Mesenchymal stem cells and immunomodulation: Current status and future prospects

Cell Death and Disease

Volumn 7, Issue 1, 2016, Pages

  Gao, F ^a   Chiu, S M ^a   Motan, D A L ^a   Zhang, Z ^a   Chen, L ^a   Ji, H L ^b   Tse, H F ^a   Fu, Q L ^c   Lian, Q ^a  

^a UNIVERSITY OF HONG KONG   (Hong Kong)

^b UNIVERSITY OF TEXAS HEALTH CENTER   (United States)

^c SUN YAT SEN UNIVERSITY   (China)

Author keywords

[No Author keywords available]

Indexed keywords

AUTOIMMUNE DISEASE; CELL CONTACT; CELL CULTURE; CELL ISOLATION; CELL THERAPY; CELL TRANSFER; CHRONIC INFLAMMATION; CRYOPRESERVATION; GRAFT VERSUS HOST REACTION; HUMAN; IMMUNOMODULATION; IMMUNOSUPPRESSIVE TREATMENT; IMMUNOTHERAPY; MESENCHYMAL STEM CELL; NONHUMAN; PLURIPOTENT STEM CELL; PRECLINICAL STUDY; PRIORITY JOURNAL; REVIEW; STEM CELL EXPANSION; IMMUNOLOGY; MESENCHYMAL STROMA CELL;

HUMANS; IMMUNOMODULATION; MESENCHYMAL STROMAL CELLS;

EID: 84975214996     PISSN: None     EISSN: 20414889     Source Type: Journal    
DOI: 10.1038/cddis.2015.327     Document Type: Review

References (166)

1. Uccelli A, Moretta L, Pistoia V. Immunoregulatory function of mesenchymal stem cells. Eur J Immunol 2006; 36: 2566–2573.
2. Siegel G, Schafer R, Dazzi F. The immunosuppressive properties of mesenchymal stem cells. Transplantation 2009; 87(9 Suppl): S45–S49.
3. Puissant B, Barreau C, Bourin P, Clavel C, Corre J, Bousquet C et al. Immunomodulatory effect of human adipose tissue-derived adult stem cells: comparison with bone marrow mesenchymal stem cells. Br J Haematol 2005; 129: 118–129.
4. Uccelli A, Pistoia V, Moretta L. Mesenchymal stem cells: a new strategy for immunosuppression? Trends Immunol 2007; 28: 219–226.
5. Sehmi R, Baatjes AJ, Denburg JA. Hemopoietic progenitor cells and hemopoietic factors: potential targets for treatment of allergic inflammatory diseases. Curr Drug Targets Inflamm Allergy 2003; 2: 271–278.
6. Denburg JA, Inman MD, Wood L, Ellis R, Sehmi R, Dahlback M et al. Bone marrow progenitors in allergic airways diseases: studies in canine and human models. Int Arch Allergy Immunol 1997; 113: 181–183.
7. Sehmi R, Denburg JA. Haemopoietic mechanisms in allergic rhinitis. Clin Exp Allergy 2005; 35: 1–3.
8. Denburg JA, Inman MD, Sehmi R, Uno M, O'Byrne PM. Hemopoietic mechanisms in allergic airway inflammation. Int Arch Allergy Immunol 1998; 117: 155–159.
9. Yanez R, Lamana ML, Garcia-Castro J, Colmenero I, Ramirez 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.
10. 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.
11. Selmani Z, Naji A, Zidi I, Favier B, Gaiffe E, Obert L et al. 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 2008; 26: 212–222.
12. 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.
13. Burchell JT, Strickland DH, Stumbles PA. The role of dendritic cells and regulatory T cells in the regulation of allergic asthma. Pharmacol Ther 2010; 125: 1–10.
14. 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.
15. 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.
16. Trivedi P, Hematti P. Derivation and immunological characterization of mesenchymal stromal cells from human embryonic stem cells. Exp Hematol 2008; 36: 350–359.
17. Yen BL, Chang CJ, Liu KJ, Chen YC, Hu HI, Bai CH et al. Brief report–human embryonic stem cell-derived mesenchymal progenitors possess strong immunosuppressive effects toward natural killer cells as well as T lymphocytes. Stem Cells 2009; 27: 451–456.
18. Tan Z, Su ZY, Wu RR, Gu B, Liu YK, Zhao XL et al. Immunomodulative effects of mesenchymal stem cells derived from human embryonic stem cells in vivo and in vitro. J Zhejiang Univ Sci B 2011; 12: 18–27.
19. Fu QL, Chow YY, Sun SJ, Zeng QX, Li HB, Shi JB et al. Mesenchymal stem cells derived from human induced pluripotent stem cells modulate T-cell phenotypes in allergic rhinitis. Allergy 2012; 67: 1215–1222.
20. 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.
21. Rafei M, Campeau PM, Aguilar-Mahecha A, Buchanan M, Williams P, Birman E et al. Mesenchymal stromal cells ameliorate experimental autoimmune encephalomyelitis by inhibiting CD4 Th17 T cells in a CC chemokine ligand 2-dependent manner. J Immunol 2009; 182: 5994–6002.
