Heart transplantation continues to be the gold standard clinical intervention to treat patients with end-stage heart failure. However, there are major complications associated with this surgical procedure that reduce the survival prognosis of heart transplant patients, including allograft rejection, malignancies, infections, and other complications that arise from the use of broad-spectrum immunosuppression drugs. Recent studies have demonstrated the use of mesenchymal stem cells (MSCs) against allotransplantation rejection in both in vitro and in vivo settings due to their immunomodulatory properties. Therefore, utilization of MSCs provides new and exciting strategies to improve heart transplantation and potentially reduce the use of broad-spectrum immunosuppression drugs while alleviating allograft rejection. In this review, we will discuss the current research on the mechanisms of cardiac allograft rejection, the physiological and immunological characteristics of MSCs, the effects of MSCs on the immune system, and immunomodulation of heart transplantation by MSCs.
KhushKKCherikhWSChambersDCHarhayMOHayesDJHsichEMeiserBPotenaLRobinsonARossanoJWSadavarteASinghTPZuckermannAStehlikJ.The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: Thirty-sixth adult heart transplantation report - 2019; focus theme: Donor and recipient size match. J Heart Lung Transplant2019;
38:1056–66
4.
LodhiSALambKEMeier-KriescheHU.Solid organ allograft survival improvement in the United States: the long-term does not mirror the dramatic short-term success. Am J Transplant2011;
11:1226–35
5.
Le BlancKMougiakakosD.Multipotent mesenchymal stromal cells and the innate immune system. Nat Rev Immunol2012;
12:383–96
6.
PodestàMARemuzziGCasiraghiF.Mesenchymal stromal cells for transplant tolerance. Front Immunol2019;
10:1287
7.
GhannamSBouffiCDjouadFJorgensenCNoëlD.Immunosuppression by mesenchymal stem cells: mechanisms and clinical applications. Stem Cell Res Ther2010;
1:2
8.
MachadoCDVTellesPDDSNascimentoILO.Immunological characteristics of mesenchymal stem cells. Rev Bras Hematol Hemoter2013;
35:62–67
9.
DominiciMLe BlancKMuellerISlaper-CortenbachIMariniFKrauseDDeansRKeatingAProckopDHorwitzE.Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy2006;
8:315–7
10.
Marquez-CurtisLAJanowska-WieczorekAMcGannLEElliottJAW.Mesenchymal stromal cells derived from various tissues: biological, clinical and cryopreservation aspects. Cryobiology2015;
71:181–97
11.
Le BlancKTammikCRosendahlKZetterbergERingdénO.HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells. Exp Hematol2003;
31:890–6
12.
WangYChenXCaoWShiY.Plasticity of mesenchymal stem cells in immunomodulation: pathological and therapeutic implications. Nat Immunol2014;
15:1009–16
13.
Moquin-BeaudryGColasCLiYBazinRGuimondJVHaddadEBeauséjourC.The tumor-immune response is not compromised by mesenchymal stromal cells in humanized mice. J Immunol2019;
203:2735–45
14.
ChowLJohnsonVImpastatoRCoyJStrumpfADowS.Antibacterial activity of human mesenchymal stem cells mediated directly by constitutively secreted factors and indirectly by activation of innate immune effector cells. Stem Cells Transl Med2020;
9:235–49
15.
LandWGAgostinisPGasserSGargADLinkermannA.Transplantation and damage-associated molecular patterns (DAMPs). Am J Transplant2016;
16:3338–61
16.
RohJSSohnDH.Damage-associated molecular patterns in inflammatory diseases. Immune Netw2018;
18:e27
17.
FrevertCWFelgenhauerJWygreckaMNastaseMVSchaeferL.Danger-associated molecular patterns derived from the extracellular matrix provide temporal control of innate immunity.J Histochem Cytochem2018;
66:213–27
18.
TakeuchiOAkiraS.Pattern recognition receptors and inflammation. Cell2010;
140:805–20
19.
VerstrepenLBekaertTChauTLTavernierJChariotABeyaertR.TLR-4, IL-1R and TNF-R signaling to NF-κB: variations on a common theme. Cell Mol Life Sci2008;
65:2964–78
20.
O'NeillLAJGolenbockDBowieAG.The history of toll-like receptors — redefining innate immunity. Nat Rev Immunol2013;
13:453–60
21.
