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Mesenchymal stromal cell ‘licensing’: a multistep process

Leukemia volume 25, pages 1408–1414 (2011)Cite this article

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Abstract

Many in vitro and in vivo data are available supporting the role of mesenchymal stromal cell (MSC) licensing in the induction of a measurable and effective immune regulation. The failure of some MSC-based protocols for immune modulation in animal models and in human clinical trials may be explained by either lack of a proper licensing by inflammatory microenviroment or wrong timing in MSC administration. Thus, optimization of MSC use for immune-regulating purposes is required to maximize their beneficial effects.

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References

  1. Caplan AI . Mesenchymal stem cells. J Orthop Res 1991; 9: 641–650.

    Article  CAS  PubMed  Google Scholar 

  2. Horwitz EM, Le Blanc K, Dominici M, Mueller I, Slaper-Cortenbach I, Marini FC et al. Clarification of the nomenclature for MSC: the International Society for Cellular Therapy position statement. Cytotherapy 2005; 7: 393–395.

    CAS  PubMed  Google Scholar 

  3. Haniffa MA, Collin MP, Buckley CD, Dazzi F . Mesenchymal stem cells: the fibroblasts’ new clothes? Haematologica 2009; 94: 258–263.

    CAS  PubMed  Google Scholar 

  4. Prockop DJ . Marrow stromal cells as stem cells for nonhemopoietic tissues. Science 1997; 276: 71–74.

    CAS  PubMed  Google Scholar 

  5. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD et al. Multilineage potential of adult human mesenchymal stem cells. Science 1999; 284: 143–147.

    CAS  PubMed  Google Scholar 

  6. Krampera M, Pasini A, Pizzolo G, Cosmi L, Romagnani S, Annunziato F . Regenerative and immunomodulatory potential of mesenchymal stem cells. Curr Opin Pharmacol 2006; 6: 435–441.

    CAS  PubMed  Google Scholar 

  7. De Ugarte DA, Morizono K, Elbarbary A, Alfonso Z, Zuk PA, Zhu M et al. Comparison of multilineage cells from human adipose tissue and bone marrow. Cells Tissues Organs 2003; 174: 101–109.

    PubMed  Google Scholar 

  8. Sato Y, Araki H, Kato J, Nakamura K, Kawano Y, Kobune M et al. Human mesenchymal stem cells xenografted directly to rat liver are differentiated into human hepatocytes without fusion. Blood 2005; 106: 756–763.

    CAS  PubMed  Google Scholar 

  9. Kotton DN, Ma BY, Cardoso WV, Sanderson EA, Summer RS, Williams MC et al. Bone marrow-derived cells as progenitors of lung alveolar epithelium. Development 2001; 128: 5181–5188.

    CAS  PubMed  Google Scholar 

  10. Woodbury D, Schwarz EJ, Prockop DJ, Black IB . Adult rat and human bone marrow stromal cells differentiate into neurons. J Neurosci Res 2000; 61: 364–370.

    CAS  PubMed  Google Scholar 

  11. Krampera M, Marconi S, Pasini A, Galiè M, Mosna F, Tinelli M et al. Induction of neural-like differentiation in human mesenchymal stem cells derived from bone marrow, fat, spleen and thymus. Bone 2007; 40: 382–390.

    CAS  PubMed  Google Scholar 

  12. Spees JL, Olson SD, Ylostlo J, Lynch PJ, Smith J, Perry A et al. Differentiation, cell fusion, and nuclear fusion during ex vivo repair of epithelium by human adult stem cells from bone marrow stroma. Proc Natl Acad Sci USA 2003; 100: 2397–2402.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Phinney DG, Prockop DJ . Concise review: mesenchymal stem/multipotent stromal cells: the state of transdifferentiation and modes of tissue repair—current views. Stem Cells 2007; 25: 2896–2902.

    PubMed  Google Scholar 

  14. Di Nicola M, Carlo-Stella C, Magni M, Milanesi M, Longoni PD, Matteucci P et al. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 2002; 99: 3838–3843.

    CAS  PubMed  Google Scholar 

  15. Le Blanc K, Tammik L, Sundberg B, Haynesworth SE, Ringden O . MSC inhibit and stimulate MLR cultures and mitogenic responses independently of the MHC. Scand J Immunol 2003; 57: 11–20.

