Skip to main content
SpringerLink
Log in

Gene delivery with IFN-γ-expression plasmids enhances the therapeutic effects of MSCs on DSS-induced mouse colitis

  • Original Research Paper
  • Published:
Inflammation Research Aims and scope Submit manuscript

Abstract

Objective

Interferon-γ (IFN-γ) is known to enhance the immunosuppressive properties of mesenchymal stem cells (MSCs). The aim of this study was to determine whether gene modification with IFN-γ-expression plasmids could boost the therapeutic effects of MSCs on DSS-induced colitis.

Methods

We first reconstructed pcDNA3.1-IFNγ plasmids, transfected them to human umbilical cord derived MSCs, and detected the basic characters of MSCs including immune phenotype, cell vitality, proliferation, apoptosis and cell cycle progression after transfection. Subsequently, we analyzed the inhibition effect of IFN-γ-MSCs on T cell proliferation in vitro. Finally, we induced colitis in female C57BL/6 mice by 3 % DSS treatment and evaluated the therapeutic efficacy of IFN-γ-MSCs on colitis.

Results

Transfection with pcDNA3.1-IFNγ did not change the basic characters of MSCs. Interestingly, IFN-γ-MSCs showed more potent immunosuppressive effects on the proliferation of T cells compared to normal MSCs. Furthermore, systemic infusion with IFN-γ-MSCs more efficiently ameliorated DSS-induced mouse colitis including colitis-related ease of body weight, increase of colon length, decrease of disease activity index, and improvement of small intestine tissues structure. In addition, IFN-γ-MSCs increased the populations of Foxp3+ Tregs and Th2 cells both in mesenteric lymph node and spleen, upregulated indoleamine 2, 3-dioxygenase expression, and suppressed inflammatory cytokine production in mouse colon.

Conclusions

Gene delivery with IFN-γ-expression plasmids enhanced the therapeutic effects of MSCs on DSS-induced mouse colitis. This study provides an effective therapeutic strategy of MSCs for inflammatory diseases.

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

Similar content being viewed by others

References

  1. Hanauer SB. Inflammatory bowel disease: epidemiology, pathogenesis, and therapeutic opportunities. Inflamm Bowel Dis. 2006;12(Suppl 1):S3–9.

    Article  PubMed  Google Scholar 

  2. Ng SC, Bernstein CN, Vatn MH, Lakatos PL, Loftus EV Jr, Tysk C, et al. Geographical variability and environmental risk factors in inflammatory bowel disease. Gut. 2013;62:630–49.

    Article  PubMed  Google Scholar 

  3. Geremia A, Biancheri P, Allan P, Corazza GR, Di Sabatino A. Innate and adaptive immunity in inflammatory bowel disease. Autoimmun Rev. 2014;13:3–10.

    Article  CAS  PubMed  Google Scholar 

  4. González MA, Gonzalez-Rey E, Rico L, Büscher D, Delgado M. Adipose-derived mesenchymal stem cells alleviate experimental colitis by inhibiting inflammatory and autoimmune responses. Gastroenterology. 2009;136:978–89.

    Article  PubMed  Google Scholar 

  5. Gonzalez-Rey E, Anderson P, González MA, Rico L, Büscher D, Delgado M. Human adult stem cells derived from adipose tissue protect against experimental colitis and sepsis. Gut. 2009;58:929–39.

    Article  CAS  PubMed  Google Scholar 

  6. He XW, He XS, Lian L, Wu XJ, Lan P. Systemic infusion of bone marrow-derived mesenchymal stem cells for treatment of experimental colitis in mice. Dig Dis Sci. 2012;57:3136–44.

    Article  PubMed  Google Scholar 

  7. Shi Y, Hu G, Su J, Li W, Chen Q, Shou P, et al. Mesenchymal stem cells: a new strategy for immunosuppression and tissue repair. Cell Res. 2010;20:510–8.

    Article  CAS  PubMed  Google Scholar 

  8. Hemeda H, Jakob M, Ludwig AK, Giebel B, Lang S, Brandau S. Interferon-gamma and tumor necrosis factor-alpha differentially affect cytokine expression and migration properties of mesenchymal stem cells. Stem Cells Dev. 2010;19:693–706.

    Article  CAS  PubMed  Google Scholar 

  9. Tanaka F, Tominaga K, Ochi M, Tanigawa T, Watanabe T, Fujiwara Y, et al. Exogenous administration of mesenchymal stem cells ameliorates dextran sulfate sodium-induced colitis via anti-inflammatory action in damaged tissue in rats. Life Sci. 2008;83:771–9.

