Substantial discoveries suggested that exosomes released from multiple sources of stem cells can affect the biological functions of target cells. In present period, the immunosuppressive properties of exosomes derived from bone marrow mesenchymal stem cells (BMMSCs-E) have been extensively recognized, but few studies have been reported about exosomes secreted from dental pulp stem cells (DPSCs-E) in the field of medical immunity. Hence, the aim of this study is to compare the immunomodulatory capacity of BMMSCs-E and DPSCs-E. Peripheral blood mononuclear cells (PBMCs) were co-cultured with them respectively and the proportion of regulatory T cells (Treg) was detected to increase. Subsequently, we stimulated CD4+T cells with BMMSCs-E and DPSCs-E to observe their effects on the polarizations, chemokines secretion, apoptosis, and proliferation of CD4+T cells. We found that DPSCs-E inhibited the differentiation of CD4+T cells into T helper 17 cells (Th17) and reduced the secretions of pro-inflammatory factors IL-17 and TNF-α, while promoted the polarization of CD4+T cells into Treg and increased the release of anti-inflammatory factors IL-10 and TGF-β. What’s more, these capabilities of DPSCs-E were stronger than those of BMMSCs-E. In addition, DPSCs-E were more effective in inducing apoptosis of CD4+T cells compared with BMMSCs-E, and DPSCs-E inhibited the proliferation of CD4+T cells, which is similar to BMMSCs-E. We draw a conclusion that DPSCs-E have stronger immune-modulating activities than BMMSCs-E, and may be a new therapeutic tool for the treatment of immunological diseases.
This is a preview of subscription content, log in to check access.
We appreciate Dan Huang, Jingwen Xiao, and Yihua Song for collecting samples and providing method of extracting DPSCs and appreciate Junling Yang for her assistance with technical help in flow cytometry. We also thank Xingyu Li for helping us buy experimental reagents.
This work was supported by National Natural Science Foundation of China (81871278; 81671616; 81471603), Science and Technology Projects of Jiangsu Province (BE2018671), the project of “333 National Science Foundation” of Jiangsu Province (BRA2016527), Science and Technology Projects of Nantong City (MS1201712-2).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Research involving human participants and/or animals
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committees and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.
Friedenstein AJ, Petrakova KV, Kurolesova AI, Frolova GP. Heterotopic of bone marrow. Analysis of precursor cells for osteogenic and hematopoietic tissues. Transplantation. 1968;6(2):230–47.CrossRefGoogle Scholar
Romanov YA, Balashova EE, Volgina NE, Kabaeva NV, Dugina TN, Sukhikh GT. Isolation of multipotent mesenchymal stromal cells from cryopreserved human umbilical cord tissue. Bull Exp Biol Med. 2016;160(4):530–4.CrossRefGoogle Scholar
Miura M, Gronthos S, Zhao M, Lu B, Fisher LW, Robey PG, et al. SHED: stem cells from human exfoliated deciduous teeth. Proc Natl Acad Sci U S A. 2003;100(10):5807–12.CrossRefGoogle Scholar
Yañez R, Lamana ML, García-Castro J, Colmenero I, Ramírez M, Bueren JA. Adipose tissue-derived mesenchymal stem cells have in vivo immunosuppressive properties applicable for the control of the graft-versus-host disease. Stem Cells. 2006;24(11):2582–91.CrossRefGoogle Scholar
Bianco P, Riminucci M, Gronthos S, Robey PG. Bone marrow stromal stem cells: nature, biology, and potential applications. Stem Cells. 2001;19(3):180–92.CrossRefGoogle Scholar
Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8(4):315–7.CrossRefGoogle Scholar
REB F, Mazurek MS, Soos A, REB SCAF, Mazurek MS, Soos A, et al. Mesenchymal stromal/stem cells in regenerative medicine and tissue engineering. Stem Cells Int. 2018;2018:8031718.Google Scholar