Di GioiaMZanoniI.Toll-like receptor co-receptors as master regulators of the immune response. Mol Immunol2015;
63:143–52
HuangYYinHHanJHuangBXuJZhengFTanZFangMRuiLChenDWangSZhengXWangCYGongF.Extracellular Hmgb1 functions as an innate immune-mediator implicated in murine cardiac allograft acute rejection. Am J Transplant2007;
7:799–808
24.
LandWGAgostinisPGasserSGargADLinkermannA.DAMP-induced allograft and tumor rejection: the circle is closing. Am J Transplant2016;
16:3322–37
25.
AngoulvantDIvanesFFerreraRMatthewsPGNatafSOvizeM.Mesenchymal stem cell conditioned media attenuates in vitro and ex vivo myocardial reperfusion injury. J Heart Lung Transplant2011;
30:95–102
PredaMBRønningenTBurlacuASimionescuMMoskaugJØValenG.Remote transplantation of mesenchymal stem cells protects the heart against ischemia-reperfusion injury. Stem Cells2014;
32:2123–34
29.
TangJXieQPanGWangJWangM.Mesenchymal stem cells participate in angiogenesis and improve heart function in rat model of myocardial ischemia with reperfusion. Eur J Cardiothorac Surg2006;
30:353–61
30.
Korkmaz-IcözSLiSHüttnerRRuppertMRadovitsTLoganathanSSayourAABrlecicPLasitschkaFKarckMSzabóG.Hypothermic perfusion of donor heart with a preservation solution supplemented by mesenchymal stem cells. J Heart Lung Transplant2019;
38:315–26
31.
NakajimaDWatanabeYOhsumiAPipkinMChenMMordantPKanouTSaitoTLamRCoutinhoRCaldaroneLJuvetSMartinuTIyerRKDaviesJEHwangDMWaddellTKCypelMLiuMKeshavjeeS.Mesenchymal stromal cell therapy during ex vivo lung perfusion ameliorates ischemia-reperfusion injury in lung transplantation. J Heart Lung Transplant2019;
38:1214–23
32.
Uemoto S, FujimotoYTerataniTKanazawaHIwasakiJXiangdongZMasanoYYagiSHataKKobayashiE. Introduction of mesenchymal stem cells for liver surgery (hepatectomy and transplantation).In: Nakao K, Minato N, Uemoto S (eds) Innovative medicine: basic research and development. Tokyo: Springer, 2015, pp.281–93
33.
MessmerDYangHTelusmaGKnollFLiJMessmerBTraceyKJChiorazziN.High mobility group box protein 1: an endogenous signal for dendritic cell maturation and Th1 polarization. J Immunol2004;
173:307–13
34.
YangDChenQYangHTraceyKJBustinMOppenheimJJ.High mobility group box-1 protein induces the migration and activation of human dendritic cells and acts as an alarmin. J Leukoc Biol2007;
81:59–66
35.
MarinoJPasterJBenichouG.Allorecognition by T lymphocytes and allograft rejection. Front Immunol2016;
7:582
36.
CozziEColpoADe SilvestroGJTScienceA.The mechanisms of rejection in solid organ transplantation. Transfus Apher Sci2017;
56:498–505
37.
NautaAJKruisselbrinkABLurvinkEWillemzeRFibbeWE.Mesenchymal stem cells inhibit generation and function of both CD34+-derived and monocyte-derived dendritic cells. J Immunol2006;
177:2080–87
38.
JiangX-XZhangYLiuBZhangS-XWuYYuX-DMaoN.Human mesenchymal stem cells inhibit differentiation and function of monocyte-derived dendritic cells. Blood2005;
105:4120–26
39.
DjouadFCharbonnierL-MBouffiCLouis-PlencePBonyCApparaillyFCantosCJorgensenCNoëlD.Mesenchymal stem cells inhibit the differentiation of dendritic cells through an interleukin-6-dependent mechanism. Stem Cells2007;
25:2025–32
40.
LiY-PPaczesnySLauretEPoiraultSBordigoniPMekhloufiFHequetOBertrandYOu-YangJ-PStoltzJ-FMiossecPEljaafariA.Human mesenchymal stem cells license adult CD34+ hemopoietic progenitor cells to differentiate into regulatory dendritic cells through activation of the notch pathway. J Immunol2008;
180:1598–608
41.