    CAS  PubMed  Google Scholar 

  16. Krampera M, Glennie S, Dyson J, Scott D, Laylor R, Simpson E et al. Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigen-specific T cells to their cognate peptide. Blood 2003; 101: 3722–3729.

    CAS  PubMed  Google Scholar 

  17. Glennie S, Soeiro I, Dyson PJ, Lam EW, Dazzi F . Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells. Blood 2005; 105: 2821–2827.

    CAS  PubMed  Google Scholar 

  18. 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: 386–398.

    CAS  PubMed  Google Scholar 

  19. Ghannam S, Pene J, Torcy-Moquet G, Jorgensen C, Yssel H . Mesenchymal stem cells inhibit human Th17 cell differentiation and function and induce a T regulatory cell phenotype. J Immunol 2010; 185: 302–312.

    CAS  PubMed  Google Scholar 

  20. Prigione I, Benvenuto F, Bocca P, Battistini L, Uccelli A, Pistoia V . Reciprocal interactions between human mesenchymal stem cells and gammadelta T cells or invariant natural killer T cells. Stem Cells 2009; 27: 693–702.

    CAS  PubMed  Google Scholar 

  21. Corcione A, Benvenuto F, Ferretti E, Giunti D, Cappiello V, Cazzanti F et al. Human mesenchymal stem cells modulate B cell functions. Blood 2006; 107: 367–372.

    CAS  PubMed  Google Scholar 

  22. Spaggiari GM, Capobianco A, Becchetti S, Mingari MC, Moretta L . Mesenchymal stem cell–natural killer cell interactions: evidence that activated NK cells are capable of killing MSCs, whereas MSCs can inhibit IL-2-induced NK-cell proliferation. Blood 2006; 107: 1484–1490.

    CAS  PubMed  Google Scholar 

  23. Ramasamy R, Fazekasova H, Lam EW, Soeiro I, Lombardi G, Dazzi F . Mesenchymal stem cells inhibit dendritic cell differentiation and function by preventing entry into the cell cycle. Transplantation 2007; 83: 71–76.

    PubMed  Google Scholar 

  24. Raffaghello L, Bianchi G, Bertolotto M, Montecucco F, Busca A, Dallegri F et al. Human mesenchymal stem cells inhibit neutrophil apoptosis: a model for neutrophil preservation in the bone marrow niche. Stem Cells 2008; 26: 151–162.

    CAS  PubMed  Google Scholar 

  25. Puissant B, Barreau C, Bourin P, Clavel C, Corre J, Bousquet C et al. Immunomodulative effect of human adipose tissue-derived adult stromal cells: comparison with bone marrow mesenchymal stem cells. Br J Haematol 2005; 129: 118–129.

    PubMed  Google Scholar 

  26. Krampera M, Sartoris S, Liotta F, Pasini A, Angeli R, Cosmi L et al. Immune regulation by mesenchymal stem cells derived from adult spleen and thymus. Stem Cells Dev 2007; 16: 797–810.

    CAS  PubMed  Google Scholar 

  27. Liu H, Kemeny DM, Heng BC, Ouyang HW, Melendez AJ, Cao T . The immunogenicity and immunomodulatory function of osteogenic cells differentiated from mesenchymal stem cells. J Immunol 2006; 176: 2864–2871.

    CAS  PubMed  Google Scholar 

  28. Le Blanc K, Tammik C, Rosendahl K, Zetterberg E, Ringden O . HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells. Exp Hematol 2003; 31: 890–896.

    CAS  PubMed  Google Scholar 

  29. Jones S, Horwood N, Cope A, Dazzi F . The antiproliferative effect of mesenchymal stem cells is a fundamental property shared by all stromal cells. J Immunol 2007; 179: 2824–2831.

    CAS  PubMed  Google Scholar 

  30. Haniffa MA, Wang XN, Holtick U, Rae M, Isaacs JD, Dickinson AM et al. Adult human fibroblasts are potent immunoregulatory cells and functionally equivalent to mesenchymal stem cells. J Immunol 2007; 179: 1595–1604.

    CAS  PubMed  Google Scholar 

  31. Groh ME, Maitra B, Szekely E, Koc ON . Human mesenchymal stem cells require monocyte-mediated activation to suppress alloreactive T cells. Exp Hematol 2005; 33: 928–934.