Shi Y, Wang Y, Li Q, Liu K, Hou J, Shao C, et al. Immunoregulatory mechanisms of mesenchymal stem and stromal cells in inflammatory diseases. Nat Rev Nephrol. 2018;14(8):493–507.CrossRefGoogle Scholar
Swart JF, de Roock S, Hofhuis FM, Rozemuller H, van den Broek T, Moerer P, et al. Mesenchymal stem cell therapy in proteoglycan induced arthritis. Ann Rheum Dis. 2015;74(4):769–77.CrossRefGoogle Scholar
Woodworth TG, Furst DE. Safety and feasibility of umbilical cord mesenchymal stem cells in treatment-refractory systemic lupus erythematosus nephritis: time for a double-blind placebocontrolled trial to determine efficacy. Arthritis Res Ther. 2014;16(4):113.CrossRefGoogle Scholar
Wu Y, Cao Y, Li X, Xu L, Wang Z, Liu P, et al. Cotransplantation of haploidentical hematopoietic and umbilical cord mesenchymal stem cells for severe aplastic anemia: successful engraftment and mild GVHD. Stem Cell Res. 2014;12(1):132–8.CrossRefGoogle Scholar
Dahbour S, Jamali F, Alhattab D, Al-Radaideh A, Ababneh O, Al-Ryalat N, et al. Mesenchymal stem cells and conditioned media in the treatment of multiple sclerosis patients: clinical, ophthalmological and radiological assessments of safety and efficacy. CNS Neurosci Ther. 2017;23(11):866–74.CrossRefGoogle Scholar
Xu K, Xiao J, Zheng K, Feng X, Zhang J, Song D, et al. MiR-21/STAT3 signal is involved in odontoblast differentiation of human dental pulp stem cells mediated by TNF-α. Cell Rep. 2018;20(2):107–16.CrossRefGoogle Scholar
Feng X, Xing J, Feng G, Sang A, Shen B, Xu Y, et al. Age-dependent impaired neurogenic differentiation capacity of dental stem cell is associated with Wnt/β-catenin signaling. Cell Mol Neurobiol. 2013;33(8):1023–31.CrossRefGoogle Scholar
Zhao Y, Wang L, Jin Y, Shi S. Fas ligand regulates the immunomodulatory properties of dental pulp stem cells. J Dent Res. 2012;91(10):948–54.CrossRefGoogle Scholar
Sonoda S, Yamaza H, Ma L, Tanaka Y, Tomoda E, Aijima R, et al. Interferon-gamma improves impaired dentinogenic and immunosuppressive functions of irreversible pulpitis-derived human dental pulp stem cells. Sci Rep. 2016;6:19286.CrossRefGoogle Scholar
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(4):695–708.CrossRefGoogle Scholar
Thery C, Zitvogel L, Amigorena S. Exosomes: composition, biogenesis and function. Nat Rev Immunol. 2002;2:569–79.CrossRefGoogle Scholar
Makino Y, Yamaza H, Akiyama K, Ma L, Hoshino Y, Nonaka K, et al. Immune therapeutic potential of stem cells from human supernumerary teeth. J Dent Res. 2013;92(7):609–15.CrossRefGoogle Scholar
Yamaza T, Kentaro A, Chen C, Liu Y, Shi Y, Gronthos S, et al. Immunomodulatory properties of stem cells from human exfoliated deciduous teeth. Stem Cell Res Ther. 2010;1(1):5.CrossRefGoogle Scholar
Huang GT, Gronthos S, Shi S. Mesenchymal stem cells derived from dental tissues vs. those from other sources: their biology and role in regenerative medicine. J Dent Res. 2009;88(9):792–806.CrossRefGoogle Scholar
Kay AG, Long G, Tyler G, Stefan A, Broadfoot SJ, Piccinini AM, et al. Mesenchymal stem cell-conditioned medium reduces disease severity and immune responses in inflammatory arthritis. Sci Rep. 2017;7(1):18019.CrossRefGoogle Scholar
Jeong JO, Han JW, Kim JM, Cho HJ, Park C, Lee N, et al. Malignant tumor formation after transplantation of short-term cultured bone marrow mesenchymal stem cells in experimental myocardial infarction and diabetic neuropathy. Circ Res. 2011;108(11):1340–7.CrossRefGoogle Scholar
Yu B, Zhang X, Li X. Exosomes derived from mesenchymal stem cells. Int J Mol Sci. 2014;15:4142–57.CrossRefGoogle Scholar
Sarvar DP, Shamsasenjan K, Akbarzadehlaleh P. Mesenchymal stem cell-derived exosomes: new opportunity in cell free therapy. Adv Pharm Bull. 2016;6(3):293–9.CrossRefGoogle Scholar
Yu J, He H, Tang C, Zhang G, Li Y, Wang R, et al. Differentiation potential of STRO-1+ dental pulp stem cells changes during cell passaging. BMC Cell Biol. 2010;11:32.CrossRefGoogle Scholar