22. Cho KS, Park HK, Park HY, Jung JS, Jeon SG, Kim YK et al. IFATS collection: immunomodulatory effects of adipose tissue-derived stem cells in an allergic rhinitis mouse model. Stem Cells 2009; 27: 259–265.
23. Cho KS, Roh HJ. Immunomodulatory effects of adipose-derived stem cells in airway allergic diseases. Curr Stem Cell Res Ther 2010; 5: 111–115.
24. Goodwin M, Sueblinvong V, Eisenhauer P, Ziats NP, LeClair L, Poynter ME et al. Bone marrow-derived mesenchymal stromal cells inhibit Th2-mediated allergic airways inflammation in mice. Stem Cells 2011; 29: 1137–1148.
25. Nemeth K, Keane-Myers A, Brown JM, Metcalfe DD, Gorham JD, Bundoc VG et al. Bone marrow stromal cells use TGF-beta to suppress allergic responses in a mouse model of ragweed-induced asthma. Proc Natl Acad Sci USA 2010; 107: 5652–5657.
26. Bonfield TL, Koloze M, Lennon DP, Zuchowski B, Yang SE, Caplan AI. Human mesenchymal stem cells suppress chronic airway inflammation in the murine ovalbumin asthma model. Am J Physiol Lung Cell Mol Physiol 2010; 299: L760–L770.
27. Bonfield TL, Nolan Koloze MT, Lennon DP, Caplan AI. Defining human mesenchymal stem cell efficacy in vivo. J Inflamm 2010; 7: 51.
28. Crop MJ, Baan CC, Korevaar SS, Ijzermans JN, Pescatori M, Stubbs AP et al. Inflammatory conditions affect gene expression and function of human adipose tissue-derived mesenchymal stem cells. Clin Exp Immunol 2010; 162: 474–486.
29. Raicevic G, Najar M, Najimi M, El Taghdouini A, van Grunsven LA, Sokal E et al. Influence of inflammation on the immunological profile of adult-derived human liver mesenchymal stromal cells and stellate cells. Cytotherapy 2015; 17: 174–185.
30. Ren G, Zhao X, Zhang L, Zhang J, L'Huillier A, Ling W et al. Inflammatory cytokine-induced intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in mesenchymal stem cells are critical for immunosuppression. J Immunol 2010; 184: 2321–2328.
31. Yagi H, Soto-Gutierrez A, Parekkadan B, Kitagawa Y, Tompkins RG, Kobayashi N et al. Mesenchymal stem cells: Mechanisms of immunomodulation and homing. Cell Transplant 2010; 19: 667–679.
32. Chabannes 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.
33. Sun YQ, Deng MX, He J, Zeng QX, Wen W, Wong DS et al. Human pluripotent stem cell-derived mesenchymal stem cells prevent allergic airway inflammation in mice. Stem Cells 2012; 30: 2692–2699.
34. 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.
35. Ryan JM, Barry F, Murphy JM, Mahon BP. Interferon-gamma does not break, but promotes the immunosuppressive capacity of adult human mesenchymal stem cells. Clin Exp Immunol 2007; 149: 353–363.
36. DelaRosa O, Lombardo E, Beraza A, Mancheno-Corvo P, Ramirez C, Menta R et al. Requirement of IFN-gamma-mediated indoleamine 2,3-dioxygenase expression in the modulation of lymphocyte proliferation by human adipose-derived stem cells. Tissue Eng Part A 2009; 15: 2795–2806.
37. 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.
38. 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.
39. Jarvinen L, Badri L, Wettlaufer S, Ohtsuka T, Standiford TJ, Toews GB et al. Lung resident mesenchymal stem cells isolated from human lung allografts inhibit T cell proliferation via a soluble mediator. J Immunol 2008; 181: 4389–4396.
40. Ge W, Jiang J, Arp J, Liu W, Garcia B, Wang H. Regulatory T-cell generation and kidney allograft tolerance induced by mesenchymal stem cells associated with indoleamine 2,3-dioxygenase expression. Transplantation 2010; 90: 1312–1320.
41. Terness P, Bauer TM, Rose L, Dufter C, Watzlik A, Simon H et al. Inhibition of allogeneic T cell proliferation by indoleamine 2,3-dioxygenase-expressing dendritic cells: mediation of suppression by tryptophan metabolites. J Exp Med 2002; 196: 447–457.
42. Mazzoni A, Bronte V, Visintin A, Spitzer JH, Apolloni E, Serafini P et al. Myeloid suppressor lines inhibit T cell responses by an NO-dependent mechanism. J Immunol 2002; 168: 689–695.
43. Wang Y, Chen X, Cao W, Shi Y. Plasticity of mesenchymal stem cells in immunomodulation: pathological and therapeutic implications. Nat Immunol 2014; 15: 1009–1016.
44. 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.
45. Sioud M, Mobergslien A, Boudabous A, Floisand Y. Mesenchymal stem cell-mediated T cell suppression occurs through secreted galectins. Int J Oncol 2011; 38: 385–390.
46. Sioud M, Mobergslien A, Boudabous A, Floisand Y. Evidence for the involvement of galectin-3 in mesenchymal stem cell suppression of allogeneic T-cell proliferation. Scand J Immunol 2010; 71: 267–274.
