Toll-like receptor triggering in cord blood mesenchymal stem cells
Lieke C.J. van den Berk
Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, Geert Grooteplein, Nijmegen, The Netherlands
These authors contributed equally to this work.
Search for more papers by this authorBastiaan J.H. Jansen
Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, Geert Grooteplein, Nijmegen, The Netherlands
These authors contributed equally to this work.
Search for more papers by this authorKim G.C. Siebers-Vermeulen
Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, Geert Grooteplein, Nijmegen, The Netherlands
Search for more papers by this authorMihai G. Netea
Department of Internal Medicine, Radboud University Nijmegen Medical Centre, Geert Grooteplein, Nijmegen, The Netherlands
Search for more papers by this authorTalia Latuhihin
Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, Geert Grooteplein, Nijmegen, The Netherlands
Search for more papers by this authorSaskia Bergevoet
Department of Hematology, University Medical Centre St. Radboud, Geert Grooteplein, Nijmegen, The Netherlands
Search for more papers by this authorReinier A. Raymakers
Department of Hematology, University Medical Centre St. Radboud, Geert Grooteplein, Nijmegen, The Netherlands
Search for more papers by this authorGesine Kögler
Institute for Transplantation Diagnostics and Cell Therapeutics, University of Duesseldorf Medical School, Moorenstrasse, Düsseldorf, Germany
Search for more papers by this authorCarl C. Figdor
Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, Geert Grooteplein, Nijmegen, The Netherlands
Search for more papers by this authorGosse J. Adema
Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, Geert Grooteplein, Nijmegen, The Netherlands
Search for more papers by this authorCorresponding Author
Ruurd Torensma
Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, Geert Grooteplein, Nijmegen, The Netherlands
Correspondence to: Ruurd TORENSMA, Department of Tumor Immunology, NCMLS, Geert Grooteplein 28, 6525 GA, Nijmegen, The Netherlands.Tel.: +31-243617600Fax: +31-243540339E-mail: [email protected].Search for more papers by this authorLieke C.J. van den Berk
Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, Geert Grooteplein, Nijmegen, The Netherlands
These authors contributed equally to this work.
Search for more papers by this authorBastiaan J.H. Jansen
Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, Geert Grooteplein, Nijmegen, The Netherlands
These authors contributed equally to this work.
Search for more papers by this authorKim G.C. Siebers-Vermeulen
Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, Geert Grooteplein, Nijmegen, The Netherlands
Search for more papers by this authorMihai G. Netea
Department of Internal Medicine, Radboud University Nijmegen Medical Centre, Geert Grooteplein, Nijmegen, The Netherlands
Search for more papers by this authorTalia Latuhihin
Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, Geert Grooteplein, Nijmegen, The Netherlands
Search for more papers by this authorSaskia Bergevoet
Department of Hematology, University Medical Centre St. Radboud, Geert Grooteplein, Nijmegen, The Netherlands
Search for more papers by this authorReinier A. Raymakers
Department of Hematology, University Medical Centre St. Radboud, Geert Grooteplein, Nijmegen, The Netherlands
Search for more papers by this authorGesine Kögler
Institute for Transplantation Diagnostics and Cell Therapeutics, University of Duesseldorf Medical School, Moorenstrasse, Düsseldorf, Germany
Search for more papers by this authorCarl C. Figdor
Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, Geert Grooteplein, Nijmegen, The Netherlands
Search for more papers by this authorGosse J. Adema
Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, Geert Grooteplein, Nijmegen, The Netherlands
Search for more papers by this authorCorresponding Author
Ruurd Torensma
Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, Geert Grooteplein, Nijmegen, The Netherlands
