Skip to main content
SpringerLink
Log in

Immunomodulatory effects of mesenchymal stromal cells-derived exosome

  • Original Article
  • Published:
Immunologic Research Aims and scope Submit manuscript

Abstract

The mechanisms underlying immunomodulatory ability of mesenchymal stromal cells (MSCs) remain unknown. Recently, studies suggested that the immunomodulatory activity of MSCs is largely mediated by paracrine factors. Among which, exosome is considered to play a major role in the communication between MSCs and target tissue. The aim of our study is to investigate the effect of MSCs-derived exosome on peripheral blood mononuclear cells (PBMCs), especially T cells. We find that the MSCs-derived exosome extracted from healthy donors’ bone marrow suppressed the secretion of pro-inflammatory factor TNF-α and IL-1β, but increased the concentration of anti-inflammatory factor TGF-β during in vitro culture. In addition, exosome may induce conversion of T helper type 1 (Th1) into T helper type 2 (Th2) cells and reduced potential of T cells to differentiate into interleukin 17-producing effector T cells (Th17). Moreover, the level of regulatory T cells (Treg) and cytotoxic T lymphocyte-associated protein 4 were also increased. These results suggested that MSC-derived exosome possesses the immunomodulatory properties. However, it showed no effects on the proliferation of PBMCs or CD3+ T cells, but increases the apoptosis of them. In addition, indoleamine 2, 3-dioxygenase (IDO) was previously shown to mediate the immunoregulation of MSCs, which was increased in PBMCs co-cultured with MSCs. In our study, IDO showed no significant changes in PBMCs exposed to MSCs-derived exosome. We conclude that exosome and MSCs might differ in their immune-modulating activities and mechanisms.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Nold P, et al. Immunosuppressive capabilities of mesenchymal stromal cells are maintained under hypoxic growth conditions and after gamma irradiation. Cytotherapy. 2015;17(2):152–62.

    Article  CAS  PubMed  Google Scholar 

  2. Tobin LM, et al. Human mesenchymal stem cells suppress donor CD4(+) T cell proliferation and reduce pathology in a humanized mouse model of acute graft-versus-host disease. Clin Exp Immunol. 2013;172(2):333–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Wuchter P, et al. Standardization of good manufacturing practice–compliant production of bone marrow–derived human mesenchymal stromal cells for immunotherapeutic applications. Cytotherapy. 2015;17(2):128–39.

    Article  CAS  PubMed  Google Scholar 

  4. Lee SM, Lee SC, Kim SJ. Contribution of human adipose tissue-derived stem cells and the secretome to the skin allograft survival in mice. J Surg Res. 2014;188(1):280–9.

    Article  CAS  PubMed  Google Scholar 

  5. Morigi M, Benigni A. Mesenchymal stem cells and kidney repair. Nephrol Dial Transplant. 2013;28(4):788–93.

    Article  CAS  PubMed  Google Scholar 

  6. Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood. 2005;105(4):1815–22.

    Article  CAS  PubMed  Google Scholar 

  7. Nauta AJ, et al. Mesenchymal stem cells inhibit generation and function of both CD34+-derived and monocyte-derived dendritic cells. J Immunol. 2006;177(4):2080–7.

    Article  CAS  PubMed  Google Scholar 

  8. Rakha A, Todeschini M, Casiraghi F. Assessment of anti-donor T cell proliferation and cytotoxic T lymphocyte-mediated lympholysis in living donor kidney transplant patients. Methods Mol Biol. 2014;1213:355–64.

    Article  CAS  PubMed  Google Scholar 

  9. Tabera S, et al. The effect of mesenchymal stem cells on the viability, proliferation and differentiation of B-lymphocytes. Haematologica. 2008;93(9):1301–9.

    Article  CAS  PubMed  Google Scholar 

  10. Swart J, et al. Mesenchymal stem cell therapy in proteoglycan induced arthritis. Ann Rheum Dis. 2015;74(4):769–77.

    Article  CAS  PubMed  Google Scholar 

  11. 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 placebo-controlled trial to determine efficacy. Arthritis Res Ther. 2014;16(4):113.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Wu Y, 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.

