Advertisement

Expression and role of Toll-like receptors on human umbilical cord mesenchymal stromal cells

  • Dandan Chen
    Affiliations
    The State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences, Tianjin, China
    Search for articles by this author
  • Author Footnotes
    ∗ These authors contributed equally to this work.
    Fengxia Ma
    Correspondence
    Correspondence: Fengxia Ma, MD, 288 Nanjing Road, Tianjin 300020, China.
    Footnotes
    ∗ These authors contributed equally to this work.
    Affiliations
    The State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences, Tianjin, China
    Search for articles by this author
  • Shuxia Xu
    Affiliations
    The State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences, Tianjin, China
    Search for articles by this author
  • Shaoguang Yang
    Affiliations
    The State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences, Tianjin, China
    Search for articles by this author
  • Fang Chen
    Affiliations
    The State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences, Tianjin, China
    Search for articles by this author
  • Lijuan Rong
    Affiliations
    The State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences, Tianjin, China
    Search for articles by this author
  • Ying Chi
    Affiliations
    The State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences, Tianjin, China
    Search for articles by this author
  • Qinjun Zhao
    Affiliations
    The State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences, Tianjin, China
    Search for articles by this author
  • Shihong Lu
    Affiliations
    The State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences, Tianjin, China
    Search for articles by this author
  • Zhibo Han
    Affiliations
    The State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences, Tianjin, China
    Search for articles by this author
  • Aiming Pang
    Affiliations
    The State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences, Tianjin, China
    Search for articles by this author
  • Author Footnotes
    ∗ These authors contributed equally to this work.
    Zhongchao Han
    Footnotes
    ∗ These authors contributed equally to this work.
    Affiliations
    The State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences, Tianjin, China
    Search for articles by this author
  • Author Footnotes
    ∗ These authors contributed equally to this work.
Published:January 25, 2013DOI:https://doi.org/10.1016/j.jcyt.2012.12.001

      Abstract

      Background aims

      Toll-like receptors (TLRs) play an important role in innate and adaptive immunity by recognizing pathogen-associated molecular patterns (PAMPs).

      Methods

      In the present study, we investigated the expression and role of TLRs on human umbilical cord mesenchymal stromal cells (UC-MSCs). The proliferation, differentiation and immunoregulatory activity of UC-MSCs primed with or without TLR ligands were determined.

      Results

      At the RNA level, the expression of TLR2, 4, 6 and 9 was relatively higher than that of other TLRs. However, TLR3 and TLR4 expression were relatively higher at the protein level. UC-MSCs expressed functional TLRs by nuclear factor-κB activation and cytokine expression assay. Poly-inosinic acid:cytidylic acid [Poly(I:C)] stimulation inhibited the proliferation of UC-MSCs, but the ligand of other TLRs had no significant effect. Poly(I:C) stimulation enhanced the adipogenic differentiation capability of UC-MSCs, but lipopolysaccharide inhibited the adipogenic differentiation. Poly(I:C) and CpG-oligonucleotide promoted the immunosuppressive potentiality of UC-MSCs, accompanied with the phosphorylation of interferon regulatory factor 3 (IRF3) and increased expression of indoleamine 2,3-dioxygenase and interferon β, whereas activation of other TLR ligands (synthetic analog fibroblast-stimulating lipopeptide-1 and lipopolysaccharide) failed to affect the immunoregulatory activity of UC-MSCs.

      Conclusions

      Taken together, our data demonstrated that TLR activation influenced the function of UC-MSCs, which might have important implications in future efforts to explore the clinical potentials of UC-MSCs.