Correspondence to: Ruurd TORENSMA, Department of Tumor Immunology, NCMLS, Geert Grooteplein 28, 6525 GA, Nijmegen, The Netherlands.Tel.: +31-243617600Fax: +31-243540339E-mail: [email protected].Search for more papers by this authorAbstract
Recently, the antagonizing effect on the differentiation of mesenchymal stem cells (MSCs) by toll-like receptor (TLR) ligands, was described. Our study shows that on more primitive cord blood derived MSCs, the expression of TLRs and ligand-induced triggering differs from that of bone marrow derived MSCs. At the RNA level, cord blood MSCs (unrestricted somatic stem cells; USSCs) express low levels of TLR1,3,5,9 and high levels of TLR4 and TLR6. At the protein level expression of TLR5 and very low expression of TLR4 was observed. NF-κB translocation studies revealed that both TLR4 and TLR5 are functional, although signalling kinetics induced by the individual ligands differed. Stimulation of USSCs with either lipopolysaccharide (LPS) or flagellin resulted in a marked increase of interleukin (IL)-6 and/or IL-8 production although levels differed significantly between both stimuli. Interestingly, tumour necrosis factor (TNF)-α was undetectable after TLR stimulation, which appeared to be due to an inactivated TNF-α promoter in USSCs. Moreover, osteoblastic differentiation was enhanced after triggering USSCs with LPS and flagellin. In summary, TLR4 and 5 signalling in USSCs is slow and results in the up-regulation of a restricted number of pro-inflammatory cytokines and enhanced osteoblastic differentiation. Apparently, the outcome of TLR signalling depends on the cell type that expresses them.
References
- 1 Medzhitov R, Janeway CA Jr. Innate immunity: impact on the adaptive immune response. Curr Opin Immunol. 1997; 9: 4–9.
- 2 Kabelitz D, Wesch D, Oberg HH. Regulation of regulatory T cells: role of dendritic cells and toll-like receptors. Crit Rev Immunol. 2006; 26: 291–306.
- 3 Janeway CA Jr, Medzhitov R. Lipoproteins take their toll on the host. Curr Biol. 1999; 9: R879–R82.
- 4 Anderson KV. Toll signaling pathways in the innate immune response. Curr Opin Immunol. 2000; 12: 13–9.
- 5 Underhill DM, Ozinsky A. Toll-like receptors: key mediators of microbe detection. Curr Opin Immunol. 2002; 14: 103–10.
- 6 Kopp E, Medzhitov R. Recognition of microbial infection by toll-like receptors. Curr Opin Immunol. 2003; 15: 396–401.
- 7 Netea MG, van der Graaf C, Van der Meer JW, et al . Toll-like receptors and the host defense against microbial pathogens: bringing specificity to the innate-immune system. J Leukoc Biol. 2004; 75: 749–55.
- 8 Doyle SL, O’Neill LA. Toll-like receptors: from the discovery of NFkappaB to new insights into transcriptional regulations in innate immunity. Biochem Pharmacol. 2006; 72: 1102–13.
- 9 Takeda K, Kaisho T, Akira S. Toll-like receptors. Annu Rev Immunol. 2003; 21: 335–76.
- 10 Gay NJ, Keith FJ. Drosophila toll and IL-1 receptor. Nature. 1991; 351: 355–6.
- 11 Medzhitov R, Preston-Hurlburt P, Janeway CA Jr. A human homologue of the Drosophila toll protein signals activation of adaptive immunity. Nature. 1997; 388: 394–7.
- 12 Rock FL, Hardiman G, Timans JC, et al . A family of human receptors structurally related to Drosophila toll. Proc Natl Acad Sci USA. 1998; 95: 588–93.
- 13 Chaudhary PM, Ferguson C, Nguyen V, et al . Cloning and characterization of two toll/interleukin-1 receptor-like genes TIL3 and TIL4: evidence for a multi-gene receptor family in humans. Blood. 1998; 91: 4020–7.
- 14 Akira S, Hemmi H. Recognition of pathogen-associated molecular patterns by TLR family. Immunol Lett. 2003; 85: 85–95.
- 15 Chuang T, Ulevitch RJ. Identification of hTLR10: a novel human toll-like receptor preferentially expressed in immune cells. Biochim Biophys Acta. 2001; 1518: 157–61.
- 16 Tomchuck SL, Zwezdaryk KJ, Coffelt SB, et al . Toll-like receptors on human mesenchymal stem cells drive their migration and immunomodulating responses. Stem Cells. 2008; 26: 99–107.