    CAS  PubMed  Google Scholar 

  32. Tse WT, Pendleton JD, Beyer WM, Egalka MC, Guinan EC . Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implications in transplantation. Transplantation 2003; 75: 389–397.

    CAS  PubMed  Google Scholar 

  33. Meisel R, Zibert A, Laryea M, Gobel U, Daubener W, Dilloo D . Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase mediated tryptophan degradation. Blood 2004; 103: 4619–4621.

    CAS  PubMed  Google Scholar 

  34. Xu G, Zhang Y, Zhang L, Ren G, Shi Y . The role of IL-6 in inhibition of lymphocyte apoptosis by mesenchymal stem cells. Biochem Biophys Res Commun 2007; 361: 745–750.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Djouad F, Charbonnier LM, Bouffi C, Louis-Plence P, Bony C, Apparailly F et al. Mesenchymal stem cells inhibit the differentiation of dendritic cells through an interleukin-6-dependent mechanism. Stem Cells 2007; 25: 2025–2032.

    CAS  PubMed  Google Scholar 

  36. Zhang W, Ge W, Li C, You S, Liao L, Han Q et al. Effects of mesenchymal stem cells on differentiation, maturation, and function of human monocyte-derived dendritic cells. Stem Cells Dev 2004; 13: 263–271.

    CAS  PubMed  Google Scholar 

  37. Jiang XX, Zhang Y, Liu B, Zhang SX, Wu Y, Yu XD et al. Human mesenchymal stem cells inhibit differentiation and function of monocyte-derived dendritic cells. Blood 2005; 105: 4120–4126.

    CAS  PubMed  Google Scholar 

  38. Aggarwal S, Pittenger MF . Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 2004; 105: 1815–1822.

    PubMed  Google Scholar 

  39. Beyth S, Borovsky Z, Mevorach D, Liebergall M, Gazit Z, Aslan H et al. Human mesenchymal stem cells alter antigen-presenting cell maturation and induce T-cell unresponsiveness. Blood 2005; 105: 2214–2219.

    CAS  PubMed  Google Scholar 

  40. Klyushnenkova E, Mosca JD, Zernetkina V, Majumdar MK, Beggs KJ, Simonetti DW et al. T cell responses to allogeneic human mesenchymal stem cells: immunogenicity, tolerance, and suppression. J Biomed Sci 2005; 12: 47–57.

    CAS  PubMed  Google Scholar 

  41. Potian JA, Aviv H, Ponzio NM, Harrison JS, Rameshwar P . Veto-like activity of mesenchymal stem cells: functional discrimination between cellular responses to alloantigens and recall antigens. J Immunol 2003; 171: 3426–3434.

    CAS  PubMed  Google Scholar 

  42. Sato K, Ozaki K, Oh I, Meguro A, Hatanaka K, Nagai T et al. Nitric oxide plays a critical role in suppression of T-cell proliferation by mesenchymal stem cells. Blood 2007; 109: 228–234.

    CAS  PubMed  Google Scholar 

  43. Cbannes D, Hill M, Merieau E, Rossignol J, Brion R, Soulillou JP et al. A role for heme oxygenase-1 in the immunosuppressive effect of adult rat and human mesenchymal stem cells. Blood 2007; 110: 3691–3694.

    Google Scholar 

  44. Selmani Z, Naji A, Zidi I, Favier B, Gaiffe E, Obert L et al. HLA-G5 secretion by human mesenchymal stem cells is required to suppress T-lymphocyte and NK function and to induce CD4+CD25highFOXP3+ regulatory T cells. Stem Cells 2008; 26: 212–222.

    CAS  PubMed  Google Scholar 

  45. Oh I, Ozaki K, Sato K, Meguro A, Tatara R, Hatanaka K et al. Interferon-gamma and NF-kappaB mediate nitric oxide production by mesenchymal stromal cells. Biochem Biophys Res Commun 2007; 355: 956–962.

    CAS  PubMed  Google Scholar 

  46. Dazzi F, Ramasamy R, Glennie S, Jones SP, Roberts I . The role of mesenchymal stem cells in haemopoiesis. Blood Rev 2006; 20: 161–171.