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Cytotherapy
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Baksh D.
        • Song L.
        • Tuan R.S.
        Adult mesenchymal stem cells: characterization, differentiation, and application in cell and gene therapy.
        J Cell Mol Med. 2004; 8: 301-316
        • Kode J.A.
        • Mukherjee S.
        • Joglekar M.V.
        • Hardikar A.A.
        Mesenchymal stem cells: immunobiology and role in immunomodulation and tissue regeneration.
        Cytotherapy. 2009; 11: 377-391
        • Liu Y.
        • Wang L.
        • Kikuiri T.
        • Akiyama K.
        • Chen C.
        • Xu X.
        • et al.
        Mesenchymal stem cell-based tissue regeneration is governed by recipient T lymphocytes via IFN-gamma and TNF-alpha.
        Nat Med. 2011; 17: 1594-1601
        • Sadan O.
        • Bahat-Stromza M.
        • Barhum Y.
        • Levy Y.S.
        • Pisnevsky A.
        • Peretz H.
        • et al.
        Protective effects of neurotrophic factor-secreting cells in a 6-OHDA rat model of Parkinson disease.
        Stem Cells Dev. 2009; 18: 1179-1190
        • Mohsin S.
        • Shams S.
        • Ali Nasir G.
        • Khan M.
        • Javaid Awan S.
        • Khan S.N.
        • et al.
        Enhanced hepatic differentiation of mesenchymal stem cells after pretreatment with injured liver tissue.
        Differentiation. 2011; 81: 42-48
        • Ghannam S.
        • Bouffi C.
        • Djouad F.
        • Jorgensen C.
        • Noel D.
        Immunosuppression by mesenchymal stem cells: mechanisms and clinical applications.
        Stem Cell Res Ther. 2010; 1: 2
        • Lu L.L.
        • Liu Y.J.
        • Yang S.G.
        • Zhao Q.J.
        • Wang X.
        • Gong W.
        • et al.
        Isolation and characterization of human umbilical cord mesenchymal stem cells with hematopoiesis-supportive function and other potentials.
        Haematologica. 2006; 91: 1017-1026
        • Troyer D.L.
        • Weiss M.L.
        Wharton's jelly-derived cells are a primitive stromal cell population.
        Stem Cells. 2008; 26: 591-599
        • Baksh D.
        • Yao R.
        • Tuan R.S.
        Comparison of proliferative and multilineage differentiation potential of human mesenchymal stem cells derived from umbilical cord and bone marrow.
        Stem Cells. 2007; 25: 1384-1392
        • Hass R.
        • Kasper C.
        • Bohm S.
        • Jacobs R.
        Different populations and sources of human mesenchymal stem cells (MSC): a comparison of adult and neonatal tissue-derived MSC.
        Cell Commun Signal. 2011; 9: 12
        • Deuse T.
        • Stubbendorff M.
        • Tang-Quan K.
        • Phillips N.
        • Kay M.A.
        • Eiermann T.
        • et al.
        Immunogenicity and immunomodulatory properties of umbilical cord lining mesenchymal stem cells.
        Cell Transplant. 2011; 20: 655-667
        • Breitbach M.
        • Bostani T.
        • Roell W.
        • Xia Y.
        • Dewald O.
        • Nygren J.M.
        • et al.
        Potential risks of bone marrow cell transplantation into infarcted hearts.
        Blood. 2007; 110: 1362-1369
        • Lund R.D.
        • Wang S.
        • Lu B.
        • Girman S.
        • Holmes T.
        • Sauve Y.
        • et al.
        Cells isolated from umbilical cord tissue rescue photoreceptors and visual functions in a rodent model of retinal disease.
        Stem Cells. 2007; 25: 602-611
        • Ren H.
        • Zhao Q.
        • Cheng T.
        • Lu S.
        • Chen Z.
        • Meng L.
        • et al.
        No contribution of umbilical cord mesenchymal stromal cells to capillarization and venularization of hepatic sinusoids accompanied by hepatic differentiation in carbon tetrachloride-induced mouse liver fibrosis.
        Cytotherapy. 2010; 12: 371-383
        • Liao W.
        • Xie J.
        • Zhong J.
        • Liu Y.
        • Du L.
        • Zhou B.
        • et al.
        Therapeutic effect of human umbilical cord multipotent mesenchymal stromal cells in a rat model of stroke.
        Transplantation. 2009; 87: 350-359
        • Liao W.
        • Zhong J.
        • Yu J.
        • Xie J.
        • Liu Y.
        • Du L.
        • et al.
        Therapeutic benefit of human umbilical cord derived mesenchymal stromal cells in intracerebral hemorrhage rat: implications of anti-inflammation and angiogenesis.
        Cell Physiol Biochem. 2009; 24: 307-316
        • Sun J.
        • Han Z.B.
        • Liao W.
        • Yang S.G.
        • Yang Z.
        • Yu J.
        • et al.
