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

Bruno C. Huber, Julia D. Ransohoff, Katherine J. Ransohoff, Johannes Riegler, Antje Ebert, Kazuki Kodo, Yongquan Gong, Veronica Sanchez-Freire, Devaveena Dey, Nigel G. Kooreman, Sebastian Diecke, Wendy Y. Zhang, Justin Odegaard, Shijun Hu, Joseph D. Gold, Robert C. Robbins, Joseph C. Wu

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Rationale: Human embryonic stem cell (hESC) derivatives are attractive candidates for therapeutic use. The engraft-ment 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. Costimu-lation- 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 car-diomyocyte survival in an ischemic myocardial injury model. Improved hESC-EC engraftment had a cardio-protective 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 immu-nosuppressive 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.

Original languageEnglish
Pages (from-to)2354-2363
Number of pages10
JournalStem Cells
Volume31
Issue number11
DOIs
Publication statusPublished - 2013 Nov 25
Externally publishedYes

Keywords

  • Costimulation blockade
  • Embryonic stem cells
  • Endothelial cells
  • Immune tolerance
  • Immunosuppressive drugs
  • Myocardial infarction

ASJC Scopus subject areas

  • Molecular Medicine
  • Developmental Biology
  • Cell Biology

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  • Cite this

    Huber, B. C., Ransohoff, J. D., Ransohoff, K. J., Riegler, J., Ebert, A., Kodo, K., Gong, Y., Sanchez-Freire, V., Dey, D., Kooreman, N. G., Diecke, S., Zhang, W. Y., Odegaard, J., Hu, S., Gold, J. D., Robbins, R. C., & Wu, J. C. (2013). Costimulation-adhesion blockade is superior to cyclosporine a and prednisone immunosuppressive therapy for preventing rejection of differentiated human embryonic stem cells following transplantation. Stem Cells, 31(11), 2354-2363. https://doi.org/10.1002/stem.1501