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 tissues. However, partial reprogramming and genetic instabilities in iPSCs 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 tissues 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 teratomas and implicated several causative genes. Nevertheless, some controversy has arisen regarding these findings. 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.

The immunogenicity of cells derived from induced pluripotent stem cells

“…However, in contrast to this general assumption, one recent study has used the inbred C57BL/ 6 (B6) mouse strain to demonstrate that cells differentiated from the B6 iPSCs within teratomas can be immunogenic in the syngeneic B6 recipient mice, raising concerns about the immunogenicity of iPSCs. 10 In support of this notion, and also relying on the B6 inbred mouse strain, Abe and colleagues 11 reported in Nature recently that cardiomyocytes differentiated from B6 iPSCs in vitro are highly immunogenic when transplanted into B6 mice. In the same report, however, the authors found that B6 iPSC-derived skin tissue obtained from chimeric mice generated by injecting B6 iPSCs into B6 blastocyts have negligible immunogenicity and are completely immune tolerated by B6 recipients.…”

“…In the same report, however, the authors found that B6 iPSC-derived skin tissue obtained from chimeric mice generated by injecting B6 iPSCs into B6 blastocyts have negligible immunogenicity and are completely immune tolerated by B6 recipients. 11 …”

“…In further support of this notion, while the study by Zhao et al 10 demonstrates that the regressing teratomas formed by B6 iPSCs in B6 mice overexpress a panel of immunogenic proteins including Hormad 1 and Zg16, these immunogenic proteins are not overexpressed in the iPSC-derived tissues in the chimeric mice. 11 …”

“…While the skin tissue of GFP-expressing B6 mice will be immune rejected when transplanted into GFP-negative B6 mice due to the expression of the immunogenic GFP minor antigen, 12,13 it is quite surprising that B6 iPSC-derived GFPexpressing skin tissue is completely immune tolerated by the GFP-negative B6 mice in this study. 11 Therefore, if using this chimeric mouse transplantation system, the B6 iPSC-derived skin cells will be immune tolerated by B6 mice even if they express minor antigens, making it an inappropriate assay to evaluate the immunogenicity of iPSC-derived cells. It is likely that, during the development of the chimeric mice, the abnormal and immunogenic B6 iPSC-derived cells have been immune rejected or rendered immune tolerated by the B6 immune system present in the chimeric mice, before their subsequent transplantation into B6 recipients to evaluate whether immunogenicity is caused by minor antigens.…”

Induced pluripotent stem cell (iPSCs) and their application in immunotherapy

“…Recently, however, several studies provided evidence to support a different point of view regarding the immunogenicity of iPSCs. [42][43][44] While the above-mentioned study by Zhao et al 41 only used a single line of syngeneic ESCs, Araki et al 43 tested seven iPSC and five embryonic stem cell lines to verify that no pronounced differences in immunogenicity existed between the teratomas formed by iPSCs and ESCs. In fact, the disparities between iPSC-or ESC-derived clones perhaps deserve more attention than the differences between these two pluripotent stem cells.…”