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Human MMSC immunosuppressive activity at low oxygen tension: Direct cell-to-cell contacts and paracrine regulation

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Abstract

In recent years, multipotent mesenchymal stromal (stem) cells (MMSCs) were identified and isolated from many tissues and their immunoprivilege and immunosuppressive potential, along with high proliferative activity and multilineage differentiation, have been demonstrated. At the same time, there is an increasing body of evidence of the MMSC plasticity due to a wide range of microenvironmental factors: extracellular matrix, cell-to-cell interactions, oxygen tension, etc. In this study, direct cell-to-cell and paracrine effects of MMSCs on human phytohemagglutinin (PHA)-activated peripheral blood mononuclear cells (MNCs) at the standard (20%) and reduced (5%) O2 concentrations in the culture medium have been compared. It has been shown that coculture with MMSCs decreases the proliferative activity of PHA-MNCs, the proportion of HLA-DR+ T cells, and the interleukin (IL)-6, IL-8, and tumor necrosis factor α (TNF-α) concentrations, and increases the IL-10 and interferon γ (IFN-γ) in the medium. A potentiating effect of low oxygen tension on the immunomodulating properties of MMSCs has been observed, which is of great importance to enchance immunosuppression.

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References

  1. Grayson, W.L., Zhao, F., Bunnell, B., and Ma, T., Hypoxia Enhances Proliferation and Tissue Formation of Human Mesenchymal Stem Cells, Biochem. Biophys. Res. Commun., 2007, vol. 358, no. 3, p. 948.

    Article  PubMed  CAS  Google Scholar 

  2. Buravkova, L.B., Grinakovskaya, O.S., Andreeva, E.R., et al., Characteristics of Human Lipoaspirate-isolated Mesenchymal Stromal Cells Cultivated under a Lower Oxygen Tension, Tsitologiia, 2009, vol. 51, no. 1, p. 5.

    PubMed  CAS  Google Scholar 

  3. Grinakovskaya, O.S., Andreeva, E.R., Buravkova, L.B., et al., Low Level of O(2) Inhibits Commitment of Cultured Mesenchymal Stromal Precursor Cells from the Adipose Tissue in Response to Osteogenic Stimuli, Bull. Exp. Biol. Med., 2009, vol. 147, no. 6, p. 704.

    Article  Google Scholar 

  4. Rylova, Yu.V., Andreeva, E.R., and Buravkova, L.B., Proliferation and Metabolic State of Adipose Mesenchymal Stromal Cells at Different Oxygen Level in the Culture Medium, Kosm. Biol. Aviakosm. Med., 2010, vol. 44, no. 5, p. 38.

    Google Scholar 

  5. Wang, D.W., Fermor, B., Gimble, J.M., et al., Influence of Oxygen on the Proliferation and Metabolism of Adipose Derived Adult Stem Cells, J. Cell Physiol., 2005, vol. 204, no. 1, p. 184.

    Article  PubMed  CAS  Google Scholar 

  6. Khan, W.S., Adesida, A.B., Tew, S.R., et al., Bone Marrow-Derived Mesenchymal Stem Cells Express the Pericyte Marker 3G5 in Culture and Show Enhanced Chondrogenesis in Hypoxic Conditions, J. Orthop. Res., 2010, vol. 28, no. 6, p. 834.

    PubMed  CAS  Google Scholar 

  7. D’Ippolito, G.D., Diabira, S., and Howard, G.A., Low Oxygen Tension Inhibits Osteogenic Differentiation and Enhances Stemness of Human MIAMI Cells, Bone, 2006, vol. 39, p. 513.

    Article  PubMed  Google Scholar 

  8. Malladi, P., Xu, Y., Chiou, M., et al., Effect of Reduced Oxygen Tension on Chondrogenesis and Osteogenesis in Adipose-Derived Mesenchymal Cells, Am. J. Physiol. Cell Physiol., 2006, vol. 290, no. 4, p. 1139.

