and new concerns. Trends Cell Biol. 20, 170–175 (2010)
Gore, A. et al. Somatic coding mutations in human induced pluripotent stem cells. Nature 471, 63–67 (2011)
Song, H., Hollstein, M. & Xu, Y. p53 gain-of-function cancer mutants induce genetic instability by inactivating ATM. Nature Cell Biol. 9, 573–580 (2007)
Song, H., Chung, S.-K. & Xu, Y. Modeling Disease in Human ESCs Using an Efficient BAC-Based Homologous Recombination System. Cell Stem Cell 6, 80–89 (2010)
We thank M. Abe, S. Ding and K. Hochedlinger for their generous supply of integration-free mouse iPSCs. We thank N. Shastri for his advice on how to identify antigen-specific T cells. We thank J. Fink and Blue Lake of Xu lab as well as UCSD Cancer Center pathologic core for technical support. This work was supported by a NIH grant and an Early Translational Award from California Institute for Regenerative Medicine to Y.X. (ET-01277).
The authors declare no competing financial interests.
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Zhao, T., Zhang, ZN., Rong, Z. et al. Immunogenicity of induced pluripotent stem cells. Nature 474, 212–215 (2011). https://doi.org/10.1038/nature10135
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