    CAS  PubMed  Google Scholar 

  47. Benvenuto F, Ferrari S, Gerdoni E, Gualandi F, Frassoni F, Pistoia V et al. Human mesenchymal stem cell promote survival of T cells in a quiescent state. Stem Cells 2007; 25: 1753–1760.

    CAS  PubMed  Google Scholar 

  48. Tabera S, Pérez-Simón JA, Díez-Campelo M, Sánchez-Abarca LI, Blanco B, López A et al. The effect of mesenchymal stem cells on the viability, proliferation and differentiation of B-lymphocytes. Haematologica 2008; 93: 1301–1309.

    CAS  PubMed  Google Scholar 

  49. Kurosaka D, LeBien TW, Pribyl JA . Comparative studies of different stromal cell microenvironments in support of human B-cell development. Exp Hematol 1999; 27: 1271–1278.

    CAS  PubMed  Google Scholar 

  50. Traggiai E, Volpi S, Schena F, Gattorno M, Ferlito F, Moretta L et al. Bone marrow-derived mesenchymal stem cells induce both polyclonal expansion and differentiation of B cells isolated from healthy donors and systemic lupus erythematosus patients. Stem Cells 2008; 26: 562–569.

    CAS  PubMed  Google Scholar 

  51. Amé-Thomas P, Maby-El Hajjami H, Monvoisin C, Jean R, Monnier D, Caulet-Maugendre S et al. Human mesenchymal stem cells isolated from bone marrow and lymphoid organs support tumor B-cell growth: role of stromal cells in follicular lymphoma pathogenesis. Blood 2007; 109: 693–702.

    PubMed  Google Scholar 

  52. Gunn WG, Conley A, Deininger L, Olson SD, Prockop DJ, Gregory CA . A crosstalk between myeloma cells and marrow stromal cells stimulates production of DKK1 and interleukin-6: a potential role in the development of lytic bone disease and tumor progression in multiple myeloma. Stem Cells 2006; 24: 986–991.

    CAS  PubMed  Google Scholar 

  53. Karnoub AE, Dash AB, Vo AP, Sullivan A, Brooks MW, Bell GW et al. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 2007; 449: 557–563.

    CAS  PubMed  Google Scholar 

  54. Chan JL, Tang KC, Patel AP, Bonilla LM, Pierobon N, Ponzio NM et al. Antigen-presenting property of mesenchymal stem cells occurs during a narrow window at low levels of interferon-{gamma}. Blood 2006; 107: 4817–4824.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Stagg J, Pommey S, Eliopoulos N, Galipeau J . Interferon-gamma-stimulated marrow stromal cells: a new type of nonhematopoietic antigen-presenting cell. Blood 2006; 107: 2570–2577.

    CAS  PubMed  Google Scholar 

  56. Francois M, Romieu-Mourez R, Stock-Martineau S, Boivin MN, Bramson JL, Galipeau J . Mesenchymal stromal cells cross-present soluble exogenous antigens as part of their antigen-presenting cell properties. Blood 2009; 114: 2632–2638.

    CAS  PubMed  Google Scholar 

  57. 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: 386–398.

    CAS  PubMed  Google Scholar 

  58. Dazzi F, Marelli-Berg FM . Mesenchymal stem cells for graft-versus-host disease: close encounters with T cells. Eur J Immunol 2008; 38: 1479–1482.

    CAS  PubMed  Google Scholar 

  59. 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: 141–150.

    CAS  PubMed  Google Scholar 

  60. Ren G, Zhao X, Zhang L, Zhang J, L’Huillier A, Ling W et al. Inflammatory cytokine-induced ICAM-1 and VCAM-1 in mesenchymal stem cells are critical for immunosuppression. J Immunol 2010; 184: 2321–2328.

    CAS  PubMed  Google Scholar 

  61. Rameshwar P . IFN-gamma and B7-H1 in the immunology of mesenchymal stem cells. Cell Res 2008; 18: 846–857.

    Google Scholar 

  62. Sheng H, Wang Y, Jin Y, Zhang Q, Zhang Y, Wang L et al. A critical role of IFN-γ in priming MSC-mediated suppression of T cell proliferation through upregulation of B7-H1. Cell Res 2008; 18: 805–806.

