Skip to main content

Advertisement

SpringerLink
Log in

Exploring the Role of Soluble Factors Associated with Immune Regulatory Properties of Mesenchymal Stem Cells

  • Published:
Stem Cell Reviews and Reports Aims and scope Submit manuscript

Abstract

Mesenchymal stem cells (MSCs) are characterized as multipotent stromal cells with the capacity for both self-renewal and differentiation into mesodermal cell lineages. MSCs also have a fibroblast-like phenotype and can be isolated from several tissues. In recent years, researchers have found that MSCs secrete several soluble factors that exert immunosuppressive effects by modulating both innate (macrophages, dendritic and NK cells) and adaptive (B cells and CD4+ and CD8+ T cells) immune responses. This review summarizes the principal trophic factors that are related to immune regulation and secreted by MSCs under both autoimmune and inflammatory conditions. The understanding of mechanisms that regulate immunity in MSCs field is important for their future use as a novel cellular-based immunotherapy with clinical applications in several 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

Similar content being viewed by others

References

  1. Luria, E. A., Panasyuk, A. F., & Friedenstein, A. Y. (1971). Fibroblast colony formation from monolayer cultures of blood cells. Transfusion, 11, 345–349.

    PubMed  CAS  Google Scholar 

  2. da Silva Meirelles, L., Chagastelles, P. C., & Nardi, N. B. (2006). Mesenchymal stem cells reside in virtually all post-natal organs and tissues. Journal of Cell Science, 119, 2204–2213.

    PubMed  Google Scholar 

  3. Kassem, M. (2004). Mesenchymal stem cells: Biological characteristics and potential clinical applications. Cloning and Stem Cells, 6, 369–374.

    PubMed  CAS  Google Scholar 

  4. Dominici, M., Le Blanc, K., Mueller, I., et al. (2006). Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy, 8, 315–317.

    PubMed  CAS  Google Scholar 

  5. Horwitz, E. M., Le Blanc, K., Dominici, M., et al. (2005). Clarification of the nomenclature for MSC: The international society for cellular therapy position statement. Cytotherapy, 7, 393–395.

    PubMed  CAS  Google Scholar 

  6. Si, Y. L., Zhao, Y. L., Hao, H. J., Fu, X. B., & Han, W. D. (2011). MSCs: Biological characteristics, clinical applications and their outstanding concerns. Ageing Research Reviews, 10, 93–103.

    PubMed  CAS  Google Scholar 

  7. Bassi, E. J., Aita, C. A., & Camara, N. O. (2011). Immune regulatory properties of multipotent mesenchymal stromal cells: Where do we stand? World Journal Stem Cells, 3, 1–8.

    Google Scholar 

  8. Secco, M., Zucconi, E., Vieira, N. M., et al. (2008). Mesenchymal stem cells from umbilical cord: do not discard the cord! Neuromuscular Disorders, 18, 17–18.

    PubMed  Google Scholar 

  9. Secco, M., Zucconi, E., Vieira, N. M., et al. (2008). Multipotent stem cells from umbilical cord: Cord is richer than blood! Stem Cells, 26, 146–150.

    PubMed  CAS  Google Scholar 

  10. Panepucci, R. A., Siufi, J. L., Silva, W. A., Jr., et al. (2004). Comparison of gene expression of umbilical cord vein and bone marrow-derived mesenchymal stem cells. Stem Cells, 22, 1263–1278.

    PubMed  CAS  Google Scholar 

  11. Wu, K. H., Zhou, B., Lu, S. H., et al. (2007). In vitro and in vivo differentiation of human umbilical cord derived stem cells into endothelial cells. Journal of Cellular Biochemistry, 100, 608–616.

    PubMed  CAS  Google Scholar 

  12. Ivanova-Todorova, E., Bochev, I., Mourdjeva, M., et al. (2009). Adipose tissue-derived mesenchymal stem cells are more potent suppressors of dendritic cells differentiation compared to bone marrow-derived mesenchymal stem cells. Immunology Letters, 126, 37–42.

    PubMed  CAS  Google Scholar 

  13. Jansen, B. J., Gilissen, C., Roelofs, H., et al. (2010). Functional differences between mesenchymal stem cell populations are reflected by their transcriptome. Stem Cells and Development, 19, 481–490.