    Article  Google Scholar 

  9. Fehrer, C., Brunauer, R., Laschober, G., et al., Reduced Oxygen Tension Attenuates Differentiation Capacity of Human Mesenchymal Stem Cells and Prolongs Their Lifespan, Aging Cell, 2007, vol. 6, no. 6, p. 745.

    Article  PubMed  CAS  Google Scholar 

  10. Iida, K., Takeda-Kawaguchi, T., Tezuka, Y., et al., Hypoxia Enhances Colony Formation and Proliferation But Inhibits Differentiation of Human Dental Pulp Cells, Arch. Oral Biology, 2010, vol. 55, no. 9, p. 648.

    Article  CAS  Google Scholar 

  11. Valorani, M.G., Germani, A., Otto, W.R., et al., Hypoxia Increases Sca-1/CD44 Co-Expression in Murine Mesenchymal Stem Cells and Enhances Their Adipogenic Differentiation Potential, Cell Tissue Res., 2010, vol. 341, no. 1, p. 111.

    Article  PubMed  CAS  Google Scholar 

  12. Nekanti, U., Dastidar, S., Venugopal, P., et al., Increased Proliferation and Analysis of Differential Gene Expression in Human Wharton’s Jelly-Derived Mesenchymal Stromal Cells Under Hypoxia, Cell, 2010, vol. 6, no. 5, p. 499.

    CAS  Google Scholar 

  13. Lavrentieva, A., Majore, I., Kasper, C., and Hass, R., Effects of Hypoxic Culture Conditions on Umbilical Cord-Derived Human Mesenchymal Stem Cells, Cell Commun. Signal., 2010, vol. 8, p. 18.

    Article  PubMed  Google Scholar 

  14. Sergeev, V.S., Immunological Properties of Stromal (Mesenchymal) Stem Cells, Klet. Tekhnol. Biol. Med., 2005, vol. 2, p. 39.

    Google Scholar 

  15. Uccelli, A., Moretta, L., and Pistoia, V., Immunoregulatory Function of Mesenchymal Stem Cells, Eur. J. Immunol., 2006, vol. 36, no. 10, p. 2566.

    Article  PubMed  CAS  Google Scholar 

  16. Nauta, A.J. and Fibbe, W.E., Immunomodulatory Properties of Mesenchymal Stromal Cells, Blood, 2007, vol. 110, p. 3499.

    Article  PubMed  CAS  Google Scholar 

  17. Jones, B.J. and McTaggart, J., Immunosuppression by Mesenchymal Stromal Cells: From Culture to Clinic, Exp. Hematol., 2008, vol. 36, p. 733.

    Article  PubMed  CAS  Google Scholar 

  18. Bartholomew, A., Sturgeon, C., Siatskas, M., et al., Mesenchymal Stem Cells Suppress Lymphocyte Proliferation In Vitro and Prolong Skin Graft Survival In Vivo, Exp. Hematol., 2002, vol. 30, p. 42.

    Article  PubMed  Google Scholar 

  19. Le Blanc, K., Rasmusson, I., Götherström, C., et al., Mesenchymal Stem Cells Inhibit the Expression of CD25 (Interleukin-2 Receptor) and CD38 on Phytohaemagglutinin-Activated Lymphocytes, Scand. J. Immunol., 2004, vol. 60, p. 307

    Article  PubMed  Google Scholar 

  20. Suva, D., Passweg, J., Arnaudeau, S., et al., In Vitro Activated Human T Lymphocytes Very Efficiently Attach to Allogeneic Multipotent Mesenchymal Stromal Cells and Transmigrate Under Them, J. Cell Physiol., 2008, vol. 214, no. 3, p. 588.

    Article  PubMed  CAS  Google Scholar 

  21. Jarvinen, L., Badri, L., Wettlaufer, S., et al., Lung Resident Mesenchymal Stem Cells Isolated from Human Lung Allografts Inhibit T Cell Proliferation Via a Soluble Mediator, J. Immunol., 2008, vol. 181, no. 6, p. 4389.

