Costimulation-adhesion blockade is superior to Cyclosporine A and prednisone immunosuppressive therapy for preventing rejection of differentiated human embryonic stem cells following transplantation

Authors

  • Bruno C. Huber,

    1. Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA
    2. Department of Medicine, Stanford University School of Medicine, Stanford, California, USA
    3. Department of Radiology, Stanford University School of Medicine, Stanford, California, USA
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  • Julia D. Ransohoff,

    1. Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA
    2. Department of Medicine, Stanford University School of Medicine, Stanford, California, USA
    3. Department of Radiology, Stanford University School of Medicine, Stanford, California, USA
    4. Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, California, USA
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  • Katherine J. Ransohoff,

    1. Department of Medicine, Stanford University School of Medicine, Stanford, California, USA
    2. Department of Radiology, Stanford University School of Medicine, Stanford, California, USA
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  • Johannes Riegler,

    1. Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA
    2. Department of Medicine, Stanford University School of Medicine, Stanford, California, USA
    3. Department of Radiology, Stanford University School of Medicine, Stanford, California, USA
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  • Antje Ebert,

    1. Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA
    2. Department of Medicine, Stanford University School of Medicine, Stanford, California, USA
    3. Department of Radiology, Stanford University School of Medicine, Stanford, California, USA
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  • Kazuki Kodo,

    1. Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA
    2. Department of Medicine, Stanford University School of Medicine, Stanford, California, USA
    3. Department of Radiology, Stanford University School of Medicine, Stanford, California, USA
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  • Yongquan Gong,

    1. Department of Medicine, Stanford University School of Medicine, Stanford, California, USA
    2. Department of Radiology, Stanford University School of Medicine, Stanford, California, USA
    3. Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, California, USA
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  • Veronica Sanchez-Freire,

    1. Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA
    2. Department of Medicine, Stanford University School of Medicine, Stanford, California, USA
    3. Department of Radiology, Stanford University School of Medicine, Stanford, California, USA
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  • Devaveena Dey,

    1. Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA
    2. Department of Medicine, Stanford University School of Medicine, Stanford, California, USA
    3. Department of Radiology, Stanford University School of Medicine, Stanford, California, USA
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  • Nigel G. Kooreman,

    1. Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA
    2. Department of Medicine, Stanford University School of Medicine, Stanford, California, USA
    3. Department of Radiology, Stanford University School of Medicine, Stanford, California, USA
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  • Sebastian Diecke,

    1. Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA
    2. Department of Medicine, Stanford University School of Medicine, Stanford, California, USA
    3. Department of Radiology, Stanford University School of Medicine, Stanford, California, USA
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  • Wendy Y. Zhang,

    1. Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA
    2. Department of Medicine, Stanford University School of Medicine, Stanford, California, USA
    3. Department of Radiology, Stanford University School of Medicine, Stanford, California, USA
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  • Justin Odegaard,

    1. Department of Pathology, Stanford University School of Medicine, Stanford, California, USA
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  • Shijun Hu,

    1. Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA
    2. Department of Medicine, Stanford University School of Medicine, Stanford, California, USA
    3. Department of Radiology, Stanford University School of Medicine, Stanford, California, USA
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  • Joseph D. Gold,

    1. Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA
    2. Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, California, USA
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  • Robert C. Robbins,

    1. Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, California, USA
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  • Joseph C. Wu

    Corresponding author
    1. Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA
    2. Department of Medicine, Stanford University School of Medicine, Stanford, California, USA
    3. Department of Radiology, Stanford University School of Medicine, Stanford, California, USA
    4. Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA
    • Correspondence: Joseph C. Wu, Ph.D., M.D., Lorry I. Lokey Stem Cell Research Building, 265 Campus Drive, Rm G1120B, Stanford, California 94305-5454, USA. Telephone: 650-736-2246; Fax: 650-736-0234; e-mail: joewu@stanford.edu

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  • Author contributions: B.C.H. and J.D.R.: conception and design, data analysis and interpretation, manuscript writing, and final approval of manuscript; K.J.R., J.R., A.E., K.K., Y.G., V.S., D.D., N.G.K., S.D., W.Y.Z., J.O., and S.H.: collection and/or assembly of data and final approval of manuscript; R.C.R. and J.D.G.: data analysis and interpretation and final approval of manuscript; J.C.W.: conception and design, financial support, manuscript writing, and final approval of manuscript. B.C.H. and J.D.R. contributed equally to this article.

Abstract

Rationale: Human embryonic stem cell (hESC) derivatives are attractive candidates for therapeutic use. The engraftment and survival of hESC derivatives as xenografts or allografts require effective immunosuppression to prevent immune cell infiltration and graft destruction. Objective: To test the hypothesis that a short-course, dual-agent regimen of two costimulation-adhesion blockade agents can induce better engraftment of hESC derivatives compared to current immunosuppressive agents. Methods and Results: We transduced hESCs with a double fusion reporter gene construct expressing firefly luciferase (Fluc) and enhanced green fluorescent protein, and differentiated these cells to endothelial cells (hESC-ECs). Reporter gene expression enabled longitudinal assessment of cell engraftment by bioluminescence imaging. Costimulation-adhesion therapy resulted in superior hESC-EC and mouse EC engraftment compared to cyclosporine therapy in a hind limb model. Costimulation-adhesion therapy also promoted robust hESC-EC and hESC-derived cardiomyocyte survival in an ischemic myocardial injury model. Improved hESC-EC engraftment had a cardioprotective effect after myocardial injury, as assessed by magnetic resonance imaging. Mechanistically, costimulation-adhesion therapy is associated with systemic and intragraft upregulation of T-cell immunoglobulin and mucin domain 3 (TIM3) and a reduced proinflammatory cytokine profile. Conclusions: Costimulation-adhesion therapy is a superior alternative to current clinical immunosuppressive strategies for preventing the post-transplant rejection of hESC derivatives. By extending the window for cellular engraftment, costimulation-adhesion therapy enhances functional preservation following ischemic injury. This regimen may function through a TIM3-dependent mechanism. Stem Cells 2013;31:2354–2363

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