    PubMed  CAS  Google Scholar 

  14. Devine, S. M., Cobbs, C., Jennings, M., Bartholomew, A., & Hoffman, R. (2003). Mesenchymal stem cells distribute to a wide range of tissues following systemic infusion into nonhuman primates. Blood, 101, 2999–3001.

    PubMed  CAS  Google Scholar 

  15. Le Blanc, K., Rasmusson, I., Gotherstrom, C., et al. (2004). Mesenchymal stem cells inhibit the expression of CD25 (interleukin-2 receptor) and CD38 on phytohaemagglutinin-activated lymphocytes. Scandinavian Journal of Immunology, 60, 307–315.

    PubMed  Google Scholar 

  16. Aggarwal, S., & Pittenger, M. F. (2005). Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood, 105, 1815–1822.

    PubMed  CAS  Google Scholar 

  17. Ghannam, S., Pene, J., Torcy-Moquet, G., Jorgensen, C., & Yssel, H. (2010). Mesenchymal stem cells inhibit human Th17 cell differentiation and function and induce a T regulatory cell phenotype. Journal of Immunology, 185, 302–312.

    CAS  Google Scholar 

  18. Hemdan, N. Y., Birkenmeier, G., Wichmann, G., et al. (2010). Interleukin-17-producing T helper cells in autoimmunity. Autoimmunity Reviews, 9, 785–792.

    PubMed  CAS  Google Scholar 

  19. Corcione, A., Benvenuto, F., Ferretti, E., et al. (2006). Human mesenchymal stem cells modulate B-cell functions. Blood, 107, 367–372.

    PubMed  CAS  Google Scholar 

  20. Tabera, S., Perez-Simon, J. A., Diez-Campelo, M., et al. (2008). The effect of mesenchymal stem cells on the viability, proliferation and differentiation of B-lymphocytes. Haematologica, 93, 1301–1309.

    PubMed  CAS  Google Scholar 

  21. Nauta, A. J., Kruisselbrink, A. B., Lurvink, E., Willemze, R., & Fibbe, W. E. (2006). Mesenchymal stem cells inhibit generation and function of both CD34+−derived and monocyte-derived dendritic cells. Journal of Immunology, 177, 2080–2087.

    CAS  Google Scholar 

  22. Khalil, N. (1999). TGF-beta: From latent to active. Microbes and Infection, 1, 1255–1263.

    PubMed  CAS  Google Scholar 

  23. Rehman, J., Traktuev, D., Li, J., et al. (2004). Secretion of angiogenic and antiapoptotic factors by human adipose stromal cells. Circulation, 109, 1292–1298.

    PubMed  Google Scholar 

  24. Tomic, S., Djokic, J., Vasilijic, S., et al. (2011). Immunomodulatory properties of mesenchymal stem cells derived from dental pulp and dental follicle are susceptible to activation by toll-like receptor agonists. Stem Cells and Development, 20, 695–708.

    PubMed  CAS  Google Scholar 

  25. English, K., Ryan, J. M., Tobin, L., Murphy, M. J., Barry, F. P., & Mahon, B. P. (2009). 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. Clinical and Experimental Immunology, 156, 149–160.

    PubMed  CAS  Google Scholar 

  26. Patel, S. A., Meyer, J. R., Greco, S. J., Corcoran, K. E., Bryan, M., & Rameshwar, P. (2010). Mesenchymal stem cells protect breast cancer cells through regulatory T cells: Role of mesenchymal stem cell-derived TGF-beta. Journal of Immunology, 184, 5885–5894.

    CAS  Google Scholar 

  27. Nemeth, K., Keane-Myers, A., Brown, J. M., et al. (2010). Bone marrow stromal cells use TGF-beta to suppress allergic responses in a mouse model of ragweed-induced asthma. Proceedings of the National Academy of Sciences of the United States of America, 107, 5652–5657.

    PubMed  CAS  Google Scholar 

  28. Nakamura, T. (1991). Structure and function of hepatocyte growth factor. Progress in Growth Factor Research, 3, 67–85.

    PubMed  CAS  Google Scholar 

  29. Segura-Flores, A. A., Galvez-Gastelum, F. J., Alvarez-Rodriguez, A., & Armendariz-Borunda, J. (2004). Hepatocyte growth factor (HGF) and its therapeutic applications. Revista de Gastroenterologia de Mexico, 69, 243–250.