    Article  CAS  PubMed  Google Scholar 

  10. Duijvestein M, Wildenberg ME, Welling MM, Hennink S, Molendijk I, van Zuylen VL, et al. Pretreatment with interferon-γ enhances the therapeutic activity of mesenchymal stromal cells in animal models of colitis. Stem Cells. 2011;29:1549–58.

    Article  CAS  PubMed  Google Scholar 

  11. Ren G, Zhang L, Zhao X, Xu G, Zhang Y, Roberts AI, et al. Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide. Cell Stem Cell. 2008;2:141–50.

    Article  CAS  PubMed  Google Scholar 

  12. Krampera M, Cosmi L, Angeli R, Pasini A, Liotta F, Andreini A, et al. Role for interferon-gamma in the immunomodulatory activity of human bone marrow mesenchymal stem cells. Stem Cells. 2006;24:386–98.

    Article  CAS  PubMed  Google Scholar 

  13. Fan H, Zhao G, Liu L, Liu F, Gong W, Liu X, et al. Pre-treatment with IL-1β enhances the efficacy of MSC transplantation in DSS-induced colitis. Cell Mol Immunol. 2012;9:473–81.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Ryan JM, Barry F, Murphy JM, Mahon BP. Interferon-gamma does not break, but promotes the immunosuppressive capacity of adult human mesenchymal stem cells. Clin Exp Immunol. 2007;149:353–63.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Ren G, Zhao X, Zhang L, Zhang J, L’Huillier A, Ling W, et al. Inflammatory cytokine-induced intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in mesenchymal stem cells are critical for immunosuppression. J Immunol. 2010;184:2321–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Croitoru-Lamoury J, Lamoury FM, Caristo M, Suzuki K, Walker D, Takikawa O, et al. Interferon-γ regulates the proliferation and differentiation of mesenchymal stem cells via activation of indoleamine 2,3 dioxygenase (IDO). PLoS ONE. 2011;6:e14698.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. François M, Romieu-Mourez R, Li M, Galipeau J. Human MSC suppression correlates with cytokine induction of indoleamine 2, 3-dioxygenase and bystander M2 macrophage differentiation. Mol Ther. 2012;2012(20):187–95.

    Article  Google Scholar 

  18. Noone C, Kihm A, English K, O’Dea S, Mahon BP. IFN-γ stimulated human umbilical-tissue-derived cells potently suppress NK activation and resist NK-mediated cytotoxicity in vitro. Stem Cells Dev. 2013;22:3003–14.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Sivanathan KN, Gronthos S, Rojas-Canales D, Thierry B, Coates PT. Interferon-gamma modification of mesenchymal stem cells: implications of autologous and allogeneic mesenchymal stem cell therapy in allotransplantation. Stem Cell Rev. 2014;10:351–75.

    Article  CAS  PubMed  Google Scholar 

  20. Kim DJ, Kim KS, Song MY, Seo SH, Kim SJ, Yang BG, et al. Delivery of IL-12p40 ameliorates DSS-induced colitis by suppressing IL-17A expression and inflammation in the intestinal mucosa. Clin Immunol. 2012;144:190–9.

    Article  CAS  PubMed  Google Scholar 

  21. Ankrum JA, Dastidar RG, Ong JF, Levy O, Karp JM. Performance-enhanced mesenchymal stem cells via intracellular delivery of steroids. Sci Rep. 2014;4:4645.

    Article  PubMed Central  PubMed  Google Scholar 

  22. Liu L, Zhao X, Li P, Zhao G, Wang Y, Hu Y, et al. A novel way to isolate MSCs from umbilical cords. Eur J Immunol. 2012;42:2190–3.

    Article  CAS  PubMed  Google Scholar 

  23. Neurath MF, Fuss I, Kelsall BL, Stüber E, Strober W. Antibodies to interleukin 12 abrogate established experimental colitis in mice. J Exp Med. 1995;182:1281–90.

    Article  CAS  PubMed  Google Scholar 

  24. Zuo L, Huang Z, Dong L, Xu L, Zhu Y, Zeng K, et al. Targeting delivery of anti-TNF alpha oligonucleotide into activated colonic macrophages protects against experimental colitis. Gut. 2010;59:470–9.

    Article  CAS  PubMed  Google Scholar 

  25. Tondreau T, Meuleman N, Delforge A, Dejeneffe M, Leroy R, Massy M, et al. Mesenchymal stem cells derived from CD133-positive cells in mobilized peripheral blood and cord blood: proliferation, Oct4 expression, and plasticity. Stem Cells. 2005;23:1105–12.

