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

1] Transcriptome Research Group, National Institute of Radiological Sciences, Chiba 263-8555, Japan [2] PRESTO, Japan Science and Technology Agency (JST), Kawaguchi 332-0012, Japan.
Nature (Impact Factor: 41.46). 01/2013; 494(7435). DOI: 10.1038/nature11807
Source: PubMed


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.

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    • "Studies which attempted to test the likelihood of immune rejection have found contradicting results based on the cell types they chose to transplant into the recipient (Guha et al. 2013; Zhao et al. 2011). Araki et al found that though many syngeneic-iPSC-derivatives showed negligible immunogenicity, iPSC-CMs were aggressively rejected (Araki et al. 2013). These inhibitions firmly put PSCs and their derivatives miles away from entering into the clinical setup at least where cardiac cell replacement therapy is concerned. "
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    • "Pluripotent stem cells (PSCs) are an important advance in stem cell research, as they allow researchers to obtain stem cells, which, in addition to be very useful tools for research, they may have therapeutic uses. Because hiPSCs are developed from a patient’s own somatic cells, it is believed that hiPSCs-based therapy would be very poorly or non-immunogenic, whereas hESCs are not (125–128). The use of these cells provides an accessible, genetically tractable, and homogenous starting cell population to efficiently study human blood cell development among others (100, 103, 108, 111, 129). "
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    • "Expression of Zg16 and Hormad1 genes has been associated with immunogenicity of iPS cells [7], however this finding has remained controversial [9], [10]. Thus, we investigated the expression of Zg16 and Hormad1 in Ser-iPS cell teratomas. "
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    ABSTRACT: Sertoli cells constitute the structural framework in testis and provide an immune-privileged environment for germ cells. Induced pluripotent stem cells (iPS cells) resemble embryonic stem cells (ES cells) and are generated from somatic cells by expression of specific reprogramming transcription factors. Here, we used C57BL/6 (B6) Sertoli cells to generate iPS cells (Ser-iPS cells) and compared the immunogenicity of Ser-iPS cells with iPS cells derived from mouse embryonic fibroblast (MEF-iPS cells). Ser-iPS cells were injected into syngeneic mice to test for their in vivo immunogenicity in teratoma assay. Teratoma assay allows assessing in vivo immunogenicity of iPS cells and of their differentiated progeny simultaneously. We observed that early-passage Ser-iPS cells formed more teratomas with less immune cell infiltration and tissue damage and necrosis than MEF-iPS cells. Differentiating Ser-iPS cells in embryoid bodies (EBs) showed reduced T cell activation potential compared to MEF-iPS cells, which was similar to syngeneic ES cells. However, Ser-iPS cells lost their reduced immunogenicity in vivo after extended passaging in vitro and late-passage Ser-iPS cells exhibited an immunogenicity similar to MEF-iPS cells. These findings indicate that early-passage Ser-iPS cells retain some somatic memory of Sertoli cells that impacts on immunogenicity of iPS cells and iPS cell-derived cells in vivo and in vitro. Our data suggest that immune-privileged Sertoli cells might represent a preferred source for iPS cell generation, if it comes to the use of iPS cell-derived cells for transplantation.
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