        Intrapulmonary delivery of human umbilical cord mesenchymal stem cells attenuates acute lung injury by expanding CD4+CD25+ Forkhead Boxp3 (FOXP3)+ regulatory T cells and balancing anti- and pro-inflammatory factors.
        Cell Physiol Biochem. 2011; 27: 587-596
        • Latifpour M.
        • Nematollahi-Mahani S.N.
        • Deilamy M.
        • Azimzadeh B.S.
        • Eftekhar-Vaghefi S.H.
        • Nabipour F.
        • et al.
        Improvement in cardiac function following transplantation of human umbilical cord matrix-derived mesenchymal cells.
        Cardiology. 2011; 120: 9-18
        • Kadam S.S.
        • Bhonde R.R.
        Islet neogenesis from the constitutively nestin expressing human umbilical cord matrix derived mesenchymal stem cells.
        Islets. 2010; 2: 112-120
        • Bianco P.
        • Robey P.G.
        • Simmons P.J.
        Mesenchymal stem cells: revisiting history, concepts, and assays.
        Cell Stem Cell. 2008; 2: 313-319
        • Phinney D.G.
        • Prockop D.J.
        Concise review: mesenchymal stem/multipotent stromal cells: the state of transdifferentiation and modes of tissue repair–current views.
        Stem Cells. 2007; 25: 2896-2902
        • Kawai T.
        • Akira S.
        The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors.
        Nat Immunol. 2010; 11: 373-384
        • Manicassamy S.
        • Pulendran B.
        Modulation of adaptive immunity with Toll-like receptors.
        Semin Immunol. 2009; 21: 185-193
        • Tsan M.F.
        • Gao B.
        Endogenous ligands of Toll-like receptors.
        J Leukoc Biol. 2004; 76: 514-519
        • Vogl T.
        • Tenbrock K.
        • Ludwig S.
        • Leukert N.
        • Ehrhardt C.
        • van Zoelen M.A.
        • et al.
        Mrp8 and Mrp14 are endogenous activators of Toll-like receptor 4, promoting lethal, endotoxin-induced shock.
        Nat Med. 2007; 13: 1042-1049
        • Yang D.
        • Chen Q.
        • Su S.B.
        • Zhang P.
        • Kurosaka K.
        • Caspi R.R.
        • et al.
        Eosinophil-derived neurotoxin acts as an alarmin to activate the TLR2-MyD88 signal pathway in dendritic cells and enhances Th2 immune responses.
        J Exp Med. 2008; 205: 79-90
        • Kulkarni R.
        • Behboudi S.
        • Sharif S.
        Insights into the role of Toll-like receptors in modulation of T cell responses.
        Cell Tissue Res. 2011; 343: 141-152
        • Zanoni I.
        • Granucci F.
        Regulation of antigen uptake, migration, and lifespan of dendritic cell by Toll-like receptors.
        J Mol Med. 2010; 88: 873-880
        • Drexler S.K.
        • Foxwell B.M.
        The role of toll-like receptors in chronic inflammation.
        Int J Biochem Cell Biol. 2010; 42: 506-518
        • Zhu J.
        • Mohan C.
        Toll-like receptor signaling pathways–therapeutic opportunities.
        Mediators Inflamm. 2010; 2010: 781235
        • So E.Y.
        • Ouchi T.
        The application of Toll like receptors for cancer therapy.
        Int J Biol Sci. 2010; 6: 675-681
        • Pevsner-Fischer M.
        • Morad V.
        • Cohen-Sfady M.
        • Rousso-Noori L.
        • Zanin-Zhorov A.
        • Cohen S.
        • et al.
        Toll-like receptors and their ligands control mesenchymal stem cell functions.
        Blood. 2007; 109: 1422-1432
        • Lombardo E.
        • DelaRosa O.
        • Mancheno-Corvo P.
        • Menta R.
        • Ramirez C.
        • Buscher D.
        Toll-like receptor-mediated signaling in human adipose-derived stem cells: implications for immunogenicity and immunosuppressive potential.
        Tissue Eng Part A. 2009; 15: 1579-1589
        • Hwa Cho H.
        • Bae Y.C.
        • Jung J.S.
        Role of toll-like receptors on human adipose-derived stromal cells.
        Stem Cells. 2006; 24: 2744-2752
        • van den Berk L.C.
        • Jansen B.J.
        • Siebers-Vermeulen K.G.
        • Netea M.G.
        • Latuhihin T.
        • Bergevoet S.
        • et al.
        Toll-like receptor triggering in cord blood mesenchymal stem cells.
        J Cell Mol Med. 2009; 13: 3415-3426
        • Tomchuck S.L.
        • Zwezdaryk K.J.
        • Coffelt S.B.
        • Waterman R.S.
        • Danka E.S.
        • Scandurro A.B.
        Toll-like receptors on human mesenchymal stem cells drive their migration and immunomodulating responses.
        Stem Cells. 2008; 26: 99-107
        • Liotta F.
        • Angeli R.
        • Cosmi L.
        • Fili L.
        • Manuelli C.
        • Frosali F.