    PubMed  Google Scholar 

  30. Di Nicola, M., Carlo-Stella, C., Magni, M., et al. (2002). Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood, 99, 3838–3843.

    PubMed  Google Scholar 

  31. Kang, J. W., Kang, K. S., Koo, H. C., Park, J. R., Choi, E. W., & Park, Y. H. (2008). Soluble factors-mediated immunomodulatory effects of canine adipose tissue-derived mesenchymal stem cells. Stem Cells and Development, 17, 681–693.

    PubMed  CAS  Google Scholar 

  32. Smith, W. L., Garavito, R. M., & DeWitt, D. L. (1996). Prostaglandin endoperoxide H synthases (cyclooxygenases)-1 and −2. Journal of Biological Chemistry, 271, 33157–33160.

    PubMed  CAS  Google Scholar 

  33. Harris, S. G., Padilla, J., Koumas, L., Ray, D., & Phipps, R. P. (2002). Prostaglandins as modulators of immunity. Trends in Immunology, 23, 144–150.

    PubMed  CAS  Google Scholar 

  34. Boniface, K., Bak-Jensen, K. S., Li, Y., et al. (2009). Prostaglandin E2 regulates Th17 cell differentiation and function through cyclic AMP and EP2/EP4 receptor signaling. The Journal of Experimental Medicine, 206, 535–548.

    PubMed  CAS  Google Scholar 

  35. Hilkens, C. M., Snijders, A., Snijdewint, F. G., Wierenga, E. A., & Kapsenberg, M. L. (1996). Modulation of T-cell cytokine secretion by accessory cell-derived products. The European Respiratory Journal. Supplement, 22, 90s–94s.

    PubMed  CAS  Google Scholar 

  36. Fedyk, E. R., Harris, S. G., Padilla, J., & Phipps, R. P. (1997). Prostaglandin receptors of the EP2 and EP4 subtypes regulate B lymphocyte activation and differentiation to IgE-secreting cells. Advances in Experimental Medicine and Biology, 433, 153–157.

    PubMed  CAS  Google Scholar 

  37. Harizi, H., Juzan, M., Grosset, C., Rashedi, M., & Gualde, N. (2001). Dendritic cells issued in vitro from bone marrow produce PGE(2) that contributes to the immunomodulation induced by antigen-presenting cells. Cellular Immunology, 209, 19–28.

    PubMed  CAS  Google Scholar 

  38. Kalinski, P., Hilkens, C. M., Snijders, A., Snijdewint, F. G., & Kapsenberg, M. L. (1997). Dendritic cells, obtained from peripheral blood precursors in the presence of PGE2, promote Th2 responses. Advances in Experimental Medicine and Biology, 417, 363–367.

    PubMed  CAS  Google Scholar 

  39. Kleiveland, C. R., Kassem, M., & Lea, T. (2008). Human mesenchymal stem cell proliferation is regulated by PGE2 through differential activation of cAMP-dependent protein kinase isoforms. Experimental Cell Research, 314, 1831–1838.

    PubMed  CAS  Google Scholar 

  40. English, K., Barry, F. P., Field-Corbett, C. P., & Mahon, B. P. (2007). IFN-gamma and TNF-alpha differentially regulate immunomodulation by murine mesenchymal stem cells. Immunology Letters, 110, 91–100.

    PubMed  CAS  Google Scholar 

  41. Chen, K., Wang, D., Du, W. T., et al. (2010). Human umbilical cord mesenchymal stem cells hUC-MSCs exert immunosuppressive activities through a PGE2-dependent mechanism. Clinical Immunology, 135, 448–458.

    PubMed  CAS  Google Scholar 

  42. Yanez, R., Oviedo, A., Aldea, M., Bueren, J. A., & Lamana, M. L. (2010). Prostaglandin E2 plays a key role in the immunosuppressive properties of adipose and bone marrow tissue-derived mesenchymal stromal cells. Experimental Cell Research, 316, 3109–3123.

    PubMed  CAS  Google Scholar 

  43. Cui, L., Yin, S., Liu, W., Li, N., Zhang, W., & Cao, Y. (2007). Expanded adipose-derived stem cells suppress mixed lymphocyte reaction by secretion of prostaglandin E2. Tissue Engineering, 13, 1185–1195.