GeWJiangJBarojaMLArpJZassokoRLiuWBartholomewAGarciaBWangH.Infusion of mesenchymal stem cells and rapamycin synergize to attenuate alloimmune responses and promote cardiac allograft tolerance. Am J Transplant2009;
9:1760–72
42.
BeythSBorovskyZMevorachDLiebergallMGazitZAslanHGalunERachmilewitzJ.Human mesenchymal stem cells alter antigen-presenting cell maturation and induce T-cell unresponsiveness. Blood2005;
105:22141–9
43.
ZhaoZ-GXuWSunLYouYLiFLiQ-BZouP.Immunomodulatory function of regulatory dendritic cells induced by mesenchymal stem cells. Immunol Invest2012;
41:183–98
44.
HuaFChenYYangZTengXHuangHShenZ.Protective action of bone marrow mesenchymal stem cells in immune tolerance of allogeneic heart transplantation by regulating CD45RB+ dendritic cells. Clin Transplant2018;
32:e13231
45.
MurailleELeoOMoserM.TH1/TH2 paradigm extended: macrophage polarization as an unappreciated pathogen-driven escape mechanism?Front Immunol2014;
5:60303
46.
RőszerT.Understanding the mysterious M2 macrophage through activation markers and effector mechanisms. Mediators Inflamm2015;
2015:1–16
47.
Chávez-GalánLOllerosMLVesinDGarciaI.Much more than M1 and M2 macrophages, there are also CD169+ and TCR+ macrophages. Front Immunol2015;
6:263
48.
NémethKLeelahavanichkulAYuenPSTMayerBParmeleeADoiKRobeyPGLeelahavanichkulKKollerBHBrownJMHuXJelinekIStarRAMezeyE.Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production. Nat Med2009;
15:42–49
49.
DayanVYannarelliGBilliaFFilomenoPWangX-HDaviesJEKeatingA.Mesenchymal stromal cells mediate a switch to alternatively activated monocytes/macrophages after acute myocardial infarction. Basic Res Cardiol2011;
106:1299–310
50.
LvHLiuQSunYYiXWeiXLiuWZhangQYiHChenG.Mesenchymal stromal cells ameliorate acute lung injury induced by LPS mainly through stanniocalcin-2 mediating macrophage polarization. Ann Transl Med2020;
8:334
51.
GaoCWangXLuJLiZJiaHChenMChangYLiuYLiPZhangBDuXQiF.Mesenchymal stem cells transfected with sFgl2 inhibit the acute rejection of heart transplantation in mice by regulating macrophage activation. Stem Cell Res Ther2020;
11:241
52.
Martín-FontechaAThomsenLLBrettSGerardCLippMLanzavecchiaASallustoF.Induced recruitment of NK cells to lymph nodes provides IFN-gamma for T(H)1 priming. Nat Immunol2004;
5:1260–65
53.
GerosaFBaldani-GuerraBNisiiCMarchesiniVCarraGTrinchieriG.Reciprocal activating interaction between natural killer cells and dendritic cells. J Exp Med2002;
195:327–33
54.
PradierAPasswegJVillardJKindlerV.Human bone marrow stromal cells and skin fibroblasts inhibit natural killer cell proliferation and cytotoxic activity. Cell Transplant2011;
20:681–91
55.
SpaggiariGMCapobiancoAAbdelrazikHBecchettiFMingariMCMorettaL.Mesenchymal stem cells inhibit natural killer–cell proliferation, cytotoxicity, and cytokine production: role of indoleamine 2,3-dioxygenase and prostaglandin E2. Blood2008;
111:1327–33
56.
ThomasHJägerMMauelKBrandauSLaskSFlohéSBPeakeJ.Interaction with mesenchymal stem cells provokes natural killer cells for enhanced IL-12/IL-18-induced interferon-gamma secretion. Mediators Inflamm2014;
2014:143463
57.
NajarMFayyad-KazanMMeulemanNBronDFayyad-KazanHLagneauxL.Mesenchymal stromal cells of the bone marrow and natural killer cells: cell interactions and cross modulation. J Cell Commun Signal2018;
12:673–88
58.
Di NicolaMCarlo-StellaCMagniMMilanesiMLongoniPDMatteucciPGrisantiSGianniAM.Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood2002;
99:3838–43
59.
