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Archives of Pharmacal Research

, Volume 35, Issue 2, pp 213–221 | Cite as

Immunomodulatory properties of mesenchymal stem cells and their therapeutic applications

  • TacGhee Yi
  • Sun U. SongEmail author
Review

Abstract

Mesenchymal stem cells (MSCs) are adult stem cells that can be isolated from most adult tissues, including bone marrow, adipose, liver, amniotic fluid, lung, skeletal muscle and kidney. The term MSC is currently being used to represent both mesenchymal stem cells and multipotent mesenchymal stromal cells. Numerous reports on systemic administration of MSCs leading to functional improvements based on the paradigm of engraftment and differentiation have been published. However, it is not only difficult to demonstrate extensive engraftment of cells, but also no convincing clinical results have been generated from phase 3 trials as of yet and prolonged responses to therapy have been noted after identification of MSCs had discontinued. It is now clear that there is another mechanism by which MSCs exert their reparative benefits. Recently, MSCs have been shown to possess immunomodulatory properties. These include suppression of T cell proliferation, influencing dendritic cell maturation and function, suppression of B cell proliferation and terminal differentiation, and immune modulation of other immune cells such as NK cells and macrophages. In terms of the clinical applications of MSCs, they are being tested in four main areas: tissue regeneration for cartilage, bone, muscle, tendon and neuronal cells; as cell vehicles for gene therapy; enhancement of hematopoietic stem cell engraftment; and treatment of immune diseases such as graft-versus-host disease, rheumatoid arthritis, experimental autoimmune encephalomyelitis, sepsis, acute pancreatitis and multiple sclerosis. In this review, the mechanisms of immunomodulatory effects of MSCs and examples of animal and clinical uses of their immunomodulatory effects are described.

Key words

Mesenchymal stem cell Immunomodulation Clinical application Allogeneic stem cell Therapeutic product Immune disease 

