Transplanted terminally differentiated induced pluripotent stem cells are accepted by immune mechanisms similar to self-tolerance

  • Nature Communications 5, Article number: 3903 (2014)
  • doi:10.1038/ncomms4903
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The exact nature of the immune response elicited by autologous-induced pluripotent stem cell (iPSC) progeny is still not well understood. Here we show in murine models that autologous iPSC-derived endothelial cells (iECs) elicit an immune response that resembles the one against a comparable somatic cell, the aortic endothelial cell (AEC). These cells exhibit long-term survival in vivo and prompt a tolerogenic immune response characterized by elevated IL-10 expression. In contrast, undifferentiated iPSCs elicit a very different immune response with high lymphocytic infiltration and elevated IFN-γ, granzyme-B and perforin intragraft. Furthermore, the clonal structure of infiltrating T cells from iEC grafts is statistically indistinguishable from that of AECs, but is different from that of undifferentiated iPSC grafts. Taken together, our results indicate that the differentiation of iPSCs results in a loss of immunogenicity and leads to the induction of tolerance, despite expected antigen expression differences between iPSC-derived versus original somatic cells.

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We thank M. Wernig for providing B6.129.F1 iPSC line; F. Lang and F. Jia for generating FVB.GFP.Luc+ iPSC lines; K. Ransohoff and J. Ransohoff for their assistance with bioluminescence imaging; M. Grova for assistance with histochemical analysis; A. Morris for assistance with figure preparations; and K. Lee and the Cell Sciences Imaging Facility (CSIF) Fluorescent Microscopy Core at Stanford University for technical assistance with confocal microscopy. This work was supported in part by grants from the California Institute of Regenerative Medicine (CIRM) TR3-05556, CIRM DR2-05394, National Institute of Health (NIH) R01 AI085575, U01 HL099776 (J.C.W.); the Oak Foundation, and the Hagey Laboratory for Pediatric Regenerative Medicine (to M.T.L.); the International Society for Heart and Lung Transplantation Fellowship (to A.); American Society for Blood and Marrow Transplantation and NIH NHLBI training grant (to E.H.M.).

Author information

Author notes

    • Patricia .E de Almeida
    • , Everett H. Meyer
    •  & Nigel G. Kooreman

    These authors contributed equally to this work


  1. Departments of Medicine and Radiology, Stanford University School of Medicine, Stanford, California 94305-5323, USA

    • Patricia .E de Almeida
    • , Nigel G. Kooreman
    • , Sebastian Diecke
    • , Devaveena Dey
    • , Veronica Sanchez-Freire
    • , Shijun Hu
    • , Antje Ebert
    • , Nicholas M. Mordwinkin
    • , Thomas P. Brouwer
    •  & Joseph C. Wu
  2. Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California 94305-5323, USA

    • Patricia .E de Almeida
    • , Nigel G. Kooreman
    • , Sebastian Diecke
    • , Devaveena Dey
    • , Veronica Sanchez-Freire
    • , Shijun Hu
    • , Antje Ebert
    • , Nicholas M. Mordwinkin
    • , Thomas P. Brouwer
    •  & Joseph C. Wu
  3. Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California 94305-5323, USA

    • Patricia .E de Almeida
    • , Nigel G. Kooreman
    • , Sebastian Diecke
    • , Devaveena Dey
    • , Veronica Sanchez-Freire
    • , Shijun Hu
    • , Antje Ebert
    • , Nicholas M. Mordwinkin
    • , Thomas P. Brouwer
    • , David Lo
    • , Daniel T. Montoro
    • , Michael T. Longaker
    •  & Joseph C. Wu
  4. Department of Medicine, Division of Blood and Marrow Transplantation, Stanford University School of Medicine, Stanford, California 94305-5323, USA

    • Everett H. Meyer
    •  & Robert S. Negrin
  5. Department of Pathology, Stanford University School of Medicine, Stanford, California 94305-5323, USA

    • Justin Odegaard
  6. Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, California 94305-5323, USA

    • David Lo
    • , Daniel T. Montoro
    •  & Michael T. Longaker


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Contributions A., E.H.M. and N.G.K. conceived, performed, interpreted experiments and wrote the manuscript; E.H.M. analysed TCR sequencing data; S.D. prepared DNA samples for TCR sequencing and assisted with iPSC derivation; D.D. and V.S.-F. conducted gene expression analysis by RT–PCR and Fluidigm and performed immunofluorescence staining of cultured cells; S.H. assisted with derivation of iPSC lines and FACS; A.E. performed IL-10 cytotoxicity assays; J.O. performed histopathological analysis of grafts; N.M. conducted Doppler analysis of vascular perfusion and assisted with histological evaluation of endothelial cell engraftment and LDL uptake; T.P.B. performed bioluminescence imaging and assisted with cell implantation; D.L. and D.M. performed immunohistochemistry for IL-10 immunoassays and assisted with cell implantation. M.T.L. provided part of the histochemical stains and assisted with manuscript writing; R.S.N. provided experimental advice and manuscript writing; and J.C.W. provided experimental advice, manuscript writing and funding support.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Joseph C. Wu.

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    Supplementary Information

    Supplementary Figures 1-12 and Supplementary Tables 1-2


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