Journal
NATURE MEDICINE
Volume 17, Issue 12, Pages 1594-U106Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.2542
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Funding
- US National Institute of Dental and Craniofacial Research, US National Institutes of Health, Department of Health and Human Services [R01DE017449, R01DE019932, R01DE019413]
- California Institute for Regenerative Medicine [RN1-00572]
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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 gamma (IFN-gamma)-induced downregulation of the runt-related transcription factor 2 (Runx-2) pathway and enhancement of tumor necrosis factor alpha (TNF-alpha) signaling in the stem cells. We also found that, through inhibition of nuclear factor kappa B (NF-kappa B), TNF-alpha converts the signaling of the IFN-gamma-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-gamma and TNF-alpha 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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