    Article  CAS  PubMed  Google Scholar 

  26. Alex P, Zachos NC, Nguyen T, Gonzales L, Chen TE, Conklin LS, et al. Distinct cytokine patterns identified from multiplex profiles of murine DSS and TNBS-induced colitis. Inflamm Bowel Dis. 2009;15:341–52.

    Article  PubMed Central  PubMed  Google Scholar 

  27. Uccelli A, Moretta L, Pistoia V. Mesenchymal stem cells in health and disease. Nat Rev Immunol. 2008;8:726–36.

    Article  CAS  PubMed  Google Scholar 

  28. Bukulmez H, Bilgin A, Bebek G, Caplan AI, Jones O. A125: immunomodulatory factors produced by mesenchymal stem cells after in vitro priming with danger signals. Arthritis Rheumatol. 2014;66(Suppl 11):S163.

    Article  Google Scholar 

  29. English K, Barry FP, Field-Corbett CP, Mahon BP. IFN-gamma and TNF-alpha differentially regulateimmunomodulation by murine mesenchymal stem cells. Immunol Lett. 2007;110:91–100.

    Article  CAS  PubMed  Google Scholar 

  30. Zhao X, Liu D, Gong W, Zhao G, Liu L, Yang L, et al. The toll-like receptor 3 ligand, poly (I:C), improves immunosuppressive function and therapeutic effect of mesenchymal stem cells on sepsis via inhibiting miR-143. Stem Cells. 2014;32:521–33.

    Article  CAS  PubMed  Google Scholar 

  31. Dumitru CA, Hemeda H, Jakob M, Lang S, Brandau S. Stimulation of mesenchymal stromal cells (MSCs) via TLR3 reveals a novel mechanism of autocrine priming. FASEB J. 2014;28:3856–66.

    Article  CAS  PubMed  Google Scholar 

  32. Luz-Crawford P, Kurte M, Bravo-Alegría J, Contreras R, Nova-Lamperti E, Tejedor G, et al. Mesenchymal stem cells generate a CD4+ CD25+ Foxp3+ regulatory T cell population during the differentiation process of Th1 and Th17 cells. Stem Cell Res Ther. 2013;4:65.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Han KH, Ro H, Hong JH, Lee EM, Cho B, Yeom HJ, et al. Immunosuppressive mechanisms of embryonic stem cells and mesenchymal stem cells in alloimmune response. Transpl Immunol. 2011;25:7–15.

    Article  CAS  PubMed  Google Scholar 

  34. Li G, Yuan L, Ren X, Nian H, Zhang L, Han ZC, et al. The effect of mesenchymal stem cells on dynamic changes of T cell subsets in experimental autoimmune uveoretinitis. Clin Exp Immunol. 2013;173:28–37.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Meisel R, Zibert A, Laryea M, Göbel U, Däubener W, Dilloo D. Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2, 3-dioxygenase-mediated tryptophan degradation. Blood. 2004;103:4619–21.

    Article  CAS  PubMed  Google Scholar 

  36. Wang D, Feng X, Lu L, Konkel JE, Zhang H, Chen Z, et al. A CD8 T cell-IDO axis is required for mesenchymal stem cell suppression of human SLE. Arthritis Rheumatol. 2014;66:2234–45.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Chinnadurai R, Copland IB, Patel SR, Galipeau J. IDO-independent suppression of T cell effector function by IFN-γ-licensed human mesenchymal stromal cells. J Immunol. 2014;192:1491–501.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the Clinical Medicine Science and Technology Projects of Jiangsu Province (BL2014069), the National Natural Science Foundation of China (81101552), and the Natural Science Foundation of Jiangsu Province (BK2011571).

Author information

Authors and Affiliations

  1. The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, People’s Republic of China

    Yueqiu Chen, Yuxian Song, Huishuang Miao, Yujun Xu, Mingming Lv, Tingting Wang & Yayi Hou

  2. Jiangsu Key Laboratory of Molecular Medicine, Nanjing, 210093, People’s Republic of China

    Tingting Wang & Yayi Hou

Authors
  1. Yueqiu Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yuxian Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Huishuang Miao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yujun Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mingming Lv
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tingting Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yayi Hou
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Yuxian Song or Yayi Hou.

Additional information

Responsible Editor: Liwu Li.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, Y., Song, Y., Miao, H. et al. Gene delivery with IFN-γ-expression plasmids enhances the therapeutic effects of MSCs on DSS-induced mouse colitis. Inflamm. Res. 64, 671–681 (2015). https://doi.org/10.1007/s00011-015-0845-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00011-015-0845-6

Keywords

Search

Navigation