47. Najar M, Raicevic G, Boufker HI, Fayyad-Kazan H, De Bruyn C, Meuleman N et al. Adipose-tissue-derived and Wharton's jelly-derived mesenchymal stromal cells suppress lymphocyte responses by secreting leukemia inhibitory factor. Tissue Eng Part A 2010; 16: 3537–3546.
48. Ward PA. The sepsis seesaw: seeking a heart salve. Nat Med 2009; 15: 497–498.
49. Han KH, Ro H, Hong JH, Lee EM, Cho B, Yeom HJ et al. Immunosuppressive mechanisms of embryonic stem cells and mesenchymal stem cells in alloimmune response. Transplant Immunol 2011; 25: 7–15.
50. 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.
51. English K, Ryan JM, Tobin L, Murphy MJ, Barry FP, Mahon BP. 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. Clin Exp Immunol 2009; 156: 149–160.
52. Sheng H, Wang Y, Jin Y, Zhang Q, Zhang Y, Wang L et al. A critical role of IFNgamma in priming MSC-mediated suppression of T cell proliferation through up-regulation of B7-H1. Cell Res 2008; 18: 846–857.
53. Najar M, Raicevic G, Fayyad-Kazan H, De Bruyn C, Bron D, Toungouz M et al. Immune-related antigens, surface molecules and regulatory factors in human-derived mesenchymal stromal cells: the expression and impact of inflammatory priming. Stem Cell Rev 2012; 8: 1188–1198.
54. Gieseke F, Bohringer J, Bussolari R, Dominici M, Handgretinger R, Muller I. Human multipotent mesenchymal stromal cells use galectin-1 to inhibit immune effector cells. Blood 2010; 116: 3770–3779.
55. Lee SH, Jang AS, Kwon JH, Park SK, Won JH, Park CS. Mesenchymal stem cell transfer suppresses airway remodeling in a toluene diisocyanate-induced murine asthma model. Allergy Asthma Immunol Res 2011; 3: 205–211.
56. Firinci F, Karaman M, Baran Y, Bagriyanik A, Ayyildiz ZA, Kiray M et al. Mesenchymal stem cells ameliorate the histopathological changes in a murine model of chronic asthma. Int Immunopharmacol 2011; 11: 1120–1126.
57. Firinci F, Karaman M, Baran Y, Bagriyanik A, Ayyildiz ZA, Kiray M et al. Mesenchymal stem cells ameliorate the histopathological changes in a murine model of chronic asthma. Int Immunopharmacol 2011; 11: 1120–1126.
58. Zhang Q, Shi S, Liu Y, Uyanne J, Shi Y, Shi S et al. Mesenchymal stem cells derived from human gingiva are capable of immunomodulatory functions and ameliorate inflammation-related tissue destruction in experimental colitis. J Immunol 2009; 183: 7787–7798.
59. Bessout R, Semont A, Demarquay C, Charcosset A, Benderitter M, Mathieu N. Mesenchymal stem cell therapy induces glucocorticoid synthesis in colonic mucosa and suppresses radiation-activated T cells: new insights into MSC immunomodulation. Mucosal Immunol 2014; 7: 656–669.
60. Xiao J, Zhang C, Zhang Y, Zhang X, Zhao J, Liang J et al. Transplantation of adipose-derived mesenchymal stem cells into a murine model of passive chronic immune thrombocytopenia. Transfusion 2012; 52: 2551–2558.
61. 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.
62. Zhou B, Yuan J, Zhou Y, Ghawji M Jr, Deng YP, Lee AJ et al. Administering human adipose-derived mesenchymal stem cells to prevent and treat experimental arthritis. Clin Immunol 2011; 141: 328–337.
63. Gonzalez MA, Gonzalez-Rey E, Rico L, Buscher D, Delgado M. Treatment of experimental arthritis by inducing immune tolerance with human adipose-derived mesenchymal stem cells. Arthritis Rheum 2009; 60: 1006–1019.
64. Liu Y, Mu R, Wang S, Long L, Liu X, Li R et al. Therapeutic potential of human umbilical cord mesenchymal stem cells in the treatment of rheumatoid arthritis. Arthritis Res Ther 2010; 12: R210.
65. Sun L, Akiyama K, Zhang H, Yamaza T, Hou Y, Zhao S et al. Mesenchymal stem cell transplantation reverses multiorgan dysfunction in systemic lupus erythematosus mice and humans. Stem Cells 2009; 27: 1421–1432.
66. Chang JW, Hung SP, Wu HH, Wu WM, Yang AH, Tsai HL et al. Therapeutic effects of umbilical cord blood-derived mesenchymal stem cell transplantation in experimental lupus nephritis. Cell Transplant 2011; 20: 245–257.
67. Sun JC, Pan K, Chen MS, Wang QJ, Wang H, Ma HQ et al. Dendritic cells-mediated CTLs targeting hepatocellular carcinoma stem cells. Cancer Biol Ther 2010; 10: 368–375.
68. Gu Z, Akiyama K, Ma X, Zhang H, Feng X, Yao G et al. Transplantation of umbilical cord mesenchymal stem cells alleviates lupus nephritis in MRL/lpr mice. Lupus 2010; 19: 1502–1514.