Zhang B, Yeo RWY, Lai RC, Sim EWK, Chin KC, Lim SK. Mesenchymal stromal cell exosome-enhanced regulatory T-cell production through an antigen-presenting cell-mediated pathway. Cytotherapy. 2018;20(5):687–96.CrossRefGoogle Scholar
Perez-Hernandez J, Redon J, Cortes R. Extracellular vesicles as therapeutic agents in systemic lupus erythematosus. Int J Mol Sci. 2017;18(4):E717.CrossRefGoogle Scholar
Harrell CR, Simovic Markovic B, Fellabaum C, Arsenijevic A, Djonov V, Arsenijevic N, et al. Therapeutic potential of mesenchymal stem cell-derived exosomes in the treatment of eye diseases. Adv Exp Med Biol. 2018;1089:47–57.CrossRefGoogle Scholar
Chen W, Huang Y, Han J, Yu L, Li Y, Lu Z, et al. Immunomodulatory effects of mesenchymal stromal cells-derived exosome. Immunol Res. 2016;64(4):831–40.CrossRefGoogle Scholar
Castro-Manrreza ME, Montesinos JJ. Immunoregulation by mesenchymal stem cells: biological aspects and clinical applications. J Immunol Res. 2015;2015(2):394917.Google Scholar
Tan L, Wu H, Liu Y, Zhao M, Li D, Lu Q. Recent advances of exosomes in immune modulation and autoimmune diseases. Autoimmunity. 2016;49(6):357–65.CrossRefGoogle Scholar
Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature. 2006;441(7090):235–8.CrossRefGoogle Scholar
Romano M, Tung SL, Smyth LA, Lombardi G. Treg therapy in transplantation: a general overview. Transpl Int. 2016;30(8):745–53.CrossRefGoogle Scholar
Van Hamburg JP, Tas SW. Molecular mechanisms underpinning T helper 17 cell heterogeneity and functions in rheumatoid arthritis. J Autoimmun. 2018;87:69–81.CrossRefGoogle Scholar
Nistala K, Wedderburn LR. Th17 and regulatory T cells: rebalancing pro- and anti-inflammatory forces in autoimmune arthritis. Rheumatology (Oxford). 2009;48(6):602–6.CrossRefGoogle Scholar
Sun L, Fu J, Zhou Y. Metabolism controls the balance of Th17/T-regulatory cells. Front Immunol. 2017;8:1632.CrossRefGoogle Scholar
Sakaguchi S. Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol. 2004;22:531–62.CrossRefGoogle Scholar
Hong JW, Lim JH, Chung CJ, Kang TJ, Kim TY, Kim YS, et al. Immune tolerance of human dental pulp-derived mesenchymal stem cells mediated by CD4+CD25+FoxP3+ regulatory T-cells and induced by TGF-β1 and IL-10. Yonsei Med J. 2017;58(5):1031–9.CrossRefGoogle Scholar
Kondo Y, Yokosawa M, Kaneko S, Furuyama K, Segawa S, Tsuboi H, et al. Review: transcriptional regulation of CD4+ T cell differentiation in experimentally induced arthritis and rheumatoid arthritis. Arthritis Rheum. 2018;70(5):653–61.CrossRefGoogle Scholar
Nakae S, Nambu A, Sudo K, Iwakura Y. Suppression of immune induction of collagen-induced arthritis in IL-17-deficient mice. J Immunol. 2003;171(11):6173–7.CrossRefGoogle Scholar
Iwanami K, Matsumoto I, Tanaka-Watanabe Y, Inoue A, Mihara M, Ohsugi Y, et al. Crucial role of the interleukin-6/interleukin-17 cytokine axis in the induction of arthritis by glucose-6-phosphate isomerase. Arthritis Rheum. 2008;58(3):754–63.CrossRefGoogle Scholar
Kondo Y, Yao Z, Tahara M, Iizuka M, Yokosawa M, Kaneko S, et al. Involvement of RORgammat-overexpressing T cells in the development of autoimmune arthritis in mice. Arthritis Res Ther. 2015;17:105.CrossRefGoogle Scholar
Chen SY, Wu CL, Lai MD, Lin CC, Yo YT, Jou IM, et al. Amelioration of rat collagen-induced arthritis through CD4+ T cells apoptosis and synovial interleukin-17 reduction by indoleamine 2,3-dioxygenase gene therapy. Hum Gene Ther. 2011;22(2):145–54.CrossRefGoogle Scholar
Del Fattore A, Luciano R, Pascucci L, Goffredo BM, Giorda E, Scapaticci M, et al. Immunoregulatory effects of mesenchymal stem cell-derived extracellular vesicles on T lymphocytes. Cell Transplant. 2015;24(12):2615–27.CrossRefGoogle Scholar
Gouveia de Andrade AV, Bertolino G, Riewaldt J, Bieback K, Karbanová J, Odendahl M, et al. Extracellular vesicles secreted by bone marrow-and adipose tissue-derived mesenchymal stromal cells fail to suppress lymphocyte proliferation. Stem Cells Dev. 2015;24(11):1374–6.CrossRefGoogle Scholar