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Immunomodulatory properties of mesenchymal stem cells and their therapeutic applications

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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.

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References

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

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  Google Scholar 

  • 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).

    PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  Google Scholar 

  • English, K., French, A., and Wood, K. J., Mesenchymal stromal cells: facilitators of successful transplantation? Cell Stem Cell, 7, 431–442 (2010).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    PubMed  CAS  Google Scholar 

  • 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).

    PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  Google Scholar 

  • 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).

    Article  PubMed  Google Scholar 

  • 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).

    Article  PubMed  Google Scholar 

  • 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).

    Article  PubMed  Google Scholar 

  • 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).

    Article  PubMed  Google Scholar 

  • 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).

    PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    PubMed  Google Scholar 

  • Mills, C. R., Osiris therapeutics announces preliminary results for prochymal phase III GVHD trials. (http://investor.osiris.com/releasedetail.dfm?releaseID=407404) (2009).

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    PubMed  CAS  Google Scholar 

  • Prockop, D. J., Marrow stromal cells as stem cells for nonhematopoietic tissues. Science, 276, 71–74 (1997).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  Google Scholar 

  • 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).

    PubMed  Google Scholar 

  • 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).

    Article  PubMed  Google Scholar 

  • 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).

    Article  PubMed  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  Google Scholar 

  • Rosenzweig, A., Cardiac cell therapy-mixed results from mixed cells. N. Engl. J. Med., 355, 1274–1277 (2006).

    Article  PubMed  CAS  Google Scholar 

  • 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 

  • Schipani, E., and Kornberg, H. M., Adult Mesenchymal Stem Cells. StemBook, Harvard Stem Cell Institute, Cambridge, (2008).

    Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  Google Scholar 

  • Spagnoli, A., Longobardi, L., and O’Rear, L., Cartilage disorders: potential therapeutic use of mesenchymal stem cells. Endocr. Dev., 9, 17–30 (2005).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • Uccelli, A., Moretta, L., and Pistoia, V., Mesenchymal stem cells in health and disease. Nat. Rev. Immunol., 8, 726–736 (2008).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    PubMed  Google Scholar 

  • Zohar, R., Sodek, J., and McCulloch, C. A., Characterization of stromal progenitor cells enriched by flow cytometry. Blood, 90, 3471–3481 (1997).

    PubMed  CAS  Google Scholar 

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Yi, T., Song, S.U. Immunomodulatory properties of mesenchymal stem cells and their therapeutic applications. Arch. Pharm. Res. 35, 213–221 (2012). https://doi.org/10.1007/s12272-012-0202-z

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