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  • Cited by 3
  • Print publication year: 2011
  • Online publication date: December 2011

45 - Mesenchymal stem cell transplantation to treat multiple sclerosis

from Section III - Clinical trials of multiple sclerosis therapies

Summary

Treatment of multiple sclerosis (MS) with pulses of high dose methylprednisolone (HDMP) is currently the treatment of choice for MS relapses in many parts of the world. The use of corticosteroids as a treatment for MS was first reported in 1951. There is emerging evidence regarding the benefits of HDMP administered in pulses on the course of MS, either alone or in combination with other disease modifying therapy. HDMP was found to improve Expanded Disability Status Scale (EDSS) better than placebo, with improvements primarily in pyramidal, cerebellar, and sensory systems. In general, corticosteroid toxicity is reduced with short-term pulsed administration of HDMP. Altogether, numerous clinical and magnetic resonance imaging (MRI) studies suggest that HDMP not only has transient beneficial effects on clinical relapses and established areas of inflammation and demyelination, but may also have a prolonged, dose-dependent benefit involving early events in MS lesion formation, lesion propagation, and lesion recovery.

References

1. Wilson A, Trumpp A. Bone-marrow haematopoietic-stem-cell niches. Nature Rev Immunol 2006; 6:93–106.
2. Prockop DJ. Marrow stromal cells as stem cells for nonhematopoietic tissues. Science 1997; 276:71–4.
3. Pittenger MF, Mackay AM, Beck SC, et al. Multilineage potential of adult human mesenchymal stem cells. Science 1999; 284:143–7.
4. Da Silva Meirelles L, Caplan AI, Nardi NB. In search of the in vivo identity of mesenchymal stem cells. Stem Cells 2008; 26:2287–99.
5. Dominici M, Le Blanc K, Mueller I, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society fo Cellular Therapy position statement. Cytotherapy. 2006; 8:315–17.
6. Barry FP, Boynton RE, Haynesworth S, Murphy JM, Zaia J. The monoclonal antibody SH-2, raised against human mesenchymal stem cells, recognizes an epitope on endoglin (CD 105). Biochem Biophys Res Commun 1999; 265:134–9.
7. Barry F, Boynton R, Murshy M, Zaia J. The SH-3 and SH-4 antibodies recognize distinct epitopes on CD73 from human mesenchymal stem cells. Biochem Biophys Res Commun 2001; 289:519–24.
8. Majumdar MK, Thiede MA, Mosca JD, Moorman M, Gerson SL. Phenotypic and functional comparison of cultures of marrow-derived mesenchymal stem cells (MSCs) and stromal cells. J Cell Physiol 1998; 176:57–66.
9. Deans RJ, Moseley AB. Mesenchymal stem cells: Biology and potential clinical uses. Exp Hematol 2000; 28:875–84.
10. Roufosse CA, Direkze NC, Otto WR, Wright NA. Circulating mesenchymal stem cells. Int J Biochem Cell Biol 2004; 36:585–97.
11. Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 2005; 105:1815–22.
12. Le Blanc K, Ringden O. Immunobiology of human mesenchymal stem cells and future use in hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2005; 11:321–34.
13. Stagg J. Immune regulation by mesenchymal stem cells: two sides to the coin. Tissue Antigens 2006; 69:1–9.
14. Noel D, Djouad F, Bouffi C, Mrugala D, Jorgensen C. Multipotent mesenchymal stromal cells and immune tolerance. Leuk Lymphoma 2007; 48:1283–9.
15. Pelagiadis I, Dimitriou H, Kalmanti M. Biologic characteristics of mesenchymal stromal cells and their clinical applications in pediatric patients. J Pediatr Hematol Oncol 2008; 30:301–9.
16. Chen X, Li Y, Wang L, et al. Ischemic rat brain extracts induce human bone marrow stromal cell growth factor production. Neuropathology 2002; 22:275–9.
17. Uccelli A, Moretta L, Pistoia V. Immunoregulatory function of mesenchymal stem cells. Eur J Immunol. 2006; 36:2566–73.
18. Newman RE, Yoo D, LeRoux MA, Danilkovitch-Miagkova A. Treatment of inflammatory diseases with mesenchymal stem cells. Inflammation Allergy–Drug Targets 2009; 8:110–23.
19. Bartholomew A, Sturgeon C, Siatskas M, et al. Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Exp Hematol 2002; 30:42–8.
20. Di Nicola M, Carlo-Stella C, Magni M, et al. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 2002; 99:3838–43.
21. Le Blanc K, Tammik L, Sundberg B, Haynesworth SE, Ringden O. Mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and mitogenic responses independently of the major histocompatability complex. Scand J Immunol 2003; 57:11–20.
22. 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; 75:389–97.
23. Djouad F, Pience P, Bony C, et al. Immunosuppressive effect of mesenchymal stem cells favors tumor growth in allogeneic animals. Blood 2003; 102:3837–44.
24. Le Blanc K, Rasmusson I, Gotherstrom C, et al. Mesenchymal stem cells inhibit the expression of CD25 (interleukin-2 receptor) and CD38 on phytohaemagglutinin-activated lymphocytes. Scand J Immunol 2004; 60:307–15.
25. Zappia E, Casazza S, Pedemonte E, et al. Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T-cell anergy. Blood 2005; 106:1755–61.
26. Darlington PJ, Boivin M-N, Renoux C, et al. Reciprocal Th1 and Th17 regulation by mesenchymal stem cells: implications for MS. Ann Neurol 2010; 68:540–5.
27. Krampera M, Glennie S, Dyson J, et al. Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigen-specific T cells to their cognate peptide. Blood 2003; 101:3722–9.
28. Glennie S, Soeiro I, Dyson PJ, Lam EW-F, Dazzi F. Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells. Blood 2005; 105:2821–7.
29. 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; 171:3426–34.
30. Meisel R, Zibert A, Laryea M, et al. Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase-mediated tryptophan degradation. Blood 2004; 103:4619–21.
31. Beyth S, Borovsky Z, Mevorach D, et al. Human mesenchymal stem cells alter antigen-presenting cell maturation and induce T-cell unresponsiveness. Blood. 2005; 105:2214–19.
32. Rasmusson I, Ringden O, Sundberg B, Le Blanc K. Mesenchymal stem cells inhibit the formation of cytotoxic T lymphocytes, but not activated cytotoxic T lymphocytes or natural killer cells. Transplantation 2003; 76:1208–13.
33. Chabannes D, Hill M, Merieau E, et al. A role for heme oxygenase-1 in the immunosuppressive effect of adult rat and human mesenchymal stem cells. Blood 2007; 110:3691–4.
34. Nasef A, Mathieu N, Chapel A, et al. Immunosuppressive effects of mesenchymal stem cells: involvement of HLA-G. Transplantation 2007; 84:231–7.
35. Gerdoni E, Gallo B, Casazza S, et al. Mesenchymal stem cells effectively modulate pathogenic immune response in experimental autoimmune encephalomyelitis. Ann Neurol 2007; 61:219–27.
36. Corcione A, Benvenuto F, Ferretti E, et al. Human mesenchymal stem cells modulate B-cell functions. Blood 2006; 107:367–72.
37. Traggiai E, Volpi S, Schena FP, 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; 26:562–9.
38. 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; 107:1484–90.
39. Jiang X-X, Zhang Y, Liu B, et al. Human mesenchymal stem cells inhibit differentiation and function of monