Reduced Immunogenicity of Induced Pluripotent Stem Cells Derived from Sertoli Cells

Wang, Xiaoying; Qin, Jie; Zhao, Robert Chunhua; Zenke, Martin

doi:10.1371/journal.pone.0106110

Cited by 17 publications

(13 citation statements)

References 43 publications

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“…Although they discovered that initially low passage SC-iPSCs were less immunogenic in vivo than MEF-iPSCs, the observed reduced immunogenicity was lost following extended culturing. Similar to the finding described by Polo et al, [38] these immune-privileged cells still exhibited reduced immunogenicity when compared to MEF-iPSCs [46]. This is likely due to epigenetic memory from the donor cell impacting the immunogenicity of the derived iPSCs.…”

Section: The Importance Of Cell Source For Ipscssupporting

confidence: 83%

“…For example, Wang et al tested whether the low immunogenicity of Sertoli cells (SC) was maintained in SC-derived iPSCs, either freshly isolated or after extensive in vitro passaging, as well as in the in vivo setting [46]. They demonstrated that SC-derived iPSCs resulted in a high frequency of teratoma formation when injected into syngeneic B6 mice, as compared to MEF-iPSCs and ES cells; suggesting that SC-derived iPSCs elict a blunted immune response thereby allowing for more efficient teratoma formation.…”

Section: The Importance Of Cell Source For Ipscsmentioning

confidence: 99%

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Modulation of human allogeneic and syngeneic pluripotent stem cells and immunological implications for transplantation

Sackett

Brown

Tremmel

et al. 2016

Transplantation Reviews

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Tissues derived from induced pluripotent stem cells (iPSCs) are a promising source of cells for building various regenerative medicine therapies; from simply transplanting cells to reseeding decellularized organs to reconstructing multicellular tissues. Although reprogramming strategies for producing iPSCs have improved, the clinical use of iPSCs is limited by the presence of unique human leukocyte antigen (HLA) genes, the main immunologic barrier to transplantation. In order to overcome the immunological hurdles associated with allogeneic tissues and organs, the generation of patient-histocompatible iPSCs (autologous or HLA-matched cells) provides an attractive platform for personalized medicine. However, concerns have been raised as to the fitness, safety and immunogenicity of iPSC derivatives because of variable differentiation potential of different lines and the identification of genetic and epigenetic aberrations that can occur during the reprogramming process. In addition, significant cost and regulatory barriers may deter commercialization of patient specific therapies in the short-term. Nonetheless, recent studies provide some evidence of immunological benefit for using autologous iPSCs. Yet, more studies are needed to evaluate the immunogenicity of various autologous and allogeneic human iPSC-derived cell types as well as test various methods to abrogate rejection. Here, we present perspectives of using allogeneic vs autologous iPSCs for transplantation therapies and the advantages and disadvantages of each related to differentiation potential, immunogenicity, genetic stability and tumorigenicity. We also review the current literature on the immunogenicity of syngeneic iPSCs and discuss evidence that questions the feasibility of HLA-matched iPSC banks. Finally, we will discuss emerging methods of abrogating or reducing host immune responses to PSC derivatives.

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Section: The Importance Of Cell Source For Ipscssupporting

confidence: 83%

Section: The Importance Of Cell Source For Ipscsmentioning

confidence: 99%

Modulation of human allogeneic and syngeneic pluripotent stem cells and immunological implications for transplantation

Sackett

Brown

Tremmel

et al. 2016

Transplantation Reviews

View full text Add to dashboard Cite

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“…Other groups have reported that iPSC derivatives showed different degrees of immunogenicity . In particular, those groups showed that iPSC‐derived cardiomyocytes and endothelial cells can induce more prominent immune responses in syngeneic mice compared with hepatocytes, neuronal cells and bone marrow cells .…”

Section: Discussionmentioning

confidence: 99%

“…Other groups have reported that iPSC derivatives showed different degrees of immunogenicity. 7,20,21 In particular, those groups showed that iPSC-derived cardiomyocytes and endothelial cells can induce more prominent immune responses in syngeneic mice compared with hepatocytes, neuronal cells and bone marrow cells. 6 During the reprogramming processes in iPS cells from somatic cells, epigenetic changes can induce the expression of minor antigens, which can possibly directly or indirectly lead to the rejection of iPSC-derivatives in syngeneic mice.…”