    PubMed  CAS  Google Scholar 

  22. Gornostaeva, A.N., Andreeva, E.R., Andrianova, I.V., and Buravkova, L.B., Immunosuppressive Effects of Multipotent Mesenchymal Stromal Cells in Cultures with Different O2 Level in the Medium, Bull. Exp. Biol. Med., 2011, vol. 2, p. 92.

    Google Scholar 

  23. Buravkova, L.B., Grigor’eva, O.V., Andreeva, E.R., et al., Subpopulation Composition and Activation of T lymphocytes during Coculturing with Mesenchymal Stromal Cells in Medium with Different O(2) Content, Bull. Exp. Biol. Med., 2011, vol. 151, no. 3, p. 319.

    Article  Google Scholar 

  24. Kronsteiner, B., Wolbank, S., Peterbauer, A., et al., Human Mesenchymal Stem Cells from Adipose Tissue and Amnion Influence T-Cells Depending on Stimulation Method and Presence of Other Immune Cells, Stem. Cells Dev., 2011, vol. 20, no. 12, p. 2115.

    Article  PubMed  CAS  Google Scholar 

  25. Aggarwal, S. and Pittenger, M., Human Mesenchymal Stem Cells Modulate Allogeneic Immune Cell Responses, Blood, 2005, vol. 105, p. 1815.

    Article  PubMed  CAS  Google Scholar 

  26. Spaggiari, G.M., Abdelrazik, H., Becchetti, F., and Moretta, L., 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, 2009, vol. 113, no. 26, p. 6576.

    Article  PubMed  CAS  Google Scholar 

  27. Di Nicola, M., Carlo-Stella, C., Magni, M., et al., Human Bone Marrow Stromal Cells Suppress T-Lymphocyte Proliferation Induced by Cellular or Nonspecific Mitogenic Stimuli, Blood, 2002, vol. 99, p. 3838.

    Article  PubMed  Google Scholar 

  28. Krampera, M., Cosmi, L., Angeli, R., et al., Role for Interferon-Gamma in the Immunomodulatory Activity of Human Bone Marrow Mesenchymal Stem Cells, Stem Cells, 2006, vol. 24, p. 386.

    Article  PubMed  CAS  Google Scholar 

  29. Puissant, B., Barreau, C., Bourin, P., et al., Immunomodulatory Effect of Human Adipose Tissue-Derived Adult Stem Cells: Comparison with Bone Marrow Mesenchymal Stem Cells, Brit. J. Haematol., 2005, vol. 129, p. 118.

    Article  Google Scholar 

  30. Li, PiraG., Ivaldi, F., Bottone, L.N., et al., Human Bone Marrow Stromal Cells Hamper Specific Interactions of CD4 and CD8 T Lymphocytes with Antigen-Presenting Cells, Hum. Immunol., 2006, vol. 67, no. 2, p. 976.

    Article  Google Scholar 

  31. Quaedackers, M.E., Baan, C.C., Weimar, W., and Hoogduijn, M.J., Cell Contact Interaction Between Adipose-Derived Stromal Cells and Allo-Activated T Lymphocytes, Eur. J. Immunol., 2009, vol. 39, no. 12, p. 3436.

    Article  PubMed  CAS  Google Scholar 

  32. Andreeva, E.R., Gornostaeva, A.N., Andrianova, E.V., et al., Morphological Characteristics of the Interaction between Immune and Multipotent Mesenchymal Stromal Cells In Vitro, in Stvolovye kletki i regenerativnaya meditsina (Stem Cells and Regenerative Medicine), Tkachuk, V.A, Ed., Moscow: Maks Press, 2011, p. 131.

    Google Scholar 

  33. Zuk, P.A., Zhu, M., Mizuno, H., et al., Multilineage Cells from Human Adipose Tissue: Implications for Cell-Based Therapies, Tissue Eng., 2001, vol. 7, no. 2, p. 211.

    Article  PubMed  CAS  Google Scholar 

  34. Parish, C.R., Fluorescent Dyes for Lymphocyte Migration and Proliferation Studies, Immunol. Cell Biol., 1999, vol. 77, no. 6, p. 499.