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References

  1. Aggarwal, S., and Pittenger, M. F., Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood, 105, 1815–1822 (2005).PubMedCrossRefGoogle Scholar
  2. Assis, A. C., Carvalho, J. L., Jacoby, B. A., Ferreira, R. L., Castanheira, P., Diniz, S. O., Cardoso, V. N., Goes, A. M., and Ferreira, A. J., Time-dependent migration of systemically delivered bone marrow mesenchymal stem cells to the infarcted heart. Cell Transplant., 19, 219–230 (2010).PubMedCrossRefGoogle Scholar
  3. Augello, A., Tasso, R., Negrini, S.M., Cancedda, R., and Pennesi, G., Cell therapy using allogeneic bone marrow mesenchymal stem cells prevents tissue damage in collagen-induced arthritis. Arthritis Rheum., 56, 1175–1186 (2007).PubMedCrossRefGoogle Scholar
  4. Bartholomew, A., Sturgeon, C., Siatskas, M., Ferrer, K., McIntosh, K., Patil, S., Hardy, W., Devine, S., Ucker, D., Deans, R., Moseley, A., and Hoffman, R., Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Exp. Hematol., 30, 42–48 (2002).PubMedCrossRefGoogle Scholar
  5. Belladonna, M. L., Grohmann, U., Guidetti, P., Volpi, C., Bianchi, R., Fioretti, M. C., Schwarcz, R., Fallarino, F., and Puccetti, P., Kynurenine pathway enzymes in dendritic cells initiate tolerogenesis in the absence of functional IDO. J. Immunol., 177, 130–137 (2006).PubMedGoogle Scholar
  6. Corcione, A., Benvenuto, F., Ferretti, E., Giunti, D., Cappiello, V., Cazzanti, F., Risso, M., Gualandi, F., Mancardi, G. L., Pistoia, V., and Uccelli, A., Human mesenchymal stem cells modulate B-cell functions. Blood, 107, 367–372 (2006).PubMedCrossRefGoogle Scholar
  7. Di Nicola, M., Carlo-Stella, C., Magni, M., Milanesi, M., Longoni, P. D., Matteucci, P., Grisanti, S., and Gianni, A. M., Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood, 99, 3838–3843 (2002).PubMedCrossRefGoogle Scholar
  8. Djouad, F., Fritz, V., Apparailly, F., Louis-Plence, P., Bony, C., Sany, J., Jorgensen, C., and Noel, D., Reversal of the immunosuppressive properties of mesenchymal stem cells by tumor necrosis factor alpha in collagen-induced arthritis. Arthritis Rheum., 52, 1595–1603 (2005).PubMedCrossRefGoogle Scholar
  9. Duijvestein, M., Vos, A. C., Roelofs, H., Wildenberg, M. E., Wendrich, B. B., Verspaget, H. W., Kooy-Winkelaar, E. M., Koning, F., Zwaginga, J. J., Fidder, H. H., Verhaar, A. P., Fibbe, W. E., van den Brink, G. R., and Hommes, D. W., Autologous bone marrow-derived mesenchymal stromal cell treatment for refractory luminal Crohn’s disease: results of a phase I study. Gut, 59, 1662–1669 (2010).PubMedCrossRefGoogle Scholar
  10. English, K., French, A., and Wood, K. J., Mesenchymal stromal cells: facilitators of successful transplantation? Cell Stem Cell, 7, 431–442 (2010).PubMedCrossRefGoogle Scholar
  11. Friedenstein, A. J., Chailakhyan, R. K., and Gerasimov, U. V., Bone marrow osteogenic stem cells: in vitro cultivation and transplantation in diffusion chambers. Cell Tissue Kinet., 20, 263–272 (1987).PubMedGoogle Scholar
  12. Friedenstein, A. J., Deriglasova, U. F., Kulagina, N. N., Panasuk, A. F., Rudakowa, S. F., Luria, E. A., and Ruadkow, I. A., Precursors for fibroblasts in different populations of hematopoietic cells as detected by the in vitro colony assay method. Exp. Hematol., 2, 83–92 (1974).PubMedGoogle Scholar
  13. Frumento, G., Rotondo, R., Tonetti, M., Damonte, G., Benatti, U., and Ferrara, G. B., Tryptophan-derived catabolites are responsible for inhibition of T and natural killer cell proliferation induced by indoleamine 2,3-dioxygenase. J. Exp. Med., 196, 459–468 (2002).PubMedCrossRefGoogle Scholar
  14. Glennie, S., Soeiro, I., Dyson, P. J., Lam, E. W., and Dazzi, F., Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells. Blood, 105, 2821–2827 (2005).PubMedCrossRefGoogle Scholar
  15. Gnecchi, M., and Melo, L. G., Bone marrow-derived mesenchymal stem cells: isolation, expansion, characterization, viral transduction, and production of conditioned medium. Methods Mol. Biol., 482, 281–294 (2009).PubMedCrossRefGoogle Scholar