69. Guo J, Yang J, Cao G, Fan H, Guo C, Ma YE et al. Xenogeneic immunosuppression of human umbilical cord mesenchymal stem cells in a major histocompatibility complex-mismatched allogeneic acute graft-versus-host disease murine model. Eur J Haematol 2011; 87: 235–243.
70. Oh DY, Cui P, Hosseini H, Mosse J, Toh BH, Chan J. Potently immunosuppressive 5-fluorouracil-resistant mesenchymal stromal cells completely remit an experimental autoimmune disease. J Immunol 2012; 188: 2207–2217.
71. Morando S, Vigo T, Esposito M, Casazza S, Novi G, Principato MC et al. The therapeutic effect of mesenchymal stem cell transplantation in experimental autoimmune encephalomyelitis is mediated by peripheral and central mechanisms. Stem Cell Res Ther 2012; 3: 3.
72. Liu XJ, Zhang JF, Sun B, Peng HS, Kong QF, Bai SS et al. Reciprocal effect of mesenchymal stem cell on experimental autoimmune encephalomyelitis is mediated by transforming growth factor-beta and interleukin-6. Clin Exp Immunol 2009; 158: 37–44.
73. Choi EW, Shin IS, Lee HW, Park SY, Park JH, Nam MH et al. Transplantation of CTLA4Ig gene-transduced adipose tissue-derived mesenchymal stem cells reduces inflammatory immune response and improves Th1/Th2 balance in experimental autoimmune thyroiditis. J Gene Med 2011; 13: 3–16.
74. Yu J, Zheng C, Ren X, Li J, Liu M, Zhang L et al. Intravenous administration of bone marrow mesenchymal stem cells benefits experimental autoimmune myasthenia gravis mice through an immunomodulatory action. Scand J Immunol 2010; 72: 242–249.
75. Zhou Y, Yuan J, Zhou B, Lee AJ, Lee AJ, Ghawji M Jr et al. The therapeutic efficacy of human adipose tissue-derived mesenchymal stem cells on experimental autoimmune hearing loss in mice. Immunology 2011; 133: 133–140.
76. Wang D, Zhang H, Liang J, Gu Z, Ma X, Huang J et al. Effect of allogeneic bone marrow-derived mesenchymal stem cells transplantation in a polyI:C-induced primary biliary cirrhosis mouse model. Clin Exp Med 2011; 11: 25–32.
77. Yang H, Aprecio RM, Zhou X, Wang Q, Zhang W, Ding Y et al. Therapeutic effect of TSG-6 engineered iPSC-derived MSCs on experimental periodontitis in rats: a pilot study. PLoS One 2014; 9: e100285.
78. Cheng PP, Liu XC, Ma PF, Gao C, Li JL, Lin YY et al. iPSC-MSCs combined with low-dose rapamycin induced islet allograft tolerance through suppressing Th1 and enhancing regulatory T-cell differentiation. Stem Cells Dev 2015; 24: 1793–1804.
79. Zhang Y, Liao S, Yang M, Liang X, Poon MW, Wong CY et al. Improved cell survival and paracrine capacity of human embryonic stem cell-derived mesenchymal stem cells promote therapeutic potential for pulmonary arterial hypertension. Cell Transplant 2012; 21: 2225–2239.
80. Sun YQ, Zhang Y, Li X, Deng MX, Gao WX, Yao Y et al. Insensitivity of human iPS cells-derived mesenchymal stem cells to interferon-gamma-induced HLA expression potentiates repair efficiency of hind limb ischemia in immune humanized NOD SCID gamma mice. Stem Cells 2015; e-pub ahead of print 14 July 2015; doi:10.1002/stem.2094.
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.
82. Perez-Simon JA, Lopez-Villar O, Andreu EJ, Rifon J, Muntion S, Campelo MD et al. Mesenchymal stem cells expanded in vitro with human serum for the treatment of acute and chronic graft-versus-host disease: results of a phase I/II clinical trial. Haematologica 2011; 96: 1072–1076.
83. Muller I, Kordowich S, Holzwarth C, Isensee G, Lang P, Neunhoeffer F et al. Application of multipotent mesenchymal stromal cells in pediatric patients following allogeneic stem cell transplantation. Blood Cells Mol Dis 2008; 40: 25–32.
84. Baron F, Lechanteur C, Willems E, Bruck F, Baudoux E, Seidel L et al. Cotransplantation of mesenchymal stem cells might prevent death from graft-versus-host disease (GVHD) without abrogating graft-versus-tumor effects after HLA-mismatched allogeneic transplantation following nonmyeloablative conditioning. Biol Blood Marrow Transplant 2010; 16: 838–847.
85. Arima N, Nakamura F, Fukunaga A, Hirata H, Machida H, Kouno S et al. Single intra-arterial injection of mesenchymal stromal cells for treatment of steroid-refractory acute graft-versus-host disease: a pilot study. Cytotherapy 2010; 12: 265–268.
86. Zhou H, Guo M, Bian C, Sun Z, Yang Z, Zeng Y et al. Efficacy of bone marrow-derived mesenchymal stem cells in the treatment of sclerodermatous chronic graft-versus-host disease: clinical report. Biol Blood Marrow Transplant 2010; 16: 403–412.
