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Negligible immunogenicity of terminally differentiated cells derived from induced pluripotent or embryonic stem cells

Abstract

The advantages of using induced pluripotent stem cells (iPSCs) instead of embryonic stem (ES) cells in regenerative medicine centre around circumventing concerns about the ethics of using ES cells and the likelihood of immune rejection of ES-cell-derived tissues1,2. However, partial reprogramming and genetic instabilities in iPSCs3,4,5,6 could elicit immune responses in transplant recipients even when iPSC-derived differentiated cells are transplanted. iPSCs are first differentiated into specific types of cells in vitro for subsequent transplantation. Although model transplantation experiments have been conducted using various iPSC-derived differentiated tissues7,8,9,10 and immune rejections have not been observed, careful investigation of the immunogenicity of iPSC-derived tissue is becoming increasingly critical, especially as this has not been the focus of most studies done so far. A recent study reported immunogenicity of iPSC- but not ES-cell-derived teratomas11 and implicated several causative genes. Nevertheless, some controversy has arisen regarding these findings12. Here we examine the immunogenicity of differentiated skin and bone marrow tissues derived from mouse iPSCs. To ensure optimal comparison of iPSCs and ES cells, we established ten integration-free iPSC and seven ES-cell lines using an inbred mouse strain, C57BL/6. We observed no differences in the rate of success of transplantation when skin and bone marrow cells derived from iPSCs were compared with ES-cell-derived tissues. Moreover, we observed limited or no immune responses, including T-cell infiltration, for tissues derived from either iPSCs or ES cells, and no increase in the expression of the immunogenicity-causing Zg16 and Hormad1 genes in regressing skin and teratoma tissues. Our findings suggest limited immunogenicity of transplanted cells differentiated from iPSCs and ES cells.

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Figure 1: Teratoma formation by iPSCs and ES cells.
Figure 2: Skin transplantation.
Figure 3: Bone marrow transplantation.
Figure 4: Expression of Zg16 and Hormad1 genes in various tissues generated from iPSCs and ES cells.

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Acknowledgements

We thank S. Yamanaka for providing the 2A plasmid vectors; K. Ito, N. Nakajima and K. Kawabata for technical advice on the transplantation experiments; H. Yoshida, K. Nishikawa, A. Ishibashi, R. Watanabe, M. Nakamura and T. Maeda for technical assistance. This work was partially funded by a research grant from Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency.

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Contributions

R.A. and M.A. designed the experiments, analysed the data and wrote the manuscript. R.A. and Y.H. established the iPSC and ES-cell lines. M.U., S.A., M.N. and Y.H. performed teratoma formation assays and transplantation assays. M. Sunayama and M. Sugiura performed molecular biological analyses. M.U., H.I., A.S. and A.N. performed immunohistochemical analyses.

Corresponding author

Correspondence to Masumi Abe.

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The authors declare no competing financial interests.

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Araki, R., Uda, M., Hoki, Y. et al. Negligible immunogenicity of terminally differentiated cells derived from induced pluripotent or embryonic stem cells. Nature 494, 100–104 (2013). https://doi.org/10.1038/nature11807

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