GlennieSSoeiro Is DysonPJLamEWFDazziF.Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells. Blood2005;
105:2821–27
60.
MeiselRZibertALaryeaMGöBelUDäUbenerWDillooD,
Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase–mediated tryptophan degradation. Blood2004;
103:4619–21
SatoKOzakiKOhIMeguroAHatanakaKNagaiTMuroiKOzawaK.Nitric oxide plays a critical role in suppression of T-cell proliferation by mesenchymal stem cells. Blood2006;
109:228–34
63.
SzaboSJSullivanBMPengSLGlimcherLH.Molecular mechanisms regulating Th1 immune responses. Annu Rev Immunol2003;
21:713–58
64.
WalkerJAMcKenzieANJ.TH2 cell development and function. Nat Rev Immunol2018;
18:121–33
65.
CrespoMPascualMTolkoff-RubinNMauiyyediSBernard CollinsAFitzpatrickDLin FarrellMWilliamsWWDelmonicoFL, BCosimiAColvinRBSaidmanSL.Acute humoral rejection in renal allograft recipients: incidence, serology and clinical characteristics. Transplantation2001;
71:652–58
66.
PuttarajappaCShapiroRTanHPAkalinE.Antibody-mediated rejection in kidney transplantation: a review. J Transplant2012;
2012:193724
67.
MichaelsPJFishbeinMCColvinRB.Humoral rejection of human organ transplants. Springer Semin Immunopathol2003;
25:119–40
68.
ItohSKimuraNAxtellRCVelottaJBGongYWangXKajiwaraNNambuAShimuraEAdachiHIwakuraYSaitoHOkumuraKSudoKSteinmanLRobbinsRCNakaeSFischbeinMP.Interleukin-17 accelerates allograft rejection by suppressing regulatory T cell expansion. Circulation2011;
124:S187–96
69.
FanHLiL-XHanD-DKouJ-TLiPHeQ.Increase of peripheral Th17 lymphocytes during acute cellular rejection in liver transplant recipients. Hepatobiliary Pancreat Dis Int2012;
11:606–11
70.
VanaudenaerdeBMDupontLJWuytsWAVerbekenEKMeytsIBullensDMDilissenELuytsLVan RaemdonckDEVerledenGM.The role of interleukin-17 during acute rejection after lung transplantation. Eur Respir J2006;
27:779–87
71.
ZhouYYangXZhangHJiangJ.The roles of T helper type 17/regulatory T cells in acute rejection after liver transplantation in rats. Transplantation2015;
99:1126–31
72.
SakaguchiSYamaguchiTNomuraTOnoM.Regulatory T cells and immune tolerance. Cell2008;
133:775–87
73.
RozenbergARezkABoivinM-NDarlingtonPJNyirendaMLiRJaliliFWinerRArtsyEAUccelliAReeseJSPlanchonSMCohenJA,
Bar-Or A. Human mesenchymal stem cells impact Th17 and Th1 responses through a prostaglandin E2 and myeloid-dependent mechanism. Stem Cells Transl Med2016;
5:1506–14
74.
Luz-CrawfordPKurteMBravo-AlegríaJContrerasRNova-LampertiETejedorGNoëlDJorgensenCFigueroaFDjouadFCarriónF.Mesenchymal stem cells generate a CD4+CD25+Foxp3+ regulatory T cell population during the differentiation process of Th1 and Th17 cells. Stem Cell Res Ther2013;
4:65
75.
LuzPNoëlDFernandezXKhouryMFigueroaFCarrionFJorgensenCDjouadF.Mesenchymal stem cells repress Th17 molecular program through the PD-1 pathway. PloS One2012;
7:e45272
76.
LiGYuanLRenXNianHZhangLHanZCLiXZhangX.The effect of mesenchymal stem cells on dynamic changes of T cell subsets in experimental autoimmune uveoretinitis. Clin Exp Immunol2013;
173:28–37
77.
GeWJiangJArpJLiuWGarciaBWangH.Regulatory T-cell generation and kidney allograft tolerance induced by mesenchymal stem cells associated with indoleamine 2,3-dioxygenase expression. Transplantation2010;
90:1312–20
78.
