Reprogramming of the MHC-I and Its Regulation by NFκB in Human-Induced Pluripotent Stem Cells§

Authors

  • Marjorie Pick,

    1. Stem Cell Unit, Department of Genetics, Institute of Life Sciences, The Hebrew University, Jerusalem, Israel
    2. Department of Hematology, Sharett Institute, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
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  • Daniel Ronen,

    Corresponding author
    1. Stem Cell Unit, Department of Genetics, Institute of Life Sciences, The Hebrew University, Jerusalem, Israel
    • Stem Cell Unit, Department of Genetics, Institute of Life Sciences, The Hebrew University, Edmund Safra Campus, Givat Ram, Jerusalem, 91904, Israel
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    • Telephone: +972 2 6585185; Fax: +972 2 6584972

  • Ofra Yanuka,

    1. Stem Cell Unit, Department of Genetics, Institute of Life Sciences, The Hebrew University, Jerusalem, Israel
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  • Nissim Benvenisty

    Corresponding author
    1. Stem Cell Unit, Department of Genetics, Institute of Life Sciences, The Hebrew University, Jerusalem, Israel
    • Stem Cell Unit, Department of Genetics, Institute of Life Sciences, The Hebrew University, Edmund Safra Campus, Givat Ram, Jerusalem, 91904, Israel
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    • Telephone: +972 2 6586774; Fax: +972 2 8584972


  • Author contributions: M.P.: conception and design, collection and/or assembly of data, data analysis and interpretation, and manuscript writing; O.Y.: conception and design, collection and/or assembly of data, and manuscript writing; D.R.: collection and/or assembly of data, data analysis and interpretation, and manuscript writing; N.B.: conception and design, financial support, data analysis and interpretation, manuscript writing, and final approval of manuscript.

  • Disclosure of potential conflicts of interest is found at the end of this article.

  • §

    First published online in STEM CELLSEXPRESS September 17, 2012.

Abstract

The immunogenicity of human pluripotent stem cells plays a major role in their potential use in the clinic. We show that, during their reprogramming, human-induced pluripotent stem (iPS) cells downregulate expression of human leukocyte antigen (HLA)-A/B/C and β2 microglobulin (β2M), the two components of major histocompatibility complex-I (MHC-I). MHC-I expression in iPS cells can be restored by differentiation or treatment with interferon-gamma (IFNγ). To analyze the molecular mechanisms that regulate the expression of the MHC-I molecules in human iPS cells, we searched for correlation between the expression of HLA-A/B/C and β2M and the expression of transcription factors that bind to the promoter of these genes. Our results show a significant positive correlation between MHC-I expression and expression of the nuclear factors, nuclear factor kappa B 1 (NFκB1) and RelA, at the levels of RNA, protein and was confirmed by chromatin binding. Concordantly, we detected robust levels of NFκB1 and RelA proteins in the nucleus of somatic cells but not in the iPS cell derived from them. Overexpression of NFκB1 and RelA in undifferentiated pluripotent stem cells led to induction in expression of MHC-I, whereas silencing NFκB1 and RelA by small hairpin RNA decreased the expression of β2M after IFNγ treatment. Our data point to the critical role of NFκB proteins in regulating the MHC-I expression in human pluripotent stem cells. STEM CELLS 2012;30:2700–2708

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