title: Mesenchymal stem cell-based tissue regeneration is governed by recipient T lymphocytes via IFN-γ and TNF-α.
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.
authors.affiliation: Center for Craniofacial Molecular Biology, Ostrow School of Dentistry, University of Southern California, Los Angeles, California, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.forename: Takashi
authors.initials: T
authors.lastname: Kikuiri
authors.forename: Kentaro
authors.initials: K
authors.lastname: Akiyama
authors.forename: Chider
authors.initials: C
authors.lastname: Chen
authors.forename: Xingtian
authors.initials: X
authors.lastname: Xu
authors.forename: Ruili
authors.initials: R
authors.lastname: Yang
authors.forename: Wanjun
authors.initials: W
authors.lastname: Chen
authors.forename: Songlin
authors.initials: S
authors.lastname: Wang
authors.forename: Songtao
authors.initials: S
authors.lastname: Shi
mesh_terms: D000818:Animals; D017209:Apoptosis; D001241:Aspirin / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D001861:Bone Regeneration; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D010012:Osteogenesis / Q000187:drug effects; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000378:metabolism; D023822:Tissue Engineering / Q000379:methods; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; C505409:Casp3 protein, mouse; C505526:Casp8 protein, mouse; D053148:Caspase 3; D053181:Caspase 8; D001241:Aspirin
references.citation: EMBO J. 2001 Aug 1;20(15):4132-42
references.pmid: 11483516
references.citation: Endocr J. 2000 Jun;47(3):293-302
references.pmid: 11036873
references.citation: PLoS One. 2008 Jul 09;3(7):e2615
references.pmid: 18612428
references.citation: Am J Transplant. 2006 Sep;6(9):2046-59
references.pmid: 16869801
references.citation: Int Immunopharmacol. 2011 Apr;11(4):496-503
references.pmid: 21238618
references.citation: J Cell Physiol. 2007 Nov;213(2):341-7
references.pmid: 17620285
references.citation: J Immunol. 2008 Mar 1;180(5):2747-51
references.pmid: 18292492
references.citation: Autoimmunity. 2011 Feb;44(1):43-50
references.pmid: 20670119
references.citation: Orthopedics. 2004 Jan;27(1 Suppl):s167-73
references.pmid: 14763552
references.citation: Stem Cells. 2009 Jun;27(6):1421-32
references.pmid: 19489103
references.citation: Hum Mol Genet. 2008 Apr 15;17(R1):R93-8
references.pmid: 18632703
references.citation: J Biol Chem. 2006 Feb 10;281(6):3569-76
references.pmid: 16299379
references.citation: Biomaterials. 2010 Mar;31(8):2121-9
references.pmid: 20004968
references.citation: Panminerva Med. 2009 Mar;51(1):25-41
references.pmid: 19352307
references.citation: Cell Stem Cell. 2010 Oct 8;7(4):431-42
references.pmid: 20887949
references.citation: Autoimmunity. 2011 Feb;44(1):33-42
references.pmid: 21091291
references.citation: Biomed Mater. 2010 Dec;5(6):062001
references.pmid: 20924139
references.citation: Endocrinology. 2003 May;144(5):1761-9
references.pmid: 12697681
references.citation: Transplantation. 1997 Apr 27;63(8):1059-69
references.pmid: 9133465
references.citation: Science. 1997 Apr 4;276(5309):71-4
references.pmid: 9082988
references.citation: Pharmacology. 2005 Jun;74(3):152-6
references.pmid: 15775706
references.citation: Stem Cells. 2010 Aug;28(8):1446-55
references.pmid: 20597105
references.citation: Nat Rev Immunol. 2002 Jun;2(6):389-400
references.pmid: 12093005
references.citation: Stem Cells Dev. 2010 May;19(5):607-14
references.pmid: 19824807
references.citation: Life Sci. 2004 Oct 29;75(24):2879-95
references.pmid: 15454340
references.citation: Nat Rev Rheumatol. 2009 Dec;5(12):685-97
references.pmid: 19901916
references.citation: Expert Opin Biol Ther. 2010 Oct;10(10):1453-68
references.pmid: 20831449
references.citation: Infect Immun. 2003 Mar;71(3):1209-16
references.pmid: 12595434
references.citation: Stem Cells. 2001;19(3):180-92
references.pmid: 11359943
references.citation: Ciba Found Symp. 1988;136:42-60
references.pmid: 3068016
references.citation: Blood. 2006 Feb 15;107(4):1484-90
references.pmid: 16239427
references.citation: J Exp Med. 1996 Jan 1;183(1):159-67
references.pmid: 8551219
references.citation: Science. 1999 Apr 2;284(5411):143-7
references.pmid: 10102814
references.citation: Mayo Clin Proc. 2009 Oct;84(10):893-902
references.pmid: 19797778
references.citation: Nat Biotechnol. 2002 Jun;20(6):587-91
references.pmid: 12042862
references.citation: Cancer Lett. 2009 Feb 8;274(1):132-42
references.pmid: 18952368
references.citation: J Biol Chem. 1999 Dec 31;274(53):37957-64
references.pmid: 10608863
references.citation: Transplantation. 1974 Apr;17(4):331-40
references.pmid: 4150881
references.citation: Proc Natl Acad Sci U S A. 2011 Jan 11;108(2):768-73
references.pmid: 21187391