87. Kebriaei P, Isola L, Bahceci E, Holland K, Rowley S, McGuirk J et al. Adult human mesenchymal stem cells added to corticosteroid therapy for the treatment of acute graft-versus-host disease. Biol Blood Marrow Transplant 2009; 15: 804–811.
88. Ringden O, Uzunel M, Rasmusson I, Remberger M, Sundberg B, Lonnies H et al. Mesenchymal stem cells for treatment of therapy-resistant graft-versus-host disease. Transplantation 2006; 81: 1390–1397.
89. Connick P, Kolappan M, Patani R, Scott MA, Crawley C, He XL et al. The mesenchymal stem cells in multiple sclerosis (MSCIMS) trial protocol and baseline cohort characteristics: an open-label pre-test: post-test study with blinded outcome assessments. Trials 2011; 12: 62.
90. Connick P, Kolappan M, Crawley C, Webber DJ, Patani R, Michell AW et al. Autologous mesenchymal stem cells for the treatment of secondary progressive multiple sclerosis: an open-label phase 2a proof-of-concept study. Lancet Neurol 2012; 11: 150–156.
91. Karussis D, Karageorgiou C, Vaknin-Dembinsky A, Gowda-Kurkalli B, Gomori JM, Kassis I et al. Safety and immunological effects of mesenchymal stem cell transplantation in patients with multiple sclerosis and amyotrophic lateral sclerosis. Arch Neurol 2010; 67: 1187–1194.
92. Yamout B, Hourani R, Salti H, Barada W, El-Hajj T, Al-Kutoubi A et al. Bone marrow mesenchymal stem cell transplantation in patients with multiple sclerosis: a pilot study. J Neuroimmunol 2010; 227: 185–189.
93. Wang D, Li J, Zhang Y, Zhang M, Chen J, Li X et al. Umbilical cord mesenchymal stem cell transplantation in active and refractory systemic lupus erythematosus: a multicenter clinical study. Arthritis Res Ther 2014; 16: R79.
94. Wang D, Zhang H, Liang J, Li X, Feng X, Wang H et al. Allogeneic mesenchymal stem cell transplantation in severe and refractory systemic lupus erythematosus: 4 years of experience. Cell Transplant 2013; 22: 2267–2277.
95. Carrion F, Nova E, Ruiz C, Diaz F, Inostroza C, Rojo D et al. Autologous mesenchymal stem cell treatment increased T regulatory cells with no effect on disease activity in two systemic lupus erythematosus patients. Lupus 2010; 19: 317–322.
96. Lu D, Chen B, Liang Z, Deng W, Jiang Y, Li S et al. Comparison of bone marrow mesenchymal stem cells with bone marrow-derived mononuclear cells for treatment of diabetic critical limb ischemia and foot ulcer: a double-blind, randomized, controlled trial. Diabetes Res Clin Pract 2011; 92: 26–36.
97. Ciccocioppo R, Bernardo ME, Sgarella A, Maccario R, Avanzini MA, Ubezio C et al. Autologous bone marrow-derived mesenchymal stromal cells in the treatment of fistulising Crohn's disease. Gut 2011; 60: 788–798.
98. Garcia-Olmo D, Garcia-Arranz M, Herreros D, Pascual I, Peiro C, Rodriguez-Montes JA. A phase I clinical trial of the treatment of Crohn's fistula by adipose mesenchymal stem cell transplantation. Dis Colon Rectum 2005; 48: 1416–1423.
99. Lazebnik LB, Kniazev OV, Konopliannikov AG, Parfenov AI, Ruchkina IN, Mikhailova ZF et al. [Allogeneic mesenchymal stromal cells in patients with ulcerative colitis: two years of observation]. Eksp Klin Gastroenterol 2010; 11: 3–15.
100. Perico N, Casiraghi F, Gotti E, Introna M, Todeschini M, Cavinato RA et al. Mesenchymal stromal cells and kidney transplantation: pretransplant infusion protects from graft dysfunction while fostering immunoregulation. Transpl Int 2013; 26: 867–878.
101. Mohamadnejad M, Alimoghaddam K, Mohyeddin-Bonab M, Bagheri M, Bashtar M, Ghanaati H et al. Phase 1 trial of autologous bone marrow mesenchymal stem cell transplantation in patients with decompensated liver cirrhosis. Arch Iran Med 2007; 10: 459–466.
102. Kharaziha P, Hellstrom PM, Noorinayer B, Farzaneh F, Aghajani K, Jafari F et al. Improvement of liver function in liver cirrhosis patients after autologous mesenchymal stem cell injection: a phase I-II clinical trial. Eur J Gastroenterol Hepatol 2009; 21: 1199–1205.
103. Amer ME, El-Sayed SZ, El-Kheir WA, Gabr H, Gomaa AA, El-Noomani N et al. Clinical and laboratory evaluation of patients with end-stage liver cell failure injected with bone marrow-derived hepatocyte-like cells. Eur J Gastroenterol Hepatol 2011; 23: 936–941.
104. El-Ansary M, Abdel-Aziz I, Mogawer S, Abdel-Hamid S, Hammam O, Teaema S et al. Phase II trial: undifferentiated versus differentiated autologous mesenchymal stem cells transplantation in Egyptian patients with HCV induced liver cirrhosis. Stem Cell Rev 2012; 8: 972–981.