    PubMed  CAS  Google Scholar 

  44. Najar, M., Raicevic, G., Boufker, H. I., et al. (2010). Mesenchymal stromal cells use PGE2 to modulate activation and proliferation of lymphocyte subsets: Combined comparison of adipose tissue, Wharton’s Jelly and bone marrow sources. Cellular Immunology, 264, 171–179.

    PubMed  CAS  Google Scholar 

  45. Spaggiari, G. M., Abdelrazik, H., Becchetti, F., & Moretta, L. (2009). MSCs inhibit monocyte-derived DC maturation and function by selectively interfering with the generation of immature DCs: Central role of MSC-derived prostaglandin E2. Blood, 113, 6576–6583.

    PubMed  CAS  Google Scholar 

  46. Nemeth, K., Leelahavanichkul, A., Yuen, P. S., et al. (2009). Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production. Nature Medicine, 15, 42–49.

    PubMed  CAS  Google Scholar 

  47. Yoshida, R., & Hayaishi, O. (1978). Induction of pulmonary indoleamine 2,3-dioxygenase by intraperitoneal injection of bacterial lipopolysaccharide. Proceedings of the National Academy of Sciences of the United States of America, 75, 3998–4000.

    PubMed  CAS  Google Scholar 

  48. Bianchi, M., Bertini, R., & Ghezzi, P. (1988). Induction of indoleamine dioxygenase by interferon in mice: A study with different recombinant interferons and various cytokines. Biochemical and Biophysical Research Communications, 152, 237–242.

    PubMed  CAS  Google Scholar 

  49. DelaRosa, O., Lombardo, E., Beraza, A., et al. (2009). Requirement of IFN-gamma-mediated indoleamine 2,3-dioxygenase expression in the modulation of lymphocyte proliferation by human adipose-derived stem cells. Tissue Engineering. Part A, 15, 2795–2806.

    PubMed  CAS  Google Scholar 

  50. Tipnis, S., Viswanathan, C., & Majumdar, A. S. (2010). Immunosuppressive properties of human umbilical cord-derived mesenchymal stem cells: role of B7-H1 and IDO. Immunology and Cell Biology, 88, 795–806.

    PubMed  Google Scholar 

  51. Ge, W., Jiang, J., Arp, J., Liu, W., Garcia, B., & Wang, H. (2010). Regulatory T-cell generation and kidney allograft tolerance induced by mesenchymal stem cells associated with indoleamine 2,3-dioxygenase expression. Transplantation, 90, 1312–1320.

    PubMed  CAS  Google Scholar 

  52. Knowles, R. G., & Moncada, S. (1994). Nitric oxide synthases in mammals. Biochemical Journal, 298(Pt 2), 249–258.

    PubMed  CAS  Google Scholar 

  53. Kleinert, H., Pautz, A., Linker, K., & Schwarz, P. M. (2004). Regulation of the expression of inducible nitric oxide synthase. European Journal of Pharmacology, 500, 255–266.

    PubMed  CAS  Google Scholar 

  54. Bingisser, R. M., Tilbrook, P. A., Holt, P. G., & Kees, U. R. (1998). Macrophage-derived nitric oxide regulates T cell activation via reversible disruption of the Jak3/STAT5 signaling pathway. Journal of Immunology, 160, 5729–5734.

    CAS  Google Scholar 

  55. Mais, A., Klein, T., Ullrich, V., Schudt, C., & Lauer, G. (2006). Prostanoid pattern and iNOS expression during chondrogenic differentiation of human mesenchymal stem cells. Journal of Cellular Biochemistry, 98, 798–809.

    PubMed  CAS  Google Scholar 

  56. Sato, K., Ozaki, K., Oh, I., et al. (2007). Nitric oxide plays a critical role in suppression of T-cell proliferation by mesenchymal stem cells. Blood, 109, 228–234.

    PubMed  CAS  Google Scholar 

  57. Oh, I., Ozaki, K., Sato, K., et al. (2007). Interferon-gamma and NF-kappaB mediate nitric oxide production by mesenchymal stromal cells. Biochemical and Biophysical Research Communications, 355, 956–962.

    PubMed  CAS  Google Scholar 

  58. Ren, G., Zhang, L., Zhao, X., et al. (2008). Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide. Cell Stem Cell, 2, 141–150.