  16. Horwitz, E. M., Le Blanc, K., Dominici, M., Mueller, I., Slaper-Cortenbach, I., Marini, F. C., Deans, R. J., Krause, D. S., and Keating, A., Clarification of the nomenclature for MSC: The International Society for Cellular Therapy position statement. Cytotherapy, 7, 393–395 (2005).PubMedCrossRefGoogle Scholar
  17. Jiang, R., Han, Z., Zhuo, G., Qu, X., Li, X., Wang, X., Shao, Y., Yang, S., and Han, Z. C., Transplantation of placentaderived mesenchymal stem cells in type 2 diabetes: a pilot study. Front. Med., 5, 94–100 (2011).PubMedCrossRefGoogle Scholar
  18. Joyner, C. J., Bennett, A., and Triffitt, J. T., Identification and enrichment of human osteoprogenitor cells by using differentiation stage-specific monoclonal antibodies. Bone, 21, 1–6 (1997).PubMedCrossRefGoogle Scholar
  19. Jung, K. H., Song, S. U., Yi, T., Jeon, M. S., Hong, S. W., Zheng, H. M., Lee, H. S., Choi, M. J., Lee, D. H., and Hong, S. S., Human bone marrow-derived clonal mesenchymal stem cells inhibit inflammation and reduce acute pancreatitis in rats. Gastroenterology, 140, 998–1008 (2011).PubMedCrossRefGoogle Scholar
  20. Kebriaei, P., Isola, L., Bahceci, E., Holland, K., Rowley, S., McGuirk, J., Devetten, M., Jansen, J., Herzig, R., Schuster, M., Monroy, R., and Uberti, J., Adult human mesenchymal stem cells added to corticosteroid therapy for the treatment of acute graft-versus-host disease. Biol. Blood Marrow Transplant., 15, 804–811 (2009).PubMedCrossRefGoogle Scholar
  21. Klyushnenkova, E., Mosca, J. D., Zernetkina, V., Majumdar, M. K., Beggs, K. J., Simonetti, D. W., Deans, R. J., and McIntosh, K. R., T cell responses to allogeneic human mesenchymal stem cells: immunogenicity, tolerance, and suppression. J. Biomed. Sci., 12, 47–57 (2005).PubMedCrossRefGoogle Scholar
  22. Krampera, M., Cosmi, L., Angeli, R., Pasini, A., Liotta, F., Andreini, A., Santarlasci, V., Mazzinghi, B., Pizzolo, G., Vinante, F., Romagnani, P., Maggi, E., Romagnani, S., and Annunziato, F., Role for interferon-gamma in the immunomodulatory activity of human bone marrow mesenchymal stem cells. Stem Cells, 24, 386–398 (2006).PubMedCrossRefGoogle Scholar
  23. Le Blanc, K., Frassoni, F., Ball, L., Locatelli, F., Roelofs, H., Lewis, I., Lanino, E., Sundberg, B., Bernardo, M. E., Remberger, M., Dini, G., Egeler, R. M., Bacigalupo, A., Fibbe, W., and Ringden, O., Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versushost disease: a phase II study. Lancet, 371, 1579–1586 (2008).PubMedCrossRefGoogle Scholar
  24. Le Blanc, K., Rasmusson, I., Sundberg, B., Gotherstrom, C., Hassan, M., Uzunel, M., and Ringden, O., Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet, 363, 1439–1441 (2004).PubMedCrossRefGoogle Scholar
  25. Le Blanc, K., Tammik, L., Sundberg, B., Haynesworth, S. E., and Ringden, O., Mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and mitogenic responses independently of the major histocompatibility complex. Scand. J. Immunol., 57, 11–20 (2003a).PubMedCrossRefGoogle Scholar
  26. Le Blanc, K., Tammik, C., Rosendahl, K., Zetterberg, E., and Ringden, O., HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells. Exp. Hematol., 31, 890–896 (2003b).PubMedCrossRefGoogle Scholar
  27. Lim, J. H., Lee, M. H., Yi, H. G., Kim, C. S., Kim, J. H., and Song, S. U., Mesenchymal stromal cells for steroid-refractory acute graft-versus-host disease: a report of two cases. Int. J. Hematol., 92, 204–207 (2010).PubMedCrossRefGoogle Scholar
  28. Maccario, R., Podesta, M., Moretta, A., Cometa, A., Comoli, P., Montagna, D., Daudt, L., Ibatici, A., Piaggio, G., Pozzi, S., Frassoni, F., and Locatelli, F., Interaction of human mesenchymal stem cells with cells involved in alloantigen- specific immune response favors the differentiation of CD4+ T-cell subsets expressing a regulatory/suppressive phenotype. Haematologica, 90, 516–525 (2005).PubMedGoogle Scholar
  29. Maitra, B., Szekely, E., Gjini, K., Laughlin, M. J., Dennis, J., Haynesworth, S. E., and Koc, O. N., Human mesenchymal stem cells support unrelated donor hematopoietic stem cells and suppress T-cell activation. Bone Marrow Transplant., 33, 597–604 (2004).PubMedCrossRefGoogle Scholar