105. Sharma RR, Pollock K, Hubel A, McKenna D. Mesenchymal stem or stromal cells: a review of clinical applications and manufacturing practices. Transfusion 2014; 54: 1418–1437.
106. Duijvestein M, Vos AC, Roelofs H, Wildenberg ME, Wendrich BB, Verspaget HW et al. Autologous bone marrow-derived mesenchymal stromal cell treatment for refractory luminal Crohn's disease: results of a phase I study. Gut 2010; 59: 1662–1669.
107. Ning H, Yang F, Jiang M, Hu L, Feng K, Zhang J et al. The correlation between cotransplantation of mesenchymal stem cells and higher recurrence rate in hematologic malignancy patients: outcome of a pilot clinical study. Leukemia 2008; 22: 593–599.
108. Galderisi U, Giordano A. The gap between the physiological and therapeutic roles of mesenchymal stem cells. Med Res Rev 2014; 34: 1100–1126.
109. Komada Y, Yamane T, Kadota D, Isono K, Takakura N, Hayashi S et al. Origins and properties of dental, thymic, and bone marrow mesenchymal cells and their stem cells. PLoS One 2012; 7: e46436.
110. Covas DT, Piccinato CE, Orellana MD, Siufi JL, Silva WA Jr, Proto-Siqueira R et al. Mesenchymal stem cells can be obtained from the human saphena vein. Exp Cell Res 2005; 309: 340–344.
111. Patel J, Shafiee A, Wang W, Fisk NM, Khosrotehrani K. Novel isolation strategy to deliver pure fetal-origin and maternal-origin mesenchymal stem cell (MSC) populations from human term placenta. Placenta 2014; 35: 969–971.
112. Campagnoli C, Roberts IA, Kumar S, Bennett PR, Bellantuono I, Fisk NM. Identification of mesenchymal stem/progenitor cells in human first-trimester fetal blood, liver, and bone marrow. Blood 2001; 98: 2396–2402.
113. Ribeiro A, Laranjeira P, Mendes S, Velada I, Leite C, Andrade P et al. Mesenchymal stem cells from umbilical cord matrix, adipose tissue and bone marrow exhibit different capability to suppress peripheral blood B, natural killer and T cells. Stem Cell Res Ther 2013; 4: 125.
114. in 't Anker PS, Noort WA, Scherjon SA, Kleijburg-van der Keur C, Kruisselbrink AB, van Bezooijen RL et al. Mesenchymal stem cells in human second-trimester bone marrow, liver, lung, and spleen exhibit a similar immunophenotype but a heterogeneous multilineage differentiation potential. Haematologica 2003; 88: 845–852.
115. Kilpinen L, Tigistu-Sahle F, Oja S, Greco D, Parmar A, Saavalainen P et al. Aging bone marrow mesenchymal stromal cells have altered membranecomposition and functionality. J Lipid Res 2013; 54: 622–635.
116. Wagner W, Bork S, Horn P, Krunic D, Walenda T, Diehlmann A et al. Aging and replicative senescence have related effects on human stem and progenitor cells. PLoS One 2009; 4: e5846.
117. Stolzing A, Jones E, McGonagle D, Scutt A. Age-related changes in human bone marrow-derived mesenchymal stem cells: consequences for cell therapies. Mech Ageing Dev 2008; 129: 163–173.
118. Sundin M, Ringden O, Sundberg B, Nava S, Gotherstrom C, Le Blanc K. No alloantibodies against mesenchymal stromal cells, but presence of anti-fetal calf serum antibodies, after transplantation in allogeneic hematopoietic stem cell recipients. Haematologica 2007; 92: 1208–1215.
119. Bieback K, Hecker A, Kocaomer A, Lannert H, Schallmoser K, Strunk D et al. Human alternatives to fetal bovine serum for the expansion of mesenchymal stromal cells from bone marrow. Stem Cells 2009; 27: 2331–2341.
120. Shahdadfar A, Fronsdal K, Haug T, Reinholt FP, Brinchmann JE. In vitro expansion of human mesenchymal stem cells: choice of serum is a determinant of cell proliferation, differentiation, gene expression, and transcriptome stability. Stem Cells 2005; 23: 1357–1366.
121. Banfi A, Muraglia A, Dozin B, Mastrogiacomo M, Cancedda R, Quarto R. Proliferation kinetics and differentiation potential of ex vivo expanded human bone marrow stromal cells: implications for their use in cell therapy. Exp Hematol 2000; 28: 707–715.
122. Berniakovich I, Giorgio M. Low oxygen tension maintains multipotency, whereas normoxia increases differentiation of mouse bone marrow stromal cells. Int J Mol Sci 2013; 14: 2119–2134.
123. Yoo HS, Yi T, Cho YK, Kim WC, Song SU, Jeon MS. Mesenchymal stem cell lines isolated by different isolation methods show variations in the regulation of graft-versus-host disease. Immune Netw 2013; 13: 133–140.
124. Holubova M, Lysak D, Vlas T, Vannucci L, Jindra P. Expanded cryopreserved mesenchymal stromal cells as an optimal source for graft-versus-host disease treatment. Biologicals 2014; 42: 139–144.
