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

Nat Med. 2011 Nov 20;17(12):1594-601. doi: 10.1038/nm.2542.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Aspirin / pharmacology
  • Bone Marrow Cells / cytology
  • Bone Marrow Cells / metabolism
  • Bone Regeneration*
  • Caspase 3 / genetics
  • Caspase 3 / metabolism
  • Caspase 8 / genetics
  • Caspase 8 / metabolism
  • Cell Survival
  • Female
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism
  • Interferon-gamma / metabolism*
  • Mesenchymal Stem Cells / cytology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • NF-kappa B / antagonists & inhibitors
  • Osteogenesis / drug effects
  • Signal Transduction
  • T-Lymphocytes, Regulatory / cytology*
  • T-Lymphocytes, Regulatory / metabolism
  • Tissue Engineering / methods
  • Tumor Necrosis Factor-alpha / metabolism*


  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • NF-kappa B
  • Tumor Necrosis Factor-alpha
  • Interferon-gamma
  • Casp3 protein, mouse
  • Casp8 protein, mouse
  • Caspase 3
  • Caspase 8
  • Aspirin