    Google Scholar 

  63. Hemeda H, Jakob M, Ludwig AK, Giebel B, Lang S, Brandau S et al. IFN-gamma and TNF-alpha differentially affect cytokine expression and migration properties of mesenchymal stem cells. Stem Cells Dev 2010; 19: 693–706.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  65. Mougiakakos D, Jitschin R, Johansson CC, Okita R, Kiessling R, Le Blanc K . The impact of inflammatory licensing on heme oxygenase-1 mediated induction of regulatory T cells by human mesenchymal stem cells. Blood 2011 (prepublished online).

  66. Kemp K, Gray E, Mallam E, Scolding N, Wilkins A . Inflammatory cytokine induced regulation of superoxide dismutase 3 expression by human mesenchymal stem cells. Stem Cell Rev 2010; 6: 548–559.

    CAS  Google Scholar 

  67. Prasanna SJ, Gopalakrishnan D, Shankar SR, Vasandan AB . Pro-inflammatory cytokines, IFNgamma and TNFalpha, influence immune properties of human bone marrow and Wharton jelly mesenchymal stem cells differentially. PLoS One 2010; 5: e9016.

    PubMed  PubMed Central  Google Scholar 

  68. Valencic E, Piscianz E, Andolina M, Ventura A, Tommasini A . The immunosuppressive effect of Wharton's jelly stromal cells depends on the timing of their licensing and on lymphocyte activation. Cytotherapy 2010; 12: 154–160.

    CAS  PubMed  Google Scholar 

  69. Meisel R, Brockers S, Heseler K, Degistirici O, Bülle H, Woite C et al. Human but not murine multipotent mesenchymal stromal cells exhibit broad-spectrum antimicrobial effector function mediated by indoleamine 2,3-dioxygenase. Leukemia 2011 (prepublished online).

  70. Polchert D, Sobinsky J, Douglas G, Kidd M, Moadsiri A, Reina E et al. IFN-gamma activation of mesenchymal stem cells for treatment and prevention of graft versus host disease. Eur J Immunol 2008; 38: 1745–1755.

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Kanzler H, Barrat FJ, Hessel EM, Coffman RL . Therapeutic targeting of innate immunity with Toll-like receptor agonists and antagonists. Nat Med 2007; 13: 552–559.

    CAS  PubMed  Google Scholar 

  72. Pevsner-Fisher M, Morad V, Cohen-Sfady M, Rousso-Noori L, Zanin-Zhorov A, Cohen S et al. Toll-like receptors and their ligands control mesenchymal stem cell functions. Blood 2007; 109: 1422–1432.

    Google Scholar 

  73. Tomchuck SL, Zwezdaryk KJ, Coffelt SB, Waterman RS, Danka ES, Scandurro AB . Toll-like receptors on human mesenchymal stem cells drive their migration and immunomodulating responses. Stem Cells 2008; 26: 99–107.

    CAS  PubMed  Google Scholar 

  74. DelaRosa O, Lombardo E . Modulation of adult mesenchymal stem cells activity by toll-like receptors: implications on therapeutic potential. Mediators Inflamm 2010; 2010: 865601.

    PubMed  PubMed Central  Google Scholar 

  75. Liotta F, Angeli R, Cosmi L, Fili L, Manuelli C, Frosali F et al. Toll-like receptors 3 and 4 are expressed by human bone marrow-derived mesenchymal stem cells and can inhibit their T-cell modulatory activity by impairing Notch signaling. Stem Cells 2008; 26: 279–289.

    CAS  PubMed  Google Scholar 

  76. Romieu-Mourez R, Francois M, Boivin MN, Bouchentouf M, Spaner DE, Galipeau J . Cytokine modulation of TLR expression and activation in mesenchymal stromal cells leads to a proinflammatory phenotype. J Immunol 2009; 182: 7963–7973.

    CAS  PubMed  Google Scholar 

  77. Opitz CA, Litzenburger UM, Lutz C, Lanz TV, Tritschler I, Koppel A et al. Toll-like receptor engagement enhances the immunosuppressive properties of human bone marrow-derived mesenchymal stem cells by inducing indoleamine-2,3-dioxygenase-1 via interferon-beta and protein kinase R. Stem Cells 2009; 27: 909–919.

