Humanized Mice Reveal Differential Immunogenicity of Cells Derived from Autologous Induced Pluripotent Stem Cells

Zhao, Tongbiao; Zhang, Zhenning; Westenskow, Peter D.; Todorova, Dilyana; Hu, Zheng; Lin, Tongxiang; Rong, Zhili; Kim, Jin Chul; He, Jingjin; Wang, Meiyan; Clegg, Dennis O.; Yang, Yong‐Guang; Zhang, Kun; Friedlander, Martin; Xu, Yiming

doi:10.1016/j.stem.2015.07.021

Cited by 209 publications

(194 citation statements)

References 22 publications

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“…As discussed previously, studies in mouse models describing rejection of iPSC-based teratomas claimed that the syngenic mouse iPSC lines can be inherently immunogenic (13,14). Other groups showed minimal or no immunogenicity of syngenic mouse iPSC lines or their cellular derivatives (15)(16)(17).…”

Section: Discussionmentioning

confidence: 90%

“…These studies claimed that the syngenic mouse iPSC lines, especially those derived with genomeintegrating viral vectors, are immunogenic (13) and that the inherent immunogenicity of these syngenic mouse iPSC lines correlates with their Ag profiles (14). Although other groups reported minimal or no immunogenicity of mouse syngenic iPSC lines and their cellular derivatives (15)(16)(17), these reports highlighted the need for an in-depth characterization of the inherent immunogenicity of hPSC.…”

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confidence: 99%

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Human Dendritic Cell–Derived Induced Pluripotent Stem Cell Lines Are Not Immunogenic

Chhabra

Chen

Batra

2017

The Journal of Immunology

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Donor-specific induced pluripotent stem cells (iPSC) can be used to generate desired cell types, including naive immune effectors, for the treatment of different diseases. However, a greater understanding of the inherent immunogenicity of human iPSC and their cellular derivatives is needed for the development of safe and effective cell-replacement therapies, given that studies in mouse models claimed that the syngenic mouse iPSC lines can be immunogenic. We report the characterization of the innate and adaptive immune mechanisms in human iPSC lines derived from peripheral blood–derived dendritic cells using a nonintegrating RNA virus, Sendai virus. We show that these iPSC lines express mRNA of TLR molecules and the Ag-presentation pathway intermediates; however, these mRNA are not translated into functional proteins, and these iPSC lines do not induce TLR-mediated inflammatory cytokine responses or inflammasome activation. We also show that these iPSC lines do not activate T cells in an allogenic MLR; however, they express low levels of MHC class I molecules that can efficiently acquire antigenic peptides from their microenvironment and present them to Ag-specific T cells. In addition, we show that these iPSC lines can be efficiently differentiated into hematopoietic stem cell precursors, as well as APC, under appropriate culture conditions. Taken together, our data show that the dedifferentiation of human dendritic cells effectively shuts down their immunogenic pathways and implicates transcriptional and posttranscriptional mechanisms in this process.

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Section: Discussionmentioning

confidence: 90%

mentioning

confidence: 99%

Human Dendritic Cell–Derived Induced Pluripotent Stem Cell Lines Are Not Immunogenic

Chhabra

Chen

Batra

2017

The Journal of Immunology

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“…In this study, we did not observe an immune rejection response upon iPSC-NSC transplantation. Together, these studies suggest that certain cells derived from iPSCs are immunogenic, while others are not (Cao et al, 2014;Zhao et al, 2015).…”

Section: Discussionmentioning

confidence: 91%

“…However, at the same time, it has been reported that the residual undifferentiated cells inside the iPSC-differentiated specific lineage might cause tumor formation after transplantation (Liu et al, 2014;Lu and Zhao, 2013). Furthermore, it has been shown that certain cells derived from iPSCs can elicit antigen-specific immune rejection responses after transplantation into the autologous recipients (Zhao et al, 2011(Zhao et al, , 2015. Thus it is necessary to extensively examine the safety and efficacy of iPSC-NSCs for therapy.…”

Section: Introductionmentioning

confidence: 99%

Treatment of multiple sclerosis by transplantation of neural stem cells derived from induced pluripotent stem cells

Zhang

Cao

et al. 2016

Sci. China Life Sci.