    PubMed  CAS  Google Scholar 

  59. Ren, G., Su, J., Zhang, L., et al. (2009). Species variation in the mechanisms of mesenchymal stem cell-mediated immunosuppression. Stem Cells, 27, 1954–1962.

    PubMed  CAS  Google Scholar 

  60. Ryter, S. W., & Choi, A. M. (2010). Heme oxygenase-1/carbon monoxide: novel therapeutic strategies in critical care medicine. Current Drug Targets, 11, 1485–1494.

    PubMed  CAS  Google Scholar 

  61. Blancou, P., Tardif, V., Simon, T., et al. (2011). Immunoregulatory properties of heme oxygenase-1. Methods in Molecular Biology, 677, 247–268.

    PubMed  CAS  Google Scholar 

  62. Chabannes, D., Hill, M., Merieau, E., et al. (2007). A role for heme oxygenase-1 in the immunosuppressive effect of adult rat and human mesenchymal stem cells. Blood, 110, 3691–3694.

    PubMed  CAS  Google Scholar 

  63. Zarjou, A., Kim, J., Traylor, A. M., et al. (2011). Paracrine effects of mesenchymal stem cells in cisplatin-induced renal injury require heme oxygenase-1. American Journal of Physiology. Renal Physiology, 300, F254–F262.

    PubMed  CAS  Google Scholar 

  64. Fiorentino, D. F., Bond, M. W., & Mosmann, T. R. (1989). Two types of mouse T helper cell. IV. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones. Journal of Experimental Medicine, 170, 2081–2095.

    PubMed  CAS  Google Scholar 

  65. Bogdan, C., Vodovotz, Y., & Nathan, C. (1991). Macrophage deactivation by interleukin 10. The Journal of Experimental Medicine, 174, 1549–1555.

    PubMed  CAS  Google Scholar 

  66. Fiorentino, D. F., Zlotnik, A., Mosmann, T. R., Howard, M., & O’Garra, A. (1991). IL-10 inhibits cytokine production by activated macrophages. Journal of Immunology, 147, 3815–3822.

    CAS  Google Scholar 

  67. Moore, K. W., de Waal Malefyt, R., Coffman, R. L., & O’Garra, A. (2001). Interleukin-10 and the interleukin-10 receptor. Annual Review of Immunology, 19, 683–765.

    PubMed  CAS  Google Scholar 

  68. Burdin, N., Van Kooten, C., Galibert, L., et al. (1995). Endogenous IL-6 and IL-10 contribute to the differentiation of CD40-activated human B lymphocytes. Journal of Immunology, 154, 2533–2544.

    CAS  Google Scholar 

  69. Macatonia, S. E., Doherty, T. M., Knight, S. C., & O’Garra, A. (1993). Differential effect of IL-10 on dendritic cell-induced T cell proliferation and IFN-gamma production. Journal of Immunology, 150, 3755–3765.

    CAS  Google Scholar 

  70. Hedrich, C. M., & Bream, J. H. (2010). Cell type-specific regulation of IL-10 expression in inflammation and disease. Immunologic Research, 47, 185–206.

    PubMed  CAS  Google Scholar 

  71. Yang, S. H., Park, M. J., Yoon, I. H., et al. (2009). Soluble mediators from mesenchymal stem cells suppress T cell proliferation by inducing IL-10. Experimental & Molecular Medicine, 41, 315–324.

    CAS  Google Scholar 

  72. Rasmusson, I., Ringden, O., Sundberg, B., & Le Blanc, K. (2005). Mesenchymal stem cells inhibit lymphocyte proliferation by mitogens and alloantigens by different mechanisms. Experimental Cell Research, 305, 33–41.

    PubMed  CAS  Google Scholar 

  73. Nasef, A., Chapel, A., Mazurier, C., et al. (2007). Identification of IL-10 and TGF-beta transcripts involved in the inhibition of T-lymphocyte proliferation during cell contact with human mesenchymal stem cells. Gene Expression, 13, 217–226.

    PubMed  Google Scholar 

  74. Burchfield, J. S., Iwasaki, M., Koyanagi, M., et al. (2008). Interleukin-10 from transplanted bone marrow mononuclear cells contributes to cardiac protection after myocardial infarction. Circulation Research, 103, 203–211.