EnglishKRyanJMTobinLMurphyMJBarryFPMahonBP.Cell contact, prostaglandin E(2) and transforming growth factor beta 1 play non-redundant roles in human mesenchymal stem cell induction of CD4+CD25(high) forkhead box P3+ regulatory T cells. Clin Exp Immunol2009;
156:149–60
79.
ZhangBYeoRWYLaiRCSimEWKChinKCLimSK.Mesenchymal stromal cell exosome-enhanced regulatory T-cell production through an antigen-presenting cell-mediated pathway. Cytotherapy2018;
20:687–96
80.
MeliefSMSchramaEBrugmanMHTiemessenMMHoogduijnMJFibbeWERoelofsH.Multipotent stromal cells induce human regulatory T cells through a novel pathway involving skewing of monocytes toward anti-inflammatory macrophages. Stem Cells2013;
31:1980–91
81.
CasiraghiFAzzolliniNCassisPImbertiBMorigiMCuginiDCavinatoRATodeschiniMSoliniSSonzogniAPericoNRemuzziGNorisM.Pretransplant infusion of mesenchymal stem cells prolongs the survival of a semiallogeneic heart transplant through the generation of regulatory T cells. J Immunol2008;
181:3933–46
82.
ZhouHPYiDHYuSQSunGCCuiQZhuHLLiuJCZhangJZWuTJ.Administration of donor-derived mesenchymal stem cells can prolong the survival of rat cardiac allograft. Transplant Proc2006;
38:3046–51
83.
HeJ-GXieQ-LLiB-BZhouLYanD.Exosomes derived from IDO1-overexpressing rat bone marrow mesenchymal stem cells promote immunotolerance of cardiac allografts. Cell Transplant2018;
27:1657–83
84.
HeJ-GLiB-BZhouLYanDXieQ-LZhaoW.Indoleamine 2,3-dioxgenase-transfected mesenchymal stem cells suppress heart allograft rejection by increasing the production and activity of dendritic cells and regulatory T cells. J Investig Med2020;
68:728–37
85.
WangWZhaoNLiBGaoHYanYGuoH.Inhibition of cardiac allograft rejection in mice using interleukin-35-modified mesenchymal stem cells. Scand J Immunol2019;
89:e12750
86.
JiangXLiuCHaoJGuoDGuoJYaoJJiangKCuiZZhuLSunWLinLLiangJ.CD4+CD25+ regulatory T cells are not required for mesenchymal stem cell function in fully MHC-mismatched mouse cardiac transplantation. Cell Tissue Res2014;
358:503–14
87.
ChoyJC.Granzymes and perforin in solid organ transplant rejection. Cell Death Differ2010;
17:567–76
88.
SuJXieQXuYLiXCDaiZ.Role of CD8(+) regulatory T cells in organ transplantation. Burns Trauma2014;
2:18–23
89.
RasmussonIRingdénOSundbergB.Le BlancK.Mesenchymal stem cells inhibit the formation of cytotoxic T lymphocytes, but not activated cytotoxic T lymphocytes or natural killer cells. Transplantation2003;
76:1208–13
90.
LiMSunXKuangXLiaoYLiHLuoD.Mesenchymal stem cells suppress CD8+ T cell-mediated activation by suppressing natural killer group 2, member D protein receptor expression and secretion of prostaglandin E2, indoleamine 2, 3-dioxygenase and transforming growth factor-β. Clin Exp Immunol2014;
178:516–24
91.
Hof-NahorILeshanskyLShivtielSEldorLAberdamDItskovitz-EldorJBerrih-AkninS.Human mesenchymal stem cells shift CD8+ T cells towards a suppressive phenotype by inducing tolerogenic monocytes. J Cell Sci2012;
125:4640–50
92.
LiuQZhengHChenXPengYHuangWLiXLiGXiaWSunQXiangAP.Human mesenchymal stromal cells enhance the immunomodulatory function of CD8+CD28− regulatory T cells. Cell Mol Immunol2015;
12:708–18
93.
YuYMaXGongRZhuJWeiLYaoJ.Recent advances in CD8(+) regulatory T cell research. Oncol Lett2018;
15:8187–94
94.
FranquesaMMensahFKHuizingaRStriniTBoonLLombardoEDelaRosaOLamanJDGrinyóJMWeimarWBetjesMGHBaanCCHoogduijnMJ.Human adipose tissue-derived mesenchymal stem cells abrogate plasmablast formation and induce regulatory B cells independently of T helper cells. Stem Cells2015;
33:880–91
95.