    Article  CAS  PubMed  Google Scholar 

  13. Chinnadurai R, et al. Mesenchymal stromal cells derived from Crohn’s patients deploy indoleamine 2, 3-dioxygenase-mediated immune suppression, independent of autophagy. Mol Ther. 2015;23(7):1248–61.

    Article  CAS  PubMed  Google Scholar 

  14. de Mare-Bredemeijer EL, et al. Human graft-derived mesenchymal stromal cells potently suppress alloreactive T-cell responses. Stem Cells Dev. 2015;24(12):1436–47.

    Article  PubMed  Google Scholar 

  15. Laranjeira P, et al. Effect of human bone marrow mesenchymal stromal cells on cytokine production by peripheral blood naive, memory, and effector T cells. Stem Cell Res Ther. 2015;6(1):3.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Najar M, et al. Bone marrow mesenchymal stromal cells induce proliferative, cytokinic and molecular changes during the t cell response: the importance of the IL-10/CD210 axis. Stem Cell Rev Rep. 2015;11(3):442–52.

    Article  CAS  Google Scholar 

  17. Akyurekli C, et al. A systematic review of preclinical studies on the therapeutic potential of mesenchymal stromal cell-derived microvesicles. Stem Cell Reviews and Reports. 2014;11(1):150–60.

    Article  Google Scholar 

  18. Robbins PD, Morelli AE. Regulation of immune responses by extracellular vesicles. Nat Rev Immunol. 2014;14(3):195–208.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Bruno S, Camussi G. Exploring mesenchymal stem cell-derived extracellular vesicles in acute kidney injury. In: Animal models for stem cell therapy. Springer; 2014. p. 139–45.

  20. Gouveia de Andrade AV, 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.

    Article  CAS  PubMed  Google Scholar 

  21. Katsuda T, et al. The therapeutic potential of mesenchymal stem cell-derived extracellular vesicles. Proteomics. 2013;13(10–11):1637–53.

    Article  CAS  PubMed  Google Scholar 

  22. Kordelas L, et al. MSC-derived exosomes: a novel tool to treat therapy-refractory graft-versus-host disease. Leukemia. 2014;28(4):970.

    CAS  PubMed  Google Scholar 

  23. Del Fattore A, et al. Immunoregulatory effects of mesenchymal stem cell-derived extracellular vesicles on T lymphocytes. Cell Transplant. 2015;24(12):2615–27.

    Article  PubMed  Google Scholar 

  24. Caby MP, et al. Exosomal-like vesicles are present in human blood plasma. Int Immunol. 2005;17(7):879–87.

    Article  CAS  PubMed  Google Scholar 

  25. Hashemi SM, et al. Comparative immunomodulatory properties of adipose-derived mesenchymal stem cells conditioned media from BALB/c, C57BL/6, and DBA mouse strains. J Cell Biochem. 2013;114(4):955–65.

    Article  CAS  PubMed  Google Scholar 

  26. Castro-Manrreza ME, Montesinos JJ. Immunoregulation by mesenchymal stem cells: biological aspects and clinical applications. J Immunol Res. 2015;2015:394917.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Rosado MM, et al. Inhibition of B-cell proliferation and antibody production by mesenchymal stromal cells is mediated by T cells. Stem Cells Dev. 2015;24(1):93–103.

    Article  CAS  PubMed  Google Scholar 

  28. Ryan J, et al. Interferon-γ does not break, but promotes the immunosuppressive capacity of adult human mesenchymal stem cells. Clin Exp Immunol. 2007;149(2):353–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Zhou Y, et al. Mesenchymal stromal cells augment CD4+ and CD8+ T-cell proliferation through a CCL2 pathway. Cytotherapy. 2013;15(10):1195–207.

    Article  CAS  PubMed  Google Scholar 

  30. Dorronsoro A, et al. Human mesenchymal stromal cells modulate T-cell responses through TNF-alpha-mediated activation of NF-kappaB. Eur J Immunol. 2014;44(2):480–8.

    Article  CAS  PubMed  Google Scholar 

  31. Silva A, et al. Bone marrow-derived mesenchymal stem cells and their conditioned medium attenuate fibrosis in an irreversible model of unilateral ureteral obstruction. Cell Transplant.  2015;24(12):2657–66.