  30. Meisel, R., Zibert, A., Laryea, M., Gobel, U., Daubener, W., and Dilloo, D., Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenasemediated tryptophan degradation. Blood, 103, 4619–4621 (2004).PubMedCrossRefGoogle Scholar
  31. Miller, R. H., Bai, L., Lennon, D. P., and Caplan, A. I., The potential of mesenchymal stem cells for neural repair. Discov. Med., 9, 236–242 (2010).PubMedGoogle Scholar
  32. Mills, C. R., Osiris therapeutics announces preliminary results for prochymal phase III GVHD trials. (http://investor.osiris.com/releasedetail.dfm?releaseID=407404) (2009).
  33. Munn, D. H., Sharma, M. D., Lee, J. R., Jhaver, K. G., Johnson, T. S., Keskin, D. B., Marshall, B., Chandler, P., Antonia, S. J., Burgess, R., Slingluff, C. L., Jr., and Mellor, A. L., Potential regulatory function of human dendritic cells expressing indoleamine 2,3-dioxygenase. Science, 297, 1867–1870 (2002).PubMedCrossRefGoogle Scholar
  34. Nauta, A. J., Kruisselbrink, A. B., Lurvink, E., Willemze, R., and Fibbe, W. E., Mesenchymal stem cells inhibit generation and function of both CD34+-derived and monocytederived dendritic cells. J. Immunol., 177, 2080–2087 (2006).PubMedGoogle Scholar
  35. Ortiz, L. A., Gambelli, F., McBride, C., Gaupp, D., Baddoo, M., Kaminski, N., and Phinney, D. G., Mesenchymal stem cell engraftment in lung is enhanced in response to bleomycin exposure and ameliorates its fibrotic effects. Proc. Natl. Acad. Sci. U. S. A., 100, 8407–8411 (2003).PubMedCrossRefGoogle Scholar
  36. Pittenger, M. F., Mackay, A. M., Beck, S. C., Jaiswal, R. K., Douglas, R., Mosca, J. D., Moorman, M. A., Simonetti, D. W., Craig, S., and Marshak, D. R., Multilineage potential of adult human mesenchymal stem cells. Science, 284, 143–147 (1999).PubMedCrossRefGoogle Scholar
  37. Poggi, A., Prevosto, C., Massaro, A. M., Negrini, S., Urbani, S., Pierri, I., Saccardi, R., Gobbi, M., and Zocchi, M. R., Interaction between human NK cells and bone marrow stromal cells induces NK cell triggering: role of NKp30 and NKG2D receptors. J. Immunol., 175, 6352–6360 (2005).PubMedGoogle Scholar
  38. Prockop, D. J., Marrow stromal cells as stem cells for nonhematopoietic tissues. Science, 276, 71–74 (1997).PubMedCrossRefGoogle Scholar
  39. Prockop, D. J., Kota, D. J., Bazhanov, N., and Reger, R. L., Evolving paradigms for repair of tissues by adult stem/ progenitor cells (MSCs). J. Cell. Mol. Med., 14, 2190–2199 (2010).PubMedCrossRefGoogle Scholar
  40. Qian, H., Yang, H., Xu, W., Yan, Y., Chen, Q., Zhu, W., Cao, H., Yin, Q., Zhou, H., Mao, F., and Chen, Y., Bone marrow mesenchymal stem cells ameliorate rat acute renal failure by differentiation into renal tubular epithelial-like cells. Int. J. Mol. Med., 22, 325–332 (2008).PubMedGoogle Scholar
  41. Ramasamy, R., Fazekasova, H., Lam, E. W., Soeiro, I., Lombardi, G., and Dazzi, F., Mesenchymal stem cells inhibit dendritic cell differentiation and function by preventing entry into the cell cycle. Transplantation, 83, 71–76 (2007).PubMedCrossRefGoogle Scholar
  42. Rasmusson, I., Ringden, O., Sundberg, B., and Le Blanc, K., Mesenchymal stem cells inhibit the formation of cytotoxic T lymphocytes, but not activated cytotoxic T lymphocytes or natural killer cells. Transplantation, 76, 1208–1213 (2003).PubMedCrossRefGoogle Scholar
  43. Reiser, J., Zhang, X. Y., Hemenway, C. S., Mondal, D., Pradhan, L., and La Russa, V. F., Potential of mesenchymal stem cells in gene therapy approaches for inherited and acquired diseases. Expert Opin. Biol. Ther., 5, 1571–1584 (2005).PubMedCrossRefGoogle Scholar
  44. Ren, G., Zhang, L., Zhao, X., Xu, G., Zhang, Y., Roberts, A. I., Zhao, R. C., and Shi, Y., Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide. Cell Stem Cell, 2, 141–150 (2008).PubMedCrossRefGoogle Scholar
  45. Ringden, O., Uzunel, M., Rasmusson, I., Remberger, M., Sundberg, B., Lonnies, H., Marschall, H. U., Dlugosz, A., Szakos, A., Hassan, Z., Omazic, B., Aschan, J., Barkholt, L., and Le Blanc, K., Mesenchymal stem cells for treatment of therapy-resistant graft-versus-host disease. Transplantation, 81, 1390–1397 (2006).PubMedCrossRefGoogle Scholar