CarterNAVasconcellosRRosserECTuloneCMuñoz-SuanoAKamanakaMEhrensteinMRFlavellRAMauriC.Mice lacking endogenous IL-10–producing regulatory B cells develop exacerbated disease and present with an increased frequency of Th1/Th17 but a decrease in regulatory T cells. J Immunol2011;
186:5569–79
96.
LukFCarreras-PlanellaLKorevaarSSde WitteSFHBorràsFEBetjesMGHBaanCCHoogduijnMJFranquesaM.Inflammatory conditions dictate the effect of mesenchymal stem or stromal cells on B cell function. Front Immunol2017;
8:1042
97.
Carreras-PlanellaLMonguió-TortajadaMBorràsFEFranquesaM.Immunomodulatory effect of MSC on B cells is independent of secreted extracellular vesicles. Front Immunol2019;
10:1288
98.
RosadoMMBernardoMEScarsellaMConfortiAGiordaEBiaginiSCascioliSRossiFGuzzoIVivarelliMDello StrologoLEmmaFLocatelliFCarsettiR.Inhibition of B-cell proliferation and antibody production by mesenchymal stromal cells is mediated by T cells. Stem Cells Dev2014;
24:93–103
99.
MaXCheNGuZHuangJWangDLiangJHouYGilkesonGLuLSunL.Allogenic mesenchymal stem cell transplantation ameliorates nephritis in lupus mice via inhibition of B-cell activation. Cell Transplant2013;
22:2279–90
100.
FanX-LZhangYLiXFuQ-L.Mechanisms underlying the protective effects of mesenchymal stem cell-based therapy. Cell Mol Life Sci2020;
77:2771–94
101.
Musiał-WysockaAKotMMajkaM.The pros and cons of mesenchymal stem cell-based therapies. Cell Transplant2019;
28:801–12
102.
LeeMJeongSYHaJKimMJinHJKwonS-JChangJWChoiSJOhWYangYSKimJ-SJeonHB.Low immunogenicity of allogeneic human umbilical cord blood-derived mesenchymal stem cells in vitro and in vivo. Biochem Biophys Res Commun2014;
446:983–89
103.
InoueSPoppFCKoehlGEPisoPSchlittHJGeisslerEKDahlkeMH.Immunomodulatory effects of mesenchymal stem cells in a rat organ transplant model. Transplantation2006;
81:1589–95
104.
EggenhoferESteinmannJFRennerPSlowikPPisoPGeisslerEKSchlittHJDahlkeMHPoppFC.Mesenchymal stem cells together with mycophenolate mofetil inhibit antigen presenting cell and T cell infiltration into allogeneic heart grafts. Transpl Immunol2011;
24:157–63
105.
WangYAbarbanellAMHerrmannJLWeilBRManukyanMCPoynterJAMeldrumDR.TLR4 inhibits mesenchymal stem cell (MSC) STAT3 activation and thereby exerts deleterious effects on MSC-mediated cardioprotection. PloS One2010;
5:e14206
106.
RaicevicGRouasRNajarMStordeurPId BoufkerHBronDMartiatPGoldmanMNevessignskyMTLagneauxL.Inflammation modifies the pattern and the function of toll-like receptors expressed by human mesenchymal stromal cells. Hum Immunol2010;
71:235–44
107.
DelaRosaOLombardoE.Modulation of adult mesenchymal stem cells activity by toll-like receptors: implications on therapeutic potential. Mediators Inflamm2010;
2010:865601
108.
OpitzCALitzenburgerUMLutzCLanzTVTritschlerIKöppelATolosaEHobergMAnderlJAicherWKWellerMWickWPlattenM.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-β and protein kinase R. Stem Cells2009;
27:909–19
109.
Pevsner-FischerMMoradVCohen-SfadyMRousso-NooriLZanin-ZhorovACohenSCohenIRZiporiD.Toll-like receptors and their ligands control mesenchymal stem cell functions. Blood2006;
109:1422–32
110.
LiottaFAngeliRCosmiLFilìLManuelliCFrosaliFMazzinghiBMaggiLPasiniALisiVSantarlasciVConsoloniLAngelottiMLRomagnaniPParronchiPKramperaMMaggiERomagnaniSAnnunziatoF.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 Cells2008;
26:279–89