    Article  PubMed  CAS  Google Scholar 

  35. Dominici, M., Le Blanc, K., Mueller, I., et al., Minimal Criteria for Defining Multipotent Mesenchymal Stromal Cells. The International Society for Cellular Therapy Position Statement, Cytotherapy, 2006, vol. 8, no. 4, p. 315.

    Article  PubMed  CAS  Google Scholar 

  36. Krieger, J.A., Landsiedel, J.C., and Lawrence, D.A., Differential In Vitro Effects of Physiological and Atmospheric Oxygen Tension on Normal Human Peripheral Blood Mononuclear Cell Proliferation, Cytokine and Immunoglobulin Production, Int. J. Immunopharmacol., 1996, vol. 8, no. 10, p. 545.

    Article  Google Scholar 

  37. Najar, M., Rouas, R., Raicevic, G., et al., 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, 2009, vol. 11, no. 5, p. 570.

    Article  PubMed  CAS  Google Scholar 

  38. Saldanha-Araujo, F., Haddad, R., Farias, K.C., et al., Mesenchymal Stem Cells Promote the Sustained Expression of CD69 on Activated T Lymphocytes: Roles of Canonical and Non-Canonical NF-κB Signaling, J. Cell. Mol. Med., 2012, vol. 16, no. 6, p. 1232.

    Article  PubMed  CAS  Google Scholar 

  39. Le Blanc, K., Tammik, C., Rosendahl, K., et al., HLA Expression and Immunologic Properties of Differentiated and Undifferentiated Mesenchymal Stem Cells, Exp. Hematol., 2003, vol. 31, p. 890.

    Article  PubMed  Google Scholar 

  40. Gotherstrom, C., Immunomodulation by Multipotent Mesenchymal Stromal Cells, Transplantation, 2007, vol. 84, p. 35.

    Article  Google Scholar 

  41. Rasmusson, I., Ringden, O., Sundberg, B., and Le Blanc, K., Mesenchymal Stem Cells Inhibit Lymphocyte Proliferation by Mitogens and Alloantigens by Different Mechanisms, Exp. Cell Res., 2005, vol. 305, p. 33.

    Article  PubMed  CAS  Google Scholar 

  42. Ramasamy, R., Tong, C.K., Seow, H.F., et al., The Immunosuppressive Effects of Human Bone Marrow-Derived Mesenchymal Stem Cells Target T Cell Proliferation But Not Its Effector Function, Cell Immunol., 2008, vol. 251, no. 2, p. 31.

    Article  Google Scholar 

  43. Prevosto, C., Zancolli, M., Canevali, P., et al., Generation of CD4+ or CD8+ Regulatory T Cells upon Mesenchymal Stem Cell-Lymphocyte Interaction, Haematologica, 2007, vol. 92, no. 7, p. 881.

    Article  PubMed  CAS  Google Scholar 

  44. Sotiropoulou, P.A., Perez, S.A., Gritzapis, A.D., et al., Interactions between Human Mesenchymal Stem Cells and Natural Killer Cells, Stem Cells, 2006, vol. 24, p. 74.

    Article  PubMed  Google Scholar 

  45. Crop, M., Baan, C.C., Korevaar, S.S., et al., Human Adipose Tissue-Derived Mesenchymal Stem Cells Induce Explosive T-Cell Proliferation, Stem Cells Dev., vol. 19(2), 2010, p. 19.

    Article  Google Scholar 

  46. Groh, M.E., Maitra, B., Szekely, E., and Koc, O.N., Human Mesenchymal Stem Cells Require Monocyte-Mediated Activation to Suppress Alloreactive T Cells, Exp. Hematol., 2005, vol. 33, p. 928.

    Article  PubMed  CAS  Google Scholar 

  47. Cappellesso-Fleury, S., Puissant-Lubrano, B., Apoil, P.A., et al., Human Fibroblasts Share Immunosuppressive Properties with Bone Marrow Mesenchymal Stem Cells, J. Clin. Immunol., 2010, vol. 30, no. 4, p. 607.

    Article  PubMed  Google Scholar 

  48. Glennie, S., Soeiro, I., Dyson, P.J., et al., Bone Marrow Mesenchymal Stem Cells Induce Division Arrest Anergy of Activated T Cells, Blood, 2005, vol. 105, p. 2821.