- 17 Hwa Cho H, Bae YC, Jung JS. Role of toll-like receptors on human adipose-derived stromal cells. Stem Cells. 2006; 24: 2744–52.
- 18 Pevsner-Fischer M, Morad V, Cohen-Sfady M, et al . Toll-like receptors and their ligands control mesenchymal stem cell functions. Blood. 2007; 109: 1422–32.
- 19 Kogler G, Sensken S, Airey JA, et al . A new human somatic stem cell from placental cord blood with intrinsic pluripotent differentiation potential. J Exp Med. 2004; 200: 123–35.
- 20 Kim BO, Tian H, Prasongsukarn K, et al . Cell transplantation improves ventricular function after a myocardial infarction: a preclinical study of human unrestricted somatic stem cells in a porcine model. Circulation. 2005; 112: I96–I104.
- 21 Roobrouck VD, Ulloa-Montoya F, Verfaillie CM. Self-renewal and differentiation capacity of young and aged stem cells. Exp Cell Res. 2008; 314: 1937–44.
- 22 Marcus AJ, Woodbury D. Fetal stem cells from extra-embryonic tissues: do not discard. J Cell Mol Med. 2008; 12: 730–42.
- 23 Chan SL, Choi M, Wnendt S, et al . Enhanced in vivo homing of uncultured and selectively amplified cord blood CD34+ cells by cotransplantation with cord blood-derived unrestricted somatic stem cells. Stem Cells. 2007; 25: 529–36.
- 24 Whetton AD, Williamson AJ, Krijgsveld J, et al . The time is right: proteome biology of stem cells. Cell Stem Cell. 2008; 2: 215–7.
- 25 Ying QL, Wray J, Nichols J, et al . The ground state of embryonic stem cell self-renewal. Nature. 2008; 453: 519–23.
- 26 Li LC, Dahiya R. MethPrimer: designing primers for methylation PCRs. Bioinformatics. 2002; 18: 1427–31.
- 27 Tsytsykova AV, Falvo JV, Schmidt-Supprian M, et al . Post-induction, stimulus-specific regulation of tumor necrosis factor mRNA expression. J Biol Chem. 2007; 282: 11629–38.
- 28 Gijzen K, Tacken PJ, Zimmerman A, et al . Relevance of DC-SIGN in DC-induced T cell proliferation. J Leukoc Biol. 2007; 81: 729–40.
- 29 Moynagh PN. The NF-kappaB pathway. J Cell Sci. 2005; 118: 4589–92.
- 30 Falvo JV, Uglialoro AM, Brinkman BM, et al . Stimulus-specific assembly of enhancer complexes on the tumor necrosis factor alpha gene promoter. Mol Cell Biol. 2000; 20: 2239–47.
- 31 Tsai EY, Jain J, Pesavento PA, et al . Tumor necrosis factor alpha gene regulation in activated T cells involves ATF-2/Jun and NFATp. Mol Cell Biol. 1996; 16: 459–67.
- 32 Tsai EY, Yie J, Thanos D, et al . Cell-type-specific regulation of the human tumor necrosis factor alpha gene in B cells and T cells by NFATp and ATF-2/JUN. Mol Cell Biol. 1996; 16: 5232–44.
- 33 Sutmuller RP, Morgan ME, Netea MG, et al . Toll-like receptors on regulatory T cells: expanding immune regulation. Trends Immunol. 2006; 27: 387–93.
- 34 Akira S. TLR signaling. Curr Top Microbiol Immunol. 2006; 311: 1–16.
- 35 Sakaguchi Y, Sekiya I, Yagishita K, et al . Comparison of human stem cells derived from various mesenchymal tissues: superiority of synovium as a cell source. Arthritis Rheum. 2005; 52: 2521–9.
- 36 Igarashi A, Segoshi K, Sakai Y, et al . Selection of common markers for bone marrow stromal cells from various bones using real-time RT-PCR: effects of passage number and donor age. Tissue Eng. 2007; 13: 2405–17.