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Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS), with focal T lymphocytic infiltration and damage of myelin and axons. The underlying mechanism of pathogenesis remains unclear and there are currently no effective treatments. The development of neural stem cell (NSC) transplantation provides a promising strategy to treat neurodegenerative disease. However, the limited availability of NSCs prevents their application in neural disease therapy. In this study, we generated NSCs from induced pluripotent stem cells (iPSCs) and transplanted these cells into mice with experimental autoimmune encephalomyelitis (EAE), a model of MS. The results showed that transplantation of iPSC-derived NSCs dramatically reduced T cell infiltration and ameliorated white matter damage in the treated EAE mice. Correspondingly, the disease symptom score was greatly decreased, and motor ability was dramatically rescued in the iPSC-NSC-treated EAE mice, indicating the effectiveness of using iPSC-NSCs to treat MS. Our study provides pre-clinical evidence to support the feasibility of treating MS by transplantation of iPSC-derived NSCs.induced pluripotent stem cell, multiple sclerosis, neural stem cell, regenerative medicine, transplantation Citation:Zhang, C., Cao, J., Li, X., Xu, H., Wang, W., Wang, L., Zhao, X., Li, W., Jiao, J., Hu, B., Zhou, Q., and Zhao, T. (2016). Treatment of multiple sclerosis by transplantation of neural stem cells derived from induced pluripotent stem cells. Sci China Life Sci 59, 950 -957.

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“…While early reports questioned the immunogenicity of iPSC (Zhao, Zhang et al, 2011), this was subsequently refuted (Guha, Morgan et al, 2013), and next shown to be dependent on the specific cell type that is delivered (Zhao, Zhang et al, 2015). While it is not unlikely that iPSCs will ultimately provide a source of tissues and cells for autologous transplantation, enabling such iPSC-based cellular therapies will require cheap plug-and-play type generation of iPSCs under xeno-free GMP compliant conditions in hospital settings and will require rapidly obtainable, robust safety criteria.…”

Section: 0: Expression Ofmentioning

confidence: 99%

Stem Cell Therapies and Radiological Imaging in Ataxia Telangiectasia

Dingwall¹

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ABSTRACT:Ataxia telangiectasia (A-T) is an autosomal recessive disorder associated with early childhood ataxia, neurodegeneration, immune deficiency, radiosensitivity, sterility, and an increased susceptibility to cancer. In spite of numerous years of research, there is still no curative treatment for A-T, nor a reliable animal model that recapitulates the prominent neurological phenotypes observed in patients. To address these deficiencies and investigate potential therapeutic approaches I have attempted to generate a universal donor pluripotent stem cell line, utilized radiological imaging to investigate a novel rat model of A-T, and tested whether bone marrow transplantation (BMT) could provide benefit in the treatment of hematological defects associated with A-T. Animal models are likely to play a key role in the development of therapeutic strategies for the treatment of A-T. While multiple mouse models of A-T currently exist and recapitulate some of the phenotypes attributed to the human disease, prominent neurodegeneration has not been observed in these animal. As such, our research group has produced a gene knock-out model in the rat, utilizing Zinc Finger Nuclease technology. Approximately 50% of the Atm -/-rats show dilated blood vessels in the eyes, microgliosis, and develop hind limb paralysis, suggesting this model may recapitulate some of the neurological defect observed in A-T patients. Magnetic resonance imaging (MRI) was utilized to assess structural changes in the brain and spinal cord. Surprisingly, no significant differences in cerebellar volume or gray/white matter ratios were observed in the brain or spinal cord of healthy animals.However, lymphomas were detected in the T12-L3 region of the spine in all of the paralysed animals tested. I utilized PET/MRI in conjunction with the radiotracer ( 18 F)PBR111, which is highly selective for the TSPO receptor of activated microglia in the brain, to assess microglial activation in vivo in 5 month old control and ATM null nonparalysed rats, three of each. No differences were observed in the cerebellum of these rats relative to WT rats, as well as multiple other brain regions assessed in healthy animals. These data provide evidence that paralysis in the A-T rat model is associated with the presence of lymphomas within the spinal column.

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Humanized Mice Reveal Differential Immunogenicity of Cells Derived from Autologous Induced Pluripotent Stem Cells

Cited by 209 publications

References 22 publications

Human Dendritic Cell–Derived Induced Pluripotent Stem Cell Lines Are Not Immunogenic

Human Dendritic Cell–Derived Induced Pluripotent Stem Cell Lines Are Not Immunogenic

Treatment of multiple sclerosis by transplantation of neural stem cells derived from induced pluripotent stem cells

Stem Cell Therapies and Radiological Imaging in Ataxia Telangiectasia

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