        • 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: 279-289
        • Kim H.S.
        • Shin T.H.
        • Yang S.R.
        • Seo M.S.
        • Kim D.J.
        • Kang S.K.
        • et al.
        Implication of NOD1 and NOD2 for the differentiation of multipotent mesenchymal stem cells derived from human umbilical cord blood.
        PLoS One. 2010; 5: e15369
        • DelaRosa O.
        • Lombardo E.
        Modulation of adult mesenchymal stem cells activity by toll-like receptors: implications on therapeutic potential.
        Mediators Inflamm. 2010; 2010: 865601
        • Yagi H.
        • Soto-Gutierrez A.
        • Parekkadan B.
        • Kitagawa Y.
        • Tompkins R.G.
        • Kobayashi N.
        • et al.
        Mesenchymal stem cells: mechanisms of immunomodulation and homing.
        Cell Transplant. 2010; 19: 667-679
        • Secco M.
        • Zucconi E.
        • Vieira N.M.
        • Fogaca L.L.
        • Cerqueira A.
        • Carvalho M.D.
        • et al.
        Multipotent stem cells from umbilical cord: cord is richer than blood!.
        Stem Cells. 2008 Jan; 26: 146-150
        • Tomic S.
        • Djokic J.
        • Vasilijic S.
        • Vucevic D.
        • Todorovic V.
        • Supic G.
        • et al.
        Immunomodulatory properties of mesenchymal stem cells derived from dental pulp and dental follicle are susceptible to activation by Toll-like receptor agonists.
        Stem Cells Dev. 2011; 20: 695-708
        • Raicevic G.
        • Najar M.
        • Stamatopoulos B.
        • De Bruyn C.
        • Meuleman N.
        • Bron D.
        • et al.
        The source of human mesenchymal stromal cells influences their TLR profile as well as their functional properties.
        Cell Immunol. 2011; 270: 207-216
        • Gu L.
        • Zhu N.
        • Zhang H.
        • Durden D.L.
        • Feng Y.
        • Zhou M.
        Regulation of XIAP translation and induction by MDM2 following irradiation.
        Cancer Cell. 2009; 15: 363-375
        • O'Neill L.A.
        • Bowie A.G.
        The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling.
        Nat Rev Immunol. 2007; 7: 353-364
        • Bohnhorst J.
        • Rasmussen T.
        • Moen S.H.
        • Flottum M.
        • Knudsen L.
        • Borset M.
        • et al.
        Toll-like receptors mediate proliferation and survival of multiple myeloma cells.
        Leukemia. 2006; 20: 1138-1144
        • Hackstein H.
        • Knoche A.
        • Nockher A.
        • Poeling J.
        • Kubin T.
        • Jurk M.
        • et al.
        The TLR7/8 ligand resiquimod targets monocyte-derived dendritic cell differentiation via TLR8 and augments functional dendritic cell generation.
        Cell Immunol. 2011; 271: 401-412
        • Waterman R.S.
        • Tomchuck S.L.
        • Henkle S.L.
        • Betancourt A.M.
        A new mesenchymal stem cell (MSC) paradigm: polarization into a pro-inflammatory MSC1 or an Immunosuppressive MSC2 phenotype.
        PLoS One. 2010; 5: e10088
        • Kern S.
        • Eichler H.
        • Stoeve J.
        • Kluter H.
        • Bieback K.
        Comparative analysis of mesenchymal stem cells from bone marrow, umbilical cord blood, or adipose tissue.
        Stem Cells. 2006; 24: 1294-1301
        • Nauta A.J.
        • Fibbe W.E.
        Immunomodulatory properties of mesenchymal stromal cells.
        Blood. 2007; 110: 3499-3506
        • Plumas J.
        • Chaperot L.
        • Richard M.J.
        • Molens J.P.
        • Bensa J.C.
        • Favrot M.C.
        Mesenchymal stem cells induce apoptosis of activated T cells.
        Leukemia. 2005; 19: 1597-1604
        • Benvenuto F.
        • Ferrari S.
        • Gerdoni E.
        • Gualandi F.
        • Frassoni F.
        • Pistoia V.
        • et al.
        Human mesenchymal stem cells promote survival of T cells in a quiescent state.
        Stem Cells. 2007; 25: 1753-1760
        • Chen K.
        • Wang D.
        • Du W.T.
        • Han Z.B.
        • Ren H.
        • Chi Y.
        • et al.
        Human umbilical cord mesenchymal stem cells hUC-MSCs exert immunosuppressive activities through a PGE2-dependent mechanism.
        Clin Immunol. 2010; 135: 448-458
        • Opitz C.A.
        • Litzenburger U.M.
        • Lutz C.
        • Lanz T.V.
        • Tritschler I.
        • Koppel A.
        • et al.
        Toll-like receptor engagement enhances the immunosuppressive properties of human bone marrow-derived mesenchymal stem cells by inducing indoleamine-2,3-dioxygenase-1 via interferon-beta and protein kinase R.
        Stem Cells. 2009; 27: 909-919