    Article  PubMed  CAS  Google Scholar 

  49. Kazuya, S., Katsutoshi, O., Iekuni, O., et al., Nitric Oxide Plays a Critical Role in Suppression of T-Cell Proliferation by Mesenchymal Stem Cells, Blood, 2007, vol. 109, p. 228.

    Article  Google Scholar 

  50. Uccelli, A., Moretta, L., and Pistoia, V., Immunoregulatory Function of Mesenchymal Stem Cells, Eur. J. Immunol., 2006, vol. 36, no. 10, p. 2566.

    Article  PubMed  CAS  Google Scholar 

  51. Buravkova, L.B. and Andreeva, E.R., Interaction of Human Mesenhymal Stromal with Immune Cells, Hum. Physiol., 2010, vol. 36, no. 5, p. 590.

    Article  CAS  Google Scholar 

  52. Jones, B.J., Brooke, G., Atkinson, K., and McTaggart, S.J., Immunosuppression by Placental Indoleamine 2.3-Dioxygenase: a Role for Mesenchymal Stem Cells, Placenta, 2007, vol. 28, p. 1174.

    Article  PubMed  CAS  Google Scholar 

  53. Meisel, R., Zibert, A., Laryea, M., et al., Human Bone Marow Stromal Cells Inhibit Allogeneic T-Cell Responses by Indoleamine 2.3-Dioxygenase-Mediated Tryptophan Degradation, Blood, 2004, vol. 103, p. 4619.

    Article  PubMed  CAS  Google Scholar 

  54. Ryan, J.M., Barry, F., Murphy, J.M., and Mahon, B.P., Interferon-Gamma Does not Break, but Promotes the Immunosuppressive Capacity of Adult Human Mesenchymal Stem Cells, Clin. Exp. Immunol., 2007, vol. 149, p. 353.

    CAS  Google Scholar 

  55. Yang, S.H., Park, M.J., Yoon, I.H., et al., Soluble Mediators from Mesenchymal Stem Cells Suppress T Cell Proliferation by Inducing IL-10, Exp. Mol. Med., 2009, vol. 41, no. 5, p. 315.

    Article  PubMed  CAS  Google Scholar 

  56. Nasef, A., Mathieu, N., Chapel, A., et al., Immunosuppressive Effects of Mesenchymal Stem Cells: Involvement of HLA-G, Transplantation, 2007, vol. 84, p. 231.

    Article  PubMed  CAS  Google Scholar 

  57. Kavanagh, H. and Mahon, B.P., Allogeneic Mesenchymal Stem Cells Prevent Allergic Airway Inflammation by Inducing Murine Regulatory T Cells, Allergy, 2011, vol. 66, p. 523.

    Article  PubMed  CAS  Google Scholar 

  58. Engela A.U., Baan C.C., Dor F.J. et al., On the Interaction between Mesenchymal Stem Cells and Regulatory T Cells for Immunomodulation in Transplantation, Front. Immunol., 2012, vol. 3, p. 126.

    Article  PubMed  Google Scholar 

  59. Hegyi, B., Kudlik, G., Monostori, E., and Uher, F., Activated T-Cells and Pro-Inflammatory Cytokines Differentially Regulate Prostaglandin E2 Secretion by Mesenchymal Stem Cells, Biochem. Biophys. Res. Commun., 2012, vol. 419, no. 2, p. 215.

    Article  PubMed  CAS  Google Scholar 

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Original Russian Text © A.N. Gornostaeva, E.R. Andreeva, L.B. Buravkova, 2013, published in Fiziologiya Cheloveka, 2013, Vol. 39, No. 2, pp. 31–42.

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Gornostaeva, A.N., Andreeva, E.R. & Buravkova, L.B. Human MMSC immunosuppressive activity at low oxygen tension: Direct cell-to-cell contacts and paracrine regulation. Hum Physiol 39, 136–146 (2013). https://doi.org/10.1134/S0362119713020059

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