125. Galipeau J. The mesenchymal stromal cells dilemma–does a negative phase III trial of random donor mesenchymal stromal cells in steroid-resistant graft-versus-host disease represent a death knell or a bump in the road? Cytotherapy 2013; 15: 2–8.
126. Herrmann R, Sturm M, Shaw K, Purtill D, Cooney J, Wright M et al. Mesenchymal stromal cell therapy for steroid-refractory acute and chronic graft versus host disease: a phase 1 study. Int J Hematol 2012; 95: 182–188.
127. Prasad VK, Lucas KG, Kleiner GI, Talano JA, Jacobsohn D, Broadwater G et al. Efficacy and safety of ex vivo cultured adult human mesenchymal stem cells (Prochymal) in pediatric patients with severe refractory acute graft-versus-host disease in a compassionate use study. Biol Blood Marrow Transplant 2011; 17: 534–541.
128. Nauta AJ, Westerhuis G, Kruisselbrink AB, Lurvink EG, Willemze R, Fibbe WE. Donor-derived mesenchymal stem cells are immunogenic in an allogeneic host and stimulate donor graft rejection in a nonmyeloablative setting. Blood 2006; 108: 2114–2120.
129. Eliopoulos N, Stagg J, Lejeune L, Pommey S, Galipeau J. Allogeneic marrow stromal cells are immune rejected by MHC class I-and class II-mismatched recipient mice. Blood 2005; 106: 4057–4065.
130. 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.
131. Wang H, Pang B, Li Y, Zhu D, Pang T, Liu Y. Dexamethasone has variable effects on mesenchymal stromal cells. Cytotherapy 2012; 14: 423–430.
132. Perez-Simon JA, Lopez-Villar O, Andreu EJ, Rifon J, Muntion S, Diez Campelo M et al. Mesenchymal stem cells expanded in vitro with human serum for the treatment of acute and chronic graft-versus-host disease: results of a phase I/II clinical trial. Haematologica 2011; 96: 1072–1076.
133. Mohyeddin Bonab M, Yazdanbakhsh S, Lotfi J, Alimoghaddom K, Talebian F, Hooshmand F et al. Does mesenchymal stem cell therapy help multiple sclerosis patients? Report of a pilot study. Iran J Immunol 2007; 4: 50–57.
134. Wang HS, Hung SC, Peng ST, Huang CC, Wei HM, Guo YJ et al. Mesenchymal stem cells in the Wharton's jelly of the human umbilical cord. Stem Cells 2004; 22: 1330–1337.
135. Lee RH, Kim B, Choi I, Kim H, Choi HS, Suh K et al. Characterization and expression analysis of mesenchymal stem cells from human bone marrow and adipose tissue. Cell Physiol Biochem 2004; 14: 311–324.
136. Crisostomo PR, Wang M, Wairiuko GM, Morrell ED, Terrell AM, Seshadri P et al. High passage number of stem cells adversely affects stem cell activation and myocardial protection. Shock 2006; 26: 575–580.
137. Heeschen C, Lehmann R, Honold J, Assmus B, Aicher A, Walter DH et al. Profoundly reduced neovascularization capacity of bone marrow mononuclear cells derived from patients with chronic ischemic heart disease. Circulation 2004; 109: 1615–1622.
138. Roobrouck VD, Ulloa-Montoya F, Verfaillie CM. Self-renewal and differentiation capacity of young and aged stem cells. Exp Cell Res 2008; 314: 1937–1944.
139. Villa-Diaz LG, Brown SE, Liu Y, Ross AM, Lahann J, Parent JM et al. Derivation of mesenchymal stem cells from human induced pluripotent stem cells cultured on synthetic substrates. Stem Cells 2012; 30: 1174–1181.
140. Frobel J, Hemeda H, Lenz M, Abagnale G, Joussen S, Denecke B et al. Epigenetic rejuvenation of mesenchymal stromal cells derived from induced pluripotent stem cells. Stem Cell Rep 2014; 3: 414–422.
141. Lian Q, Zhang Y, Zhang J, Zhang HK, Wu X, Zhang Y et al. Functional mesenchymal stem cells derived from human induced pluripotent stem cells attenuate limb ischemia in mice. Circulation 2010; 121: 1113–1123.
142. Lian Q, Lye E, Suan Yeo K, Khia Way Tan E, Salto-Tellez M, Liu TM et al. Derivation of clinically compliant MSCs from CD105+, CD24-differentiated human ESCs. Stem Cells 2007; 25: 425–436.
143. Tannenbaum SE, Turetsky TT, Singer O, Aizenman E, Kirshberg S, Ilouz N et al. Derivation of xeno-free and GMP-grade human embryonic stem cells–platforms for future clinical applications. PLoS One 2012; 7: e35325.
144. Ausubel LJ, Lopez PM, Couture LA. GMP scale-up and banking of pluripotent stem cells for cellular therapy applications. Methods Mol Biol 2011; 767: 147–159.
145. Luzzani C, Neiman G, Garate X, Questa M, Solari C, Fernandez Espinosa D et al. A therapy-grade protocol for differentiation of pluripotent stem cells into mesenchymal stem cells using platelet lysate as supplement. Stem Cell Res Ther 2015; 6: 6.
