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Mesenchymal stem cell–based tissue regeneration is governed by recipient T lymphocytes via IFN-γ and TNF-α

Nature Medicine volume 17, pages 1594–1601 (2011)Cite this article

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Abstract

Stem cell–based regenerative medicine is a promising approach in tissue reconstruction. Here we show that proinflammatory T cells inhibit the ability of exogenously added bone marrow mesenchymal stem cells (BMMSCs) to mediate bone repair. This inhibition is due to interferon γ (IFN-γ)–induced downregulation of the runt-related transcription factor 2 (Runx-2) pathway and enhancement of tumor necrosis factor α (TNF-α) signaling in the stem cells. We also found that, through inhibition of nuclear factor κB (NF-κB), TNF-α converts the signaling of the IFN-γ–activated, nonapoptotic form of TNF receptor superfamily member 6 (Fas) in BMMSCs to a caspase 3– and caspase 8–associated proapoptotic cascade, resulting in the apoptosis of these cells. Conversely, reduction of IFN-γ and TNF-α concentrations by systemic infusion of Foxp3+ regulatory T cells, or by local administration of aspirin, markedly improved BMMSC-based bone regeneration and calvarial defect repair in C57BL/6 mice. These data collectively show a previously unrecognized role of recipient T cells in BMMSC-based tissue engineering.

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Figure 1: T cells regulated BMMSC-mediated bone formation.
Figure 2: Treg cells improved BMMSC-mediated bone formation in wild-type C57BL/6 mice.
Figure 3: IFN-γ inhibited the osteogenic differentiation of BMMSCs.
Figure 4: IFN-γ synergistically enhanced BMMSC apoptosis induced by TNF-α through the Fas apoptotic pathway.
Figure 5: IFN-γ synergistically enhanced TNF-α–induced BMMSC apoptosis through inhibition of the TNFR2–NF-κB pathway and Fas internalization.
Figure 6: Treg cell infusion and aspirin treatment improved BMMSC-mediated bone formation.

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Acknowledgements

We thank X. Duan and T. Zhou of the Fourth Military Medical University for generating microCT images. This work was supported by grants from the US National Institute of Dental and Craniofacial Research, US National Institutes of Health, Department of Health and Human Services (R01DE017449, R01DE019932 and R01DE019413 to S.S.), a grant from California Institute for Regenerative Medicine (RN1-00572 to S.S.) and the Intramural Program of the US National Institute of Dental and Craniofacial Research, US National Institutes of Health, Department of Health and Human Services.

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Authors and Affiliations

  1. Center for Craniofacial Molecular Biology, Ostrow School of Dentistry, University of Southern California, Los Angeles, California, USA

    Yi Liu, Lei Wang, Takashi Kikuiri, Kentaro Akiyama, Chider Chen, Xingtian Xu, Ruili Yang & Songtao Shi

  2. Molecular Laboratory for Gene Therapy and Tooth Regeneration, Capital Medical University School of Stomatology, Beijing, China

    Yi Liu & Songlin Wang

  3. Fourth Military Medical University School of Stomatology, Xi'an, Shaanxi, China.,

    Lei Wang

  4. Key Laboratory of Translational Research, Tong Ji University School of Stomatology, Shanghai, China

    Xingtian Xu

  5. National Institute of Dental and Craniofacial Research, US National Institutes of Health, Bethesda, Maryland, USA

    WanJun Chen

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Contributions

Y.L. and L.W. performed the majority of the experiments, analyzed data and prepared the manuscript. T.K. maintained mice and helped with the in vivo bone formation assay. K.A. and C.C. helped with the cell apoptosis assay. X.X. helped with the flow cytometric analysis. R.Y. helped with in vivo experiments. W.C. and S.W. provided suggestions for the project. S.S. supervised the project and wrote the manuscript.

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Correspondence to Songtao Shi.

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Liu, Y., Wang, L., Kikuiri, T. et al. Mesenchymal stem cell–based tissue regeneration is governed by recipient T lymphocytes via IFN-γ and TNF-α. Nat Med 17, 1594–1601 (2011). https://doi.org/10.1038/nm.2542

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