Araki, R, Uda, M, Hoki, Y, Sunayama, M, Nakamura, M, Ando, S et al.. Negligible immunogenicity of terminally differentiated cells derived from induced pluripotent or embryonic stem cells. Nature 494: 100-104

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.

    • "In addition, the disease-specific iPSCs could provide the unique opportunity to develop the much needed disease models in drug discovery. While it has been assumed that the immune rejection problem challenging hESCs could be mitigated by the development of patient-specific hiPSCs without the concern of immune rejection (Park et al., 2008; Takahashi et al., 2007; Yu et al., 2007), recent studies have shown that certain cell types derived from mouse iPSCs such as cardiomyocytes are immunogenic in syngeneic recipients, and other immunogenic cell types such as endothelial cells are immune tolerated by expressing high levels of immune-suppressive cytokines such as IL-10 (Araki et al., 2013; de Almeida et al., 2014; Zhao et al., 2011). Therefore, as an integral part of the effort to develop hiPSCs into human cell therapy, it is important to evaluate the immunogenicity of hiPSC-derived cells in the context of an autologous human immune system. "
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    ABSTRACT: The breakthrough of induced pluripotent stem cell (iPSC) technology has raised the possibility that patient-specific iPSCs may become a renewable source of autologous cells for cell therapy without the concern of immune rejection. However, the immunogenicity of autologous human iPSC (hiPSC)-derived cells is not well understood. Using a humanized mouse model (denoted Hu-mice) reconstituted with a functional human immune system, we demonstrate that most teratomas formed by autologous integration-free hiPSCs exhibit local infiltration of antigen-specific T cells and associated tissue necrosis, indicating immune rejection of certain hiPSC-derived cells. In this context, autologous hiPSC-derived smooth muscle cells (SMCs) appear to be highly immunogenic, while autologous hiPSC-derived retinal pigment epithelial (RPE) cells are immune tolerated even in non-ocular locations. This differential immunogenicity is due in part to abnormal expression of immunogenic antigens in hiPSC-derived SMCs, but not in hiPSC-derived RPEs. These findings support the feasibility of developing hiPSC-derived RPEs for treating macular degeneration. Copyright © 2015 Elsevier Inc. All rights reserved.
    No preview · Article · Aug 2015 · Cell stem cell
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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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    ABSTRACT: Cardiac injury and loss of cardiomyocytes is a causative as well as a resultant condition of cardiovascular disorders which are the leading cause of death throughout the world. This loss of cardiomyocytes cannot be completely addressed through the present available drugs being administered, which mainly work only in relieving the symptoms. There is a huge potential being investigated for regenerative and cell replacement therapies through recruiting stem cells of various origins namely embryonic, reprogramming/induction and adult tissue. These sources are being actively studied to be translated to clinical scenarios. In this review, we attempt to discuss some of such promises, the clinical trials and the obstacles that need to be overcome, and hope to address the direction in which the stem cell therapy is heading to.
    Full-text · Article · May 2015 · Canadian Journal of Physiology and Pharmacology
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    • "Although the transgenes present in iPSCs raised concerns regarding their clinical application, these cells represent an unlimited source for cell therapy with clearly reduced immune rejection events (Araki et al., 2013). On the basis of these powerful characteristics, differentiated gene-targeted autologous iPSCs have served as therapeutic cells for clinical treatment (Deyle et al., 2012). "
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    ABSTRACT: Abstract Induced pluripotent stem cells (iPSCs) are reprogrammed from somatic cells via ectopic gene expression and, similarly to embryonic stem cells (ESCs), possess powerful abilities to self-renew and differentiate into cells of various lineages. However, the neural differentiation potency of iPSCs remains unknown. In this study, we demonstrated the neural differentiation ability of iPSCs compared with ESCs using an retinoic acid (RA) induction system. The neural differentiation efficiency of iPSCs was obviously lower than that of ESCs. Retinoic acid receptor-α (RARα) was critical in the RA-induced neural differentiation of iPSCs, and the effect of RARα was confirmed by applying a specific RARα antagonist ER50891 to ESCs. These findings indicate that iPSCs do not possess the complete properties that ESCs have.
    Full-text · Article · Nov 2014 · Cellular Reprogramming
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