    PubMed  CAS  Google Scholar 

  75. Razmkhah, M., Jaberipour, M., Erfani, N., Habibagahi, M., Talei, A. R., Ghaderi, A. Adipose derived stem cells (ASCs) isolated from breast cancer tissue express IL-4, IL-10 and TGF-beta1 and upregulate expression of regulatory molecules on T cells: Do they protect breast cancer cells from the immune response? Cell Immunol, 266, 116–122.

  76. Kishimoto, T. (2006). Interleukin-6: Discovery of a pleiotropic cytokine. Arthritis Research and Therapy, 8(Suppl 2), S2.

    PubMed  Google Scholar 

  77. Gabay, C. (2006). Interleukin-6 and chronic inflammation. Arthritis Research and Therapy, 8(Suppl 2), S3.

    PubMed  Google Scholar 

  78. Djouad, F., Charbonnier, L. M., Bouffi, C., et al. (2007). Mesenchymal stem cells inhibit the differentiation of dendritic cells through an interleukin-6-dependent mechanism. Stem Cells, 25, 2025–2032.

    PubMed  CAS  Google Scholar 

  79. Najar, M., Rouas, R., Raicevic, G., et al. (2009). Mesenchymal stromal cells promote or suppress the proliferation of T lymphocytes from cord blood and peripheral blood: The importance of low cell ratio and role of interleukin-6. Cytotherapy, 11, 570–583.

    PubMed  CAS  Google Scholar 

  80. Xu, G., Zhang, Y., Zhang, L., Ren, G., & Shi, Y. (2007). The role of IL-6 in inhibition of lymphocyte apoptosis by mesenchymal stem cells. Biochemical and Biophysical Research Communications, 361, 745–750.

    PubMed  CAS  Google Scholar 

  81. Guo, Z., Zheng, C., Chen, Z., et al. (2009). Fetal BM-derived mesenchymal stem cells promote the expansion of human Th17 cells, but inhibit the production of Th1 cells. European Journal of Immunology, 39, 2840–2849.

    PubMed  CAS  Google Scholar 

  82. Chen, B., Hu, J., Liao, L., et al. (2010). Flk-1+ mesenchymal stem cells aggravate collagen-induced arthritis by up-regulating interleukin-6. Clinical and Experimental Immunology, 159, 292–302.

    PubMed  CAS  Google Scholar 

  83. Liu, X. J., Zhang, J. F., Sun, B., et al. (2009). Reciprocal effect of mesenchymal stem cell on experimental autoimmune encephalomyelitis is mediated by transforming growth factor-beta and interleukin-6. Clinical and Experimental Immunology, 158, 37–44.

    PubMed  CAS  Google Scholar 

  84. Bai, L., Lennon, D. P., Eaton, V., et al. (2009). Human bone marrow-derived mesenchymal stem cells induce Th2-polarized immune response and promote endogenous repair in animal models of multiple sclerosis. Glia, 57, 1192–1203.

    PubMed  Google Scholar 

  85. Malemud, C. J. (2006). Matrix metalloproteinases (MMPs) in health and disease: An overview. Frontiers in Bioscience, 11, 1696–1701.

    PubMed  CAS  Google Scholar 

  86. Parks, W. C., Wilson, C. L., & Lopez-Boado, Y. S. (2004). Matrix metalloproteinases as modulators of inflammation and innate immunity. Nature Reviews Immunology, 4, 617–629.

    PubMed  CAS  Google Scholar 

  87. Ito, A., Mukaiyama, A., Itoh, Y., et al. (1996). Degradation of interleukin 1beta by matrix metalloproteinases. Journal of Biological Chemistry, 271, 14657–14660.

    PubMed  CAS  Google Scholar 

  88. McQuibban, G. A., Gong, J. H., Tam, E. M., McCulloch, C. A., Clark-Lewis, I., & Overall, C. M. (2000). Inflammation dampened by gelatinase A cleavage of monocyte chemoattractant protein-3. Science, 289, 1202–1206.

    PubMed  CAS  Google Scholar 

  89. Itoh, T., Matsuda, H., Tanioka, M., Kuwabara, K., Itohara, S., & Suzuki, R. (2002). The role of matrix metalloproteinase-2 and matrix metalloproteinase-9 in antibody-induced arthritis. Journal of Immunology, 169, 2643–2647.