    CAS  PubMed  Google Scholar 

  78. Mantovani A, Sica A, Locati M . Macrophage polarization comes of age. Immunity 2005; 23: 344–346.

    CAS  PubMed  Google Scholar 

  79. Waterman RS, Tomchuck SL, Henkle SL, Betancourt AM . A new mesenchymal stem cell (MSC) paradigm: polarization into a pro-inflammatory MSC1 or an Immunosuppressive MSC2 phenotype. PLoS One 2010; 5: e10088.

    PubMed  PubMed Central  Google Scholar 

  80. Le Blanc K, Rasmusson I, Sundberg B, Gotherstrom C, Hassan M, Uzunel M et al. Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet 2004; 363: 1439–1441.

    PubMed  Google Scholar 

  81. Le Blanc K, Frassoni F, Ball L, Locatelli F, Roelofs H, Lewis I et al. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet 2008; 371: 1579–1586.

    CAS  PubMed  Google Scholar 

  82. Gonzalez-Rey E, Anderson P, Gonzalez MA, Rico L, Buscher D, Delgado M . Human adult stem cells derived from adipose tissue protect against experimental colitis and sepsis. Gut 2009; 58: 929–939.

    CAS  PubMed  Google Scholar 

  83. Togel F, Hu Z, Weiss K, Isaac J, Lange C, Westenfelder C et al. Amelioration of acute renal failure by stem cell therapy—paracrine secretion versus transdifferentiation into resident cells: administered mesenchymal stem cells protect against ischemic acute renal failure through differentiation-independent mechanisms. J Am Soc Nephrol 2005; 16: 1153–1163.

    Google Scholar 

  84. Sudres M, Norol F, Trenado A, Gregoire S, Charlotte F, Levacher B et al. Bone marrow mesenchymal stem cells suppress lymphocyte proliferation in vitro but fail to prevent graft-versus-host disease in mice. J Immunol 2006; 176: 7761–7767.

    CAS  PubMed  Google Scholar 

  85. Tisato V, Naresh K, Girdlestone J, Navarrete C, Dazzi F . Mesenchymal stem cells of cord blood origin are effective at preventing but not treating graft-versus-host disease. Leukemia 2007; 21: 1992–1999.

    CAS  PubMed  Google Scholar 

  86. Lazarus HM, Koc ON, Devine SM, Curtin P, Maziarz RT, Holland HK et al. Cotransplantation of HLA-identical sibling culture-expanded mesenchymal stem cells and hematopoietic stem cells in hematologic malignancy patients. Biol Blood Marrow Transplant 2005; 11: 389–398.

    PubMed  Google Scholar 

  87. Yanez R, Lamana ML, García-Castro J, Colmenero I, Ramírez M, Bueren JA . Adipose tissue-derived mesenchymal stem cells have in vivo immunosuppressive properties applicable for the control of the graft-versus-host disease. Stem Cells 2006; 24: 2582–2591.

    CAS  PubMed  Google Scholar 

  88. Zappia E, Casazza S, Pedemonte E, Benvenuto F, Bonanni I, Gerdoni E et al. Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T-cell anergy. Blood 2005; 106: 1755–1761.

    CAS  PubMed  Google Scholar 

  89. Constantin G, Marconi S, Rossi B, Angiari S, Calderan L, Anghileri E et al. Adipose-derived mesenchymal stem cells ameliorate chronic experimental autoimmune encephalomyelitis. Stem Cells 2009; 27: 2624–2635.

    CAS  PubMed  Google Scholar 

  90. Zhao RC, Liao L, Han Q . Mechanisms of and perspectives on the mesenchymal stem cell in immunotherapy. J Lab Clin Med 2004; 143: 284–291.

    PubMed  Google Scholar 

  91. Pereira RF, Halford KW, O’Hara MD, Leeper LB, Sokolov BP, Pollard MD et al. Cultured adherent cells from marrow can serve as long-lasting precursor cells for bone, cartilage, and lung in irradiated mice. Proc Natl Acad Sci USA 1995; 92: 4857–4861.

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Studeny M, Marini FC, Champlin RE, Zompetta C, Fidler IJ, Andreeff M . Bone marrow-derived mesenchymal stem cells as vehicles for interferon-â delivery into tumours. Cancer Res 2002; 62: 3603–3608.