Section: Discussionmentioning

confidence: 99%

Induced pluripotent stem cell‐derived gamete‐associated proteins incite rejection of induced pluripotent stem cells in syngeneic mice

2017

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The safety of induced pluripotent stem cells (iPSCs) in autologous recipients has been questioned after iPSCs, but not embryonic stem cells (ESCs), were reported to be rejected in syngeneic mice. This important topic has remained controversial because there has not been a mechanistic explanation for this phenomenon. Here, we hypothesize that iPSCs, but not ESCs, readily differentiate into gamete-forming cells that express meiotic antigens normally found in immune-privileged gonads. Because peripheral blood T cells are not tolerized to these antigens in the thymus, gamete-associated-proteins (GAPs) sensitize T cells leading to rejection. Here, we provide evidence that GAPs expressed in iPSC teratomas, but not in ESC teratomas, are responsible for the immunological rejection of iPSCs. Furthermore, silencing the expression of Stra8, 'the master regulator of meiosis', in iPSCs, using short hairpin RNA led to significant abrogation of the rejection of iPSCs, supporting our central hypothesis that GAPs expressed after initiation of meiosis in iPSCs were responsible for rejection. In contrast to iPSCs, iPSC-derivatives, such as haematopoietic progenitor cells, are able to engraft long-term into syngeneic recipients because they no longer express GAPs. Our findings, for the first time, provide a unifying explanation of why iPSCs, but not ESCs, are rejected in syngeneic recipients, ending the current controversy on the safety of iPSCs and their derivatives.

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“…From late in vitro passages, Ser‐iPSCs behaved similarly to MEF‐iPSCs in vivo . It appears that immune‐privileged Sertoli cells gave rise to Ser‐iPSC, which retained some somatic memory of their origin, a feature that makes them a good candidate for regenerative medicine …”

Section: Pluripotency/malignancy Teratoma Assaymentioning

confidence: 99%

Teratoma: from spontaneous tumors to the pluripotency/malignancy assay

Bulić-Jakuš

Bojanac

Jurić-Lekić

et al. 2015

WIREs Developmental Biology

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A teratoma is a benign tumor containing a mixture of differentiated tissues and organotypic derivatives of the three germ layers, while a teratocarcinoma also contains embryonal carcinoma cells (EC cells). Experimental teratomas and teratocarcinomas have been derived from early mammalian embryos transplanted into the adult animal (ectopic sites). In the rat, the pluripotency of the transplanted epiblast was demonstrated and a quantifiable restriction of developmental potential persisted after subsequent transplantation of chemically defined cultivated postimplantation embryos. The rat is nonpermissive for teratocarcinoma development and rat pluripotent cell lines have been established only recently. Transplantation of mouse embryos, epiblast, or embryonic stem cells (mESCs) gave rise to teratocarcinomas. The pluripotency of reprogrammed human cells has been tested by a 'gold standard' trilaminar teratoma assay in immunocompromised mice in vivo. Human pluripotent stem cells proposed for use in regenerative medicine such as human embryonic stem cell (hESC), human nuclear-transfer/therapeutic cloning embryonic stem cell (NT-ESC), or human induced pluripotent stem cell (hiPSC) lines, once differentiated in vitro to the desired cell type, should be again tested in a long-term animal teratoma assay to exclude their malignancy. Such an approach led to a recently implemented human therapy with retinal pigmented epithelium. For greater biosafety, the teratoma assay should be standardized and complemented by assessments of mutations/epimutations, RNA/protein expression, and possible immunogenicity of autologous pluripotent cells. Furthermore, the standardized teratoma assay should be directed more to the assessment of EC/malignant cell features than of differentiated tissues, especially after a unique case of human therapy with neural stem cells was found to lead to malignancy. For further resources related to this article, please visit the WIREs website.

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Reduced Immunogenicity of Induced Pluripotent Stem Cells Derived from Sertoli Cells

Cited by 17 publications

References 43 publications

Modulation of human allogeneic and syngeneic pluripotent stem cells and immunological implications for transplantation

Modulation of human allogeneic and syngeneic pluripotent stem cells and immunological implications for transplantation

Induced pluripotent stem cell‐derived gamete‐associated proteins incite rejection of induced pluripotent stem cells in syngeneic mice

Teratoma: from spontaneous tumors to the pluripotency/malignancy assay

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