    Article  PubMed  Google Scholar 

  32. Uchibori R, et al. Cancer gene therapy using mesenchymal stem cells. Int J Hematol. 2014;99(4):377–82.

    Article  CAS  PubMed  Google Scholar 

  33. Castro-Manrreza ME, Montesinos JJ. Immunoregulation by mesenchymal stem cells: biological aspects and clinical applications. J Immunol Res. 2015;2015:394917.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Conforti A, et al. Microvescicles derived from mesenchymal stromal cells are not as effective as their cellular counterpart in the ability to modulate immune responses in vitro. Stem cells and development. 2014;23(21):2591–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Lai RC, Yeo RW, Lim SK. Mesenchymal stem cell exosomes. Semin Cell Dev Biol. 2015;40:82–8.

    Article  CAS  PubMed  Google Scholar 

  36. Tan CY, Lai RC, Wong W, Dan YY, Lim S-K, Ho HK. Mesenchymal stem cell-derived exosomes promote hepatic regeneration in drug-induced liver injury models. Stem Cell Res Ther. 2014;5:76.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Collino F, et al. Microvesicles derived from adult human bone marrow and tissue specific mesenchymal stem cells shuttle selected pattern of miRNAs. PLoS One. 2010;5(7):e11803.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Kilpinen L, et al. Extracellular membrane vesicles from umbilical cord blood-derived MSC protect against ischemic acute kidney injury, a feature that is lost after inflammatory conditioning. J Extracell Vesicles. 2013;2:21927.

    Article  Google Scholar 

  39. Mokarizadeh A, et al. Microvesicles derived from mesenchymal stem cells: potent organelles for induction of tolerogenic signaling. Immunol Lett. 2012;147(1):47–54.

    Article  CAS  PubMed  Google Scholar 

  40. Takahashi T, et al. Immunologic self-tolerance maintained by CD25(+) CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp Med. 2000;192(2):303–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Sivanathan KN, et al. Interleukin-17A-induced human mesenchymal stem cells are superior modulators of immunological function. Stem Cells. 2015;33(9):2850–63.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by Important Special Subject Foundation of Guangzhou (201400000003-1; 201400000003-4) and Key Project of Natural Science Foundation of Guangdong Province (2014A0303110066), National Natural Science Foundation of China (81570107).

Author information

Author notes

    Authors and Affiliations

    1. Southern Medical University, Guangzhou, 510515, China

      Wancheng Chen, Yukai Huang, Jiaochan Han, Lili Yu, Yanli Li, Ziyuan Lu, Hongbo Li, Chenyan Shi, Fengqi Duan & Yang Xiao

    2. Department of Hematology, General Hospital of Guangzhou Military Command, Guangzhou, 510010, China

      Wancheng Chen, Hongbo Li, Zenghui Liu, Chenyan Shi, Fengqi Duan & Yang Xiao

    3. Department of Hematology, The Third Affiliated Hospital of Southern Medical University (Academy of Orthopedics-Guangdong Province), Guangzhou, 510630, China

      Yang Xiao

    Authors
    1. Wancheng Chen
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Yukai Huang
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Jiaochan Han
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Lili Yu
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Yanli Li
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Ziyuan Lu
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Hongbo Li
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Zenghui Liu
      View author publications

      You can also search for this author in PubMed Google Scholar

    9. Chenyan Shi
      View author publications

      You can also search for this author in PubMed Google Scholar

    10. Fengqi Duan
      View author publications

      You can also search for this author in PubMed Google Scholar

    11. Yang Xiao
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Yang Xiao.

    Ethics declarations

    Conflict of interest

    The authors declare that they have no conflict of interest.

    Ethical standard

    All applicable international, national and/or institutional guidelines for the care and use of animals were followed.

    Additional information

    Wancheng Chen and Yukai Huang have contributed equally to this work.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Chen, W., Huang, Y., Han, J. et al. Immunomodulatory effects of mesenchymal stromal cells-derived exosome. Immunol Res 64, 831–840 (2016). https://doi.org/10.1007/s12026-016-8798-6

    Download citation

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s12026-016-8798-6

    Keywords

    Search

    Navigation