    CAS  Google Scholar 

  90. Ding, Y., Xu, D., Feng, G., Bushell, A., Muschel, R. J., & Wood, K. J. (2009). Mesenchymal stem cells prevent the rejection of fully allogenic islet grafts by the immunosuppressive activity of matrix metalloproteinase-2 and −9. Diabetes, 58, 1797–1806.

    PubMed  CAS  Google Scholar 

  91. Shen, Y., Winkler, I. G., Barbier, V., Sims, N. A., Hendy, J., & Levesque, J. P. (2010). Tissue inhibitor of metalloproteinase-3 (TIMP-3) regulates hematopoiesis and bone formation in vivo. PloS One, 5, e13086. doi:10.1371/journal.pone.0013086.

    PubMed  Google Scholar 

  92. Lozito, T. P., & Tuan, R. S. (2011). Mesenchymal stem cells inhibit both endogenous and exogenous MMPs via secreted TIMPs. Journal of Cellular Physiology, 226, 385–396.

    PubMed  CAS  Google Scholar 

  93. Tondreau, T., Meuleman, N., Stamatopoulos, B., et al. (2009). In vitro study of matrix metalloproteinase/tissue inhibitor of metalloproteinase production by mesenchymal stromal cells in response to inflammatory cytokines: the role of their migration in injured tissues. Cytotherapy, 11, 559–569.

    PubMed  CAS  Google Scholar 

  94. Ries, C., Egea, V., Karow, M., Kolb, H., Jochum, M., & Neth, P. (2007). MMP-2, MT1-MMP, and TIMP-2 are essential for the invasive capacity of human mesenchymal stem cells: differential regulation by inflammatory cytokines. Blood, 109, 4055–4063.

    PubMed  CAS  Google Scholar 

  95. Shu, T., Zeng, B., Ren, X., & Li, Y. (2010). HO-1 modified mesenchymal stem cells modulate MMPs/TIMPs system and adverse remodeling in infarcted myocardium. Tissue & Cell, 42, 217–222.

    CAS  Google Scholar 

  96. Carosella, E. D., HoWangYin, K. Y., Favier, B., & LeMaoult, J. (2008). HLA-G-dependent suppressor cells: Diverse by nature, function, and significance. Human Immunology, 69, 700–707.

    PubMed  CAS  Google Scholar 

  97. Fainardi, E., Castellazzi, M., Stignani, M., et al. (2011). Emerging topics and new perspectives on HLA-G. Cellular and Molecular Life Sciences, 68, 433–451.

    PubMed  CAS  Google Scholar 

  98. Rouas-Freiss, N., Goncalves, R. M., Menier, C., Dausset, J., & Carosella, E. D. (1997). Direct evidence to support the role of HLA-G in protecting the fetus from maternal uterine natural killer cytolysis. Proceedings of the National Academy of Sciences of the United States of America, 94, 11520–11525.

    PubMed  CAS  Google Scholar 

  99. Lila, N., Amrein, C., Guillemain, R., et al. (2002). Human leukocyte antigen-G expression after heart transplantation is associated with a reduced incidence of rejection. Circulation, 105, 1949–1954.

    PubMed  Google Scholar 

  100. LeMaoult, J., Zafaranloo, K., Le Danff, C., & Carosella, E. D. (2005). HLA-G up-regulates ILT2, ILT3, ILT4, and KIR2DL4 in antigen presenting cells, NK cells, and T cells. The FASEB Journal, 19, 662–664.

    CAS  Google Scholar 

  101. Selmani, Z., Naji, A., Zidi, I., et al. (2008). Human leukocyte antigen-G5 secretion by human mesenchymal stem cells is required to suppress T lymphocyte and natural killer function and to induce CD4+CD25highFOXP3+ regulatory T cells. Stem Cells, 26, 212–222.

    PubMed  CAS  Google Scholar 

  102. Davis, D. M. (2007). Intercellular transfer of cell-surface proteins is common and can affect many stages of an immune response. Nature Reviews Immunology, 7, 238–243.

    PubMed  CAS  Google Scholar 

  103. Deshmane, S. L., Kremlev, S., Amini, S., & Sawaya, B. E. (2009). Monocyte chemoattractant protein-1 (MCP-1): An overview. Journal of Interferon & Cytokine Research, 29, 313–326.

    CAS  Google Scholar 

  104. Rafei, M., Hsieh, J., Fortier, S., et al. (2008). Mesenchymal stromal cell-derived CCL2 suppresses plasma cell immunoglobulin production via STAT3 inactivation and PAX5 induction. Blood, 112, 4991–4998.