    CAS  PubMed  Google Scholar 

  93. Rønnov-Jessen L, Petersen OW, Koteliansky VE, Bissell MJ . The origin of the myofibroblasts in breast cancer. Recapitulation of tumor environment in culture unravels diversity and implicates converted fibroblasts and recruited smooth muscle cells. J Clin Invest 1995; 95: 859–873.

    PubMed  PubMed Central  Google Scholar 

  94. Galiè M, Konstantinidou G, Peroni D, Scambi I, Marchini C, Lisi V et al. Mesenchymal stem cells share molecular signature with mesenchymal tumor cells and favor the early tumor growth in syngeneic mice. Oncogene 2008; 27: 2542–2551.

    PubMed  Google Scholar 

  95. Mantovani A, Allavena P, Sica A, Balkwill F . Cancer-related inflammation. Nature 2008; 454: 436–444.

    CAS  PubMed  Google Scholar 

  96. Chang HY, Sneddon JB, Alizadeh AA, Sood R, West RB, Montgomery K et al. Gene expression signature of fibroblast serum response predicts human cancer progression: similarities between tumors and wounds. PLoS Biol 2004; 2: E7.

    PubMed  PubMed Central  Google Scholar 

  97. Hasebe T, Mukai K, Tsuda H, Ochiai A . New prognostic histological parameter of invasive ductal carcinoma of the breast: clinicopathological significance of fibrotic focus. Pathol Int 2000; 50: 263–272.

    CAS  PubMed  Google Scholar 

  98. Beckermann BM, Kallifatidis G, Groth A, Frommhold D, Apel A, Mattern J et al. VEGF expression by mesenchymal stem cells contributes to angiogenesis in pancreatic carcinoma. Br J Cancer 2008; 99: 622–631.

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Orimo A, Gupta PB, Sgroi DC, Arenzana-Seisdedos F, Delaunay T, Naeem R et al. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 2005; 121: 335–348.

    CAS  PubMed  Google Scholar 

  100. Littlepage LB, Egeblad M, Werb Z . Coevolution of cancer and stromal cellular response. Cancer Cell 2005; 7: 485–496.

    Google Scholar 

  101. Rigo A, Gottardi M, Zamò A, Mauri P, Bonifacio M, Krampera M et al. Macrophages may promote cancer growth via a GM-CSF/HB-EGF paracrine loop that is enhanced by CXCL12. Mol Cancer 2010; 9: 273.

    PubMed  PubMed Central  Google Scholar 

  102. Studeny M, Marini FC, Dembinski JL, Zompetta C, Cabreira-Hansen M, Bekele BN et al. Mesenchymal stem cells: potential precursors for tumor stroma and targeted-delivery vehicles for anticancer agents. J Natl Cancer Inst 2004; 96: 1593–1603.

    CAS  PubMed  Google Scholar 

  103. Sartoris S, Mazzocco M, Tinelli M, Martini M, Mosna F, Lisi V et al. Efficacy assessment of interferon-alpha-engineered mesenchymal stromal cells in a mouse plasmacytoma model. Stem Cells Dev 2011; 20: 709–719.

    CAS  PubMed  Google Scholar 

  104. Ren C, Kumar S, Chanda D, Chen J, Mountz JD, Ponnazhagan S . Therapeutic potential of mesenchymal stem cells producing interferon-á in a mouse melanoma lung metastasis model. Stem Cells 2008; 26: 2332–2338.

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Loebinger MR, Eddaoudi A, Davies D, Janes SM . Mesenchymal stem cell delivery of TRAIL can eliminate metastatic cancer. Cancer Res 2009; 69: 4134–4142.

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Nakamizo A, Marini F, Amano T, Khan A, Studeny M, Gumin J et al. Human bone marrow-derived mesenchymal stem cells in the treatment of gliomas. Cancer Res 2005; 65: 3307–3318.

    CAS  PubMed  Google Scholar 

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Acknowledgements

I would like to really thank Francesco Dazzi for helpful discussion.

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  1. Department of Medicine, Stem Cell Research Laboratory, Section of Hematology, University of Verona, Verona, Italy

    M Krampera

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Krampera, M. Mesenchymal stromal cell ‘licensing’: a multistep process. Leukemia 25, 1408–1414 (2011). https://doi.org/10.1038/leu.2011.108

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  • DOI: https://doi.org/10.1038/leu.2011.108

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