  46. Rosenzweig, A., Cardiac cell therapy-mixed results from mixed cells. N. Engl. J. Med., 355, 1274–1277 (2006).PubMedCrossRefGoogle Scholar
  47. Sage, E. K., Loebinger, M. R., Polak, J., and Janes, S. M., The Role of Bone Marrow-derived Stem Cells in Lung Regeneration and Repair. StemBook, Harvard Stem Cell Institute, Cambridge, (2008).Google Scholar
  48. Schipani, E., and Kornberg, H. M., Adult Mesenchymal Stem Cells. StemBook, Harvard Stem Cell Institute, Cambridge, (2008).Google Scholar
  49. Song, S. U., Kim, C. S., Yoon, S. P., Kim, S. K., Lee, M. H., Kang, J. S., Choi, G. S., Moon, S. H., Choi, M. S., Cho, Y. K., and Son, B. K., Variations of clonal marrow stem cell lines established from human bone marrow in surface epitopes, differentiation potential, gene expression, and cytokine secretion. Stem Cells Dev., 17, 451–461 (2008).PubMedCrossRefGoogle Scholar
  50. Sotiropoulou, P. A., Perez, S. A., Gritzapis, A. D., Baxevanis, C. N., and Papamichail, M., Interactions between human mesenchymal stem cells and natural killer cells. Stem Cells, 24, 74–85 (2006).PubMedCrossRefGoogle Scholar
  51. Spagnoli, A., Longobardi, L., and O’Rear, L., Cartilage disorders: potential therapeutic use of mesenchymal stem cells. Endocr. Dev., 9, 17–30 (2005).PubMedCrossRefGoogle Scholar
  52. Tian, H., Bharadwaj, S., Liu, Y., Ma, P. X., Atala, A., and Zhang, Y., Differentiation of human bone marrow mesenchymal stem cells into bladder cells: potential for urological tissue engineering. Tissue Eng. Part A, 16, 1769–1779 (2010).PubMedCrossRefGoogle Scholar
  53. Tolar, J., Le Blanc, K., Keating, A., and Blazar, B. R., Concise review: hitting the right spot with mesenchymal stromal cells. Stem Cells, 28, 1446–1455 (2010).PubMedCrossRefGoogle Scholar
  54. Tse, W. T., Pendleton, J. D., Beyer, W. M., Egalka, M. C., and Guinan, E. C., Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implications in transplantation. Transplantation, 75, 389–397 (2003).PubMedCrossRefGoogle Scholar
  55. Uccelli, A., Moretta, L., and Pistoia, V., Mesenchymal stem cells in health and disease. Nat. Rev. Immunol., 8, 726–736 (2008).PubMedCrossRefGoogle Scholar
  56. Waller, E. K., Olweus, J., Lund-Johansen, F., Huang, S., Nguyen, M., Guo, G. R., and Terstappen, L., The “common stem cell” hypothesis reevaluated: human fetal bone marrow contains separate populations of hematopoietic and stromal progenitors. Blood, 85, 2422–2435 (1995).PubMedGoogle Scholar
  57. Yamout, B., Hourani, R., Salti, H., Barada, W., El-Hajj, T., Al-Kutoubi, A., Herlopian, A., Baz, E. K., Mahfouz, R., Khalil-Hamdan, R., Kreidieh, N. M., El-Sabban, M., and Bazarbachi, A., Bone marrow mesenchymal stem cell transplantation in patients with multiple sclerosis: a pilot study. J. Neuroimmunol., 227, 185–189 (2010).PubMedCrossRefGoogle Scholar
  58. Zappia, E., Casazza, S., Pedemonte, E., Benvenuto, F., Bonanni, I., Gerdoni, E., Giunti, D., Ceravolo, A., Cazzanti, F., Frassoni, F., Mancardi, G., and Uccelli, A., Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T-cell anergy. Blood, 106, 1755–1761 (2005).PubMedCrossRefGoogle Scholar
  59. Zhao, D. C., Lei, J. X., Chen, R., Yu, W.H., Zhang, X. M., Li, S. N., and Xiang, P., Bone marrow-derived mesenchymal stem cells protect against experimental liver fibrosis in rats. World J. Gastroenterol., 11, 3431–3440 (2005).PubMedGoogle Scholar
  60. Zohar, R., Sodek, J., and McCulloch, C. A., Characterization of stromal progenitor cells enriched by flow cytometry. Blood, 90, 3471–3481 (1997).PubMedGoogle Scholar

Copyright information

© The Pharmaceutical Society of Korea and Springer Netherlands 2012

Authors and Affiliations

  1. 1.Clinical Research Center, Inha Research InstituteInha University School of MedicineIncheonKorea
  2. 2.Clinical Research Center, College of MedicineInha UniversityIncheonKorea

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