Main Text

Zhao et al., 2011 Zhao T.

Zhang Z.N.

Rong Z.

Xu Y. Yamanaka, 2012 Yamanaka S. Okano et al., 2013 Okano H.

Nakamura M.

Yoshida K.

Okada Y.

Tsuji O.

Nori S.

Ikeda E.

Yamanaka S.

Miura K. Guha et al., 2013 Guha P.

Morgan J.W.

Mostslavsky G.

Rodrigues N.P.

Boyd A.S. Araki et al., 2013 Araki R.

Uda M.

Hoki Y.

Sunayama M.

Nakamura M.

Ando S.

Sugiura M.

Ideno H.

Shimada A.

Nifuji A.

Abe M. The possibility of using autologous iPSCs in a therapeutic setting has been met with a high degree of caution due to previous findings reporting the potential of iPSC-derived teratomas to elicit an immune response in syngeneic hosts. However, two recent reports in favor of their safety have now shifted the debate to a more optimistic outlook. The debate started from a report that revealed unexpected immune responses to teratomas, tumors containing differentiated cells of all three germ layers that were derived from syngeneic murine iPSCs (). It had been believed that syngeneic “self”-iPSCs and their progeny would not cause any immune response in the host due to self-tolerance, a central dogma of immunology. The study by Zhao and colleagues, however, cautioned against such an optimistic view by showing abnormal protein expression, T cell infiltration, and immune rejection of the teratomas. In our view, the media reacted too quickly to these findings and reported them from an unnecessarily pessimistic point of view, casting doubt on the usage of iPSCs in regenerative medicine. Fortunately, the stem cell research community pleaded for patience because the report left many unanswered questions. Most notably, it remained to be determined whether immune responses could be elicited by differentiated tissues derived from syngeneic iPSCs, especially from those made using integration-free approaches (). In this issue of Cell Stem Cell, Boyd and colleagues addressed the question of immunogenicity by using in vitro differentiated cells derived from syngeneic iPSCs that represented each germ layer (). This report, in combination with a recent report by Abe and colleagues (), has shifted the balance regarding immunogenicity of syngeneic iPSCs in favor of their ability to engender self-tolerance.

Guha et al. first generated terminally differentiated endothelial cells, hepatocytes, and neuronal cells from ESCs and iPSCs in vitro. They then tested the immunogenicity of those cells in vitro and in vivo by measuring T cell responses in coculture and tissue engraftment, respectively, in a transplantation setting. In the initial characterization, some types of differentiated cells were found to express MHC class I and costimulatory molecules that would enable them to induce T cell responses to antigenic peptides (i.e., nonself peptides or tumor-associated peptides) if they were presented on MHC class I of the cell surface. However, coculture experiments revealed a lack of T cell response to undifferentiated syngeneic iPSCs or their differentiated progenies. To further assess the potential for immunogenicity in a more clinically relevant setting, they transplanted the three types of in vitro differentiated cells into syngeneic mice. Consistent with the in vitro result, lack of T cell infiltration was confirmed by histology and immunohistochemistry of transplanted tissue, and no immunological memory to syngeneic tissue was established in peripheral T cells of transplanted mice. In contrast, allogeneic tissues immediately induced severe immune reactions both in vitro and in vivo. These findings suggest that no immunogenic protein was produced, at least in iPSC-derived endothelial cells, hepatocytes, and neuronal cells.

Araki et al. (2013) Araki R.

Uda M.

Hoki Y.

Sunayama M.

Nakamura M.

Ando S.

Sugiura M.

Ideno H.

Shimada A.

Nifuji A.

Abe M. Guha et al. (2013) Guha P.

Morgan J.W.

Mostslavsky G.

Rodrigues N.P.

Boyd A.S. Araki et al. (2013) Araki R.

Uda M.

Hoki Y.

Sunayama M.

Nakamura M.

Ando S.

Sugiura M.

Ideno H.

Shimada A.

Nifuji A.

Abe M. took a similar approach, but focused their comparison on the immunogenicity of iPSCs compared to ESCs. Like, they found no evidence of immune rejection upon transplantation of iPSC- or ESC-derived tissues. For their transplantation studies, however,used skin grafts and bone marrow from chimeric iPSC- or ESC-derived mice rather than that from cells that were generated from pluripotent cells through directed differentiation in vitro. Although both papers come to the same conclusion, one can imagine that the differences in cell sources could have clinical implications, because in vitro derived cells represent a promising source of therapeutically useful cells.

Zhao et al. (2011) Zhao T.

Zhang Z.N.

Rong Z.

Xu Y. Araki et al. (2013) Araki R.

Uda M.

Hoki Y.

Sunayama M.

Nakamura M.

Ando S.

Sugiura M.

Ideno H.

Shimada A.

Nifuji A.

Abe M. A controversial aspect of all three reports relates to aberrant expression of a specific set of genes that were initially implicated in the immune rejection of iPSC-derived teratomas.showed a significantly higher rejection rate of iPSC-derived teratomas than ESC-derived teratomas, which was linked to overexpression of tumor-related genes, including Hormad and Zg16, in teratomas derived from syngeneic iPSCs. They also showed that these tumor-associated antigens induced cytokine responses by T cells. However, by using multiple pluripotent stem cell lines,showed negligible immune reaction to teratomas derived from syngeneic iPSCs and syngeneic ESCs. Moreover, they observed no significant elevation of Hormad and Zg16 in either teratoma or dermal cells. In addition, they confirmed indistinguishable expression profiles between tissue panels of adult mice generated by tetraploid complementation of ESCs and iPSCs. Guha et al. also demonstrated syngeneic teratoma formation in 100% of transplanted recipients regardless of whether ESCs or iPSCs were used and no differences in expression of Hormad, Zg16, and Retn genes in teratomas of both origins.

Even with the two current comprehensive studies, we should not be overly optimistic about the potential for immunogenicity of iPSCs. Primate and human iPSCs have not been tested for their immunological activities. In addition, each type of mature cell expresses a different set of genes and proteins; therefore, it will be necessary to carefully screen each cell type used in clinical applications for potential immunogenicity.