146. Deak E, Seifried E, Henschler R. Homing pathways of mesenchymal stromal cells (MSCs) and their role in clinical applications. Int Rev Immunol 2010; 29: 514–529.
147. Ip JE, Wu Y, Huang J, Zhang L, Pratt RE, Dzau VJ. Mesenchymal stem cells use integrin beta1 not CXC chemokine receptor 4 for myocardial migration and engraftment. Mol Biol Cell 2007; 18: 2873–2882.
148. Haider H, Jiang S, Idris NM, Ashraf M. IGF-1-overexpressing mesenchymal stem cells accelerate bone marrow stem cell mobilization via paracrine activation of SDF-1alpha/CXCR4 signaling to promote myocardial repair. Circ Res 2008; 103: 1300–1308.
149. Li H, Jiang Y, Jiang X, Guo X, Ning H, Li Y et al. CCR7 guides migration of mesenchymal stem cell to secondary lymphoid organs: a novel approach to separate GvHD from GvL effect. Stem Cells 2014; 32: 1890–1903.
150. 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.
151. Su WR, Zhang QZ, Shi SH, Nguyen AL, Le AD. Human gingiva-derived mesenchymal stromal cells attenuate contact hypersensitivity via prostaglandin E2-dependent mechanisms. Stem Cells 2011; 29: 1849–1860.
152. Kavanagh H, Mahon BP. Allogeneic mesenchymal stem cells prevent allergic airway inflammation by inducing murine regulatory T cells. Allergy 2011; 66: 523–531.
153. Ou-Yang HF, Huang Y, Hu XB, Wu CG. Suppression of allergic airway inflammation in a mouse model of asthma by exogenous mesenchymal stem cells. Exp Biol Med 2011; 236: 1461–1467.
154. Park HK, Cho KS, Park HY, Shin DH, Kim YK, Jung JS et al. Adipose-derived stromal cells inhibit allergic airway inflammation in mice. Stem Cells Dev 2010; 19: 1811–1818.
155. Odinak MM, Bisaga GN, Novitskii AV, Tyrenko VV, Fominykh MS, Bilibina AA et al. [Transplantation of mesenchymal stem cells in multiple sclerosis]. Zh Nevrol Psikhiatr Im SS Korsakova 2011; 111: 72–76.
156. Mohajeri M, Farazmand A, Mohyeddin Bonab M, Nikbin B, Minagar A. FOXP3 gene expression in multiple sclerosis patients pre-and post mesenchymal stem cell therapy. Iran J Allergy Asthma Immunol 2011; 10: 155–161.
157. Llufriu S, Sepulveda M, Blanco Y, Marin P, Moreno B, Berenguer J et al. Randomized placebo-controlled phase II trial of autologous mesenchymal stem cells in multiple sclerosis. PLoS One 2014; 9: e113936.
158. Lublin FD, Bowen JD, Huddlestone J, Kremenchutzky M, Carpenter A, Corboy JR et al. Human placenta-derived cells (PDA-001) for the treatment of adults with multiple sclerosis: a randomized, placebo-controlled, multiple-dose study. Mult Scler Relat Disord 2014; 3: 696–704.
159. Tan J, Wu W, Xu X, Liao L, Zheng F, Messinger S et al. Induction therapy with autologous mesenchymal stem cells in living-related kidney transplants: a randomized controlled trial. JAMA 2012; 307: 1169–1177.
160. Perico N, Casiraghi F, Introna M, Gotti E, Todeschini M, Cavinato RA et al. Autologous mesenchymal stromal cells and kidney transplantation: a pilot study of safety and clinical feasibility. Clin J Am Soc Nephrol 2011; 6: 412–422.
161. Reinders ME, de Fijter JW, Roelofs H, Bajema IM, de Vries DK, Schaapherder AF et al. Autologous bone marrow-derived mesenchymal stromal cells for the treatment of allograft rejection after renal transplantation: results of a phase I study. Stem Cells Transl Med 2013; 2: 107–111.
162. Jiang R, Han Z, Zhuo G, Qu X, Li X, Wang X et al. Transplantation of placenta-derived mesenchymal stem cells in type 2 diabetes: a pilot study. Front Med 2011; 5: 94–100.
163. Davatchi F, Abdollahi BS, Mohyeddin M, Shahram F, Nikbin B. Mesenchymal stem cell therapy for knee osteoarthritis. Preliminary report of four patients. Int J Rheum Dis 2011; 14: 211–215.
164. Mayer L, Pandak WM, Melmed GY, Hanauer SB, Johnson K, Payne D et al. Safety and tolerability of human placenta-derived cells (PDA001) in treatment-resistant crohn's disease: a phase 1 study. Inflamm Bowel Dis 2013; 19: 754–760.
165. Forbes GM, Sturm MJ, Leong RW, Sparrow MP, Segarajasingam D, Cummins AG et al. A phase 2 study of allogeneic mesenchymal stromal cells for luminal Crohn's disease refractory to biologic therapy. Clin Gastroenterol Hepatol 2014; 12: 64–71.
166. Liang J, Zhang H, Hua B, Wang H, Lu L, Shi S et al. Allogenic mesenchymal stem cells transplantation in refractory systemic lupus erythematosus: a pilot clinical study. Ann Rheum Dis 2010; 69: 1423–1429.