    PubMed  CAS  Google Scholar 

  105. Luther, S. A., & Cyster, J. G. (2001). Chemokines as regulators of T cell differentiation. Nature Immunology, 2, 102–107.

    PubMed  CAS  Google Scholar 

  106. Meirelles Lda, S., Fontes, A. M., Covas, D. T., & Caplan, A. I. (2009). Mechanisms involved in the therapeutic properties of mesenchymal stem cells. Cytokine & Growth Factor Reviews, 20, 419–427.

    Google Scholar 

  107. Rafei, M., Campeau, P. M., Aguilar-Mahecha, A., et al. (2009). Mesenchymal stromal cells ameliorate experimental autoimmune encephalomyelitis by inhibiting CD4 Th17 T cells in a CC chemokine ligand 2-dependent manner. Journal of Immunology, 182, 5994–6002.

    CAS  Google Scholar 

  108. Karnoub, A. E., Dash, A. B., Vo, A. P., et al. (2007). Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature, 449, 557–563.

    PubMed  CAS  Google Scholar 

  109. Pinilla, S., Alt, E., Abdul Khalek, F. J., et al. (2009). Tissue resident stem cells produce CCL5 under the influence of cancer cells and thereby promote breast cancer cell invasion. Cancer Letters, 284, 80–85.

    PubMed  CAS  Google Scholar 

  110. Soria, G., & Ben-Baruch, A. (2008). The inflammatory chemokines CCL2 and CCL5 in breast cancer. Cancer Letters, 267, 271–285.

    PubMed  CAS  Google Scholar 

  111. Aghajanova, L. (2004). Leukemia inhibitory factor and human embryo implantation. Annals of the New York Academy of Sciences, 1034, 176–183.

    PubMed  CAS  Google Scholar 

  112. Metcalf, D. (2003). The unsolved enigmas of leukemia inhibitory factor. Stem Cells, 21, 5–14.

    PubMed  CAS  Google Scholar 

  113. Nasef, A., Mazurier, C., Bouchet, S., et al. (2008). Leukemia inhibitory factor: Role in human mesenchymal stem cells mediated immunosuppression. Cellular Immunology, 253, 16–22.

    PubMed  CAS  Google Scholar 

  114. Najar, M., Raicevic, G., Boufker, H. I., et al. (2010). Adipose-tissue-derived and Wharton’s jelly-derived mesenchymal stromal cells suppress lymphocyte responses by secreting leukemia inhibitory factor. Tissue Engineering. Part A, 16, 3537–3546.

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by grants 08/55447-1, 09/51649-1, 10/12295-7, 10/16213-5 and 07/07139-3 from the State of Sao Paulo Foundation for Research Support (FAPESP), Brazilian Council of Scientific and Technologic Development (470533/2007-2, CNPq/DECIT/MS) and Complex Fluids INCT.

Conflicts of interest

The authors declare no potential conflicts of interest

Author information

Authors and Affiliations

  1. Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences IV, Universidade de São Paulo-USP, 05508-000, São Paulo, Brazil

    Ênio José Bassi, Pedro Manoel Mendes Moraes-Vieira & Niels Olsen Saraiva Câmara

  2. Nephrology Division, Medicine Department, Universidade Federal de São Paulo-UNIFESP, 04039-000, São Paulo, SP, Brazil

    Danilo Candido de Almeida

  3. Department of Immunology, Institute of Biomedical Sciences IV, University of São Paulo, Av. Prof. Lineu Prestes, 1730, 05508-000, São Paulo, SP, Brazil

    Niels Olsen Saraiva Câmara

Authors
  1. Ênio José Bassi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Danilo Candido de Almeida
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pedro Manoel Mendes Moraes-Vieira
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Niels Olsen Saraiva Câmara
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Niels Olsen Saraiva Câmara.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bassi, Ê.J., de Almeida, D.C., Moraes-Vieira, P.M.M. et al. Exploring the Role of Soluble Factors Associated with Immune Regulatory Properties of Mesenchymal Stem Cells. Stem Cell Rev and Rep 8, 329–342 (2012). https://doi.org/10.1007/s12015-011-9311-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12015-011-9311-1

Keywords

Search

Navigation