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Humanized Mice Aid the Study of Immune Response to hiPSC-derived Cells



Review of “Humanized Mice Reveal Differential Immunogenicity of Cells Derived from Autologous Induced Pluripotent Stem Cells” from Cell Stem Cell by Stuart P. Atkinson.

Induced pluripotent stem cell (iPSC) technology has the potential to revolutionize personalized regenerative medicine through creating replacement cells and tissues and creating disease-specific models for drug discovery. However, a few stumbling blocks still loom on the horizon. One of the most important is the question of the immunogenic nature of iPSCs and their derivatives. While many assumed that the patient-specific nature of iPSCs would mitigate any problems of possible cell/tissue rejection, some studies in mice have uncovered data to the contrary [1-3].

To assess the problem using a human immune system, researchers from the laboratory of Yang Xu (UC San Diego) have used a mouse with a humanized immune system (Hu-mice) [4] to assess responses to human iPSCs and iPSC-derived cells. Their findings, published in Cell Stem Cell, suggest that while some differentiated cell types are immune tolerated, other are not, and that this may be due to abnormal expression of immunogenic antigens [5].

Initial studies compared autologous integration-free hiPSCs (created from the same source as the Hu-mice immune system) and allogeneic hESCs following teratoma formation in mice. hESCs formed teratomas with large amounts of T immune cell infiltration and necrosis while hiPSC-derived tumors displayed a more muted response. Indeed, upon closer inspection, certain areas of the hiPSCs-derived tumor displayed an absence of immune cell infiltration. After analyzing sections of the teratomas, the researchers identified retinal pigment epithelial (RPE) cells as being an immune-privileged cell type, while noting that smooth muscle cells (SMCs), on the contrary, demonstrated high levels of infiltration. To confirm these results, the authors differentiated pure populations of said cells from both pluripotent cell sources and injected them into the muscles of Hu-mice. While hiPSC-RPE cells displayed no signs of immunogenicity, hESC-RPE cells as well as both hESC- and hiPSC-SMCs raised an immune response, demonstrating the immunogenic nature of both allogeneic and autologous SMCs.

So why one iPSC-derived cell type and not the other? Screening of both cell types pointed to the over-expression of two immunogenic antigens, Zg16 and Hormad1, in SMCs in comparison to RPE. They confirmed a key role for such antigens by demonstrating the lack of teratoma growth, indicative of immune rejection, after injection of Zg16 overexpressing hiPSCs. Furthermore, even RPE cells differentiated from Zg16-hiPSCs were immune rejected underscoring an important role for such antigens in cellular immune rejection.

While this study appears to give the all clear for the clinical use of hiPSC-derived RPE cells, it suggests caution and further testing for other cell types. But are SMCs alone in their high immunogenicity, or is the RPE a singularly safe cell type due to the assumed immune privileged nature of the eye? Interestingly, Zg16 and Hormad1 are again identified as being important regulators of immune rejection [3], and the question occurs – If we knock out these genes in hiPSCs, can we generate additional safe and immune-privileged derivatives for clinical applications? The authors do note that normal human SMCs do not express these immune antigens, which suggests that we may also need to revise differentiation protocols to mitigate the expression of this unwanted immune antigen response.


  1. Araki R, Uda M, Hoki Y, et al. Negligible immunogenicity of terminally differentiated cells derived from induced pluripotent or embryonic stem cells. Nature 2013;494:100-104.
  2. de Almeida PE, Meyer EH, Kooreman NG, et al. Transplanted terminally differentiated induced pluripotent stem cells are accepted by immune mechanisms similar to self-tolerance. Nat Commun 2014;5:3903.
  3. Zhao T, Zhang ZN, Rong Z, et al. Immunogenicity of induced pluripotent stem cells. Nature 2011;474:212-215.
  4. Rong Z, Wang M, Hu Z, et al. An effective approach to prevent immune rejection of human ESC-derived allografts. Cell Stem Cell 2014;14:121-130.
  5. Zhao T, Zhang ZN, Westenskow PD, et al. Humanized Mice Reveal Differential Immunogenicity of Cells Derived from Autologous Induced Pluripotent Stem Cells. Cell Stem Cell 2015;17:353-359.