- 37 Sivasubramaniyan K, Atluri RR, Sarda K, et al . Endotoxin-induced silencing of mesoderm induction and functional differentiation: role of HMGB1 in pluripotency and infection. Regen Med. 2008; 3: 23–31.
- 38 Schedel J, Distler O, Woenckhaus M, et al . Discrepancy between mRNA and protein expression of tumour suppressor maspin in synovial tissue may contribute to synovial hyperplasia in rheumatoid arthritis. Ann Rheum Dis. 2004; 63: 1205–11.
- 39 Gu X, Lundqvist EN, Coates PJ, et al . Dysregulation of TAp63 mRNA and protein levels in psoriasis. J Invest Dermatol. 2006; 126: 137–41.
- 40 Cho ML, Ju JH, Kim HR, et al . Toll-like receptor 2 ligand mediates the upregulation of angiogenic factor, vascular endothelial growth factor and interleukin-8/CXCL8 in human rheumatoid synovial fibroblasts. Immunol Lett. 2007; 108: 121–8.
- 41 Zhang W, Ge W, Li C, et al . Effects of mesenchymal stem cells on differentiation, maturation, and function of human monocyte-derived dendritic cells. Stem Cells Dev. 2004; 13: 263–71.
- 42 Kang YJ, Kim SO, Shimada S, et al . Cell surface 4–1BBL mediates sequential signaling pathways ‘downstream’ of TLR and is required for sustained TNF production in macrophages. Nat Immunol. 2007; 8: 601–9.
- 43 Kogler G, Radke TF, Lefort A, et al . Cytokine production and hematopoiesis supporting activity of cord blood-derived unrestricted somatic stem cells. Exp Hematol. 2005; 33: 573–83.
- 44 Kochanek S, Radbruch A, Tesch H, et al . DNA methylation profiles in the human genes for tumor necrosis factors alpha and beta in subpopulations of leukocytes and in leukemias. Proc Natl Acad Sci USA. 1991; 88: 5759–63.
- 45 Kochanek S, Toth M, Dehmel A, et al . Interindividual concordance of methylation profiles in human genes for tumor necrosis factors alpha and beta. Proc Natl Acad Sci USA. 1990; 87: 8830–4.
- 46 Kruys V, Thompson P, Beutler B. Extinction of the tumor necrosis factor locus, and of genes encoding the lipopolysaccharide signaling pathway. J Exp Med. 1993; 177: 1383–90.
- 47 Crisostomo PR, Wang M, Herring CM, et al . Gender differences in injury induced mesenchymal stem cell apoptosis and VEGF, TNF, IL-6 expression: role of the 55 kDa TNF receptor (TNFR1). J Mol Cell Cardiol. 2007; 42: 142–9.
- 48 Liotta F, Angeli R, Cosmi L, et al . Toll-like receptors 3 and 4 are expressed by human bone marrow-derived mesenchymal stem cells and can inhibit their T-cell modulatory activity by impairing Notch signaling. Stem Cells. 2008; 26: 279–89.
- 49 Migliaccio G, Migliaccio AR, Petti S, et al . Human embryonic hemopoiesis. Kinetics of progenitors and precursors underlying the yolk sac–liver transition. J Clin Invest. 1986; 78: 51–60.
- 50 Zanjani ED, Ascensao JL, Tavassoli M. Liver-derived fetal hematopoietic stem cells selectively and preferentially home to the fetal bone marrow. Blood. 1993; 81: 399–404.
- 51 Vaziri H, Dragowska W, Allsopp RC, et al . Evidence for a mitotic clock in human hematopoietic stem cells: loss of telomeric DNA with age. Proc Natl Acad Sci USA. 1994; 91: 9857–60.
- 52 Szilvassy SJ, Meyerrose TE, Ragland PL, et al . Differential homing and engraftment properties of hematopoietic progenitor cells from murine bone marrow, mobilized peripheral blood, and fetal liver. Blood. 2001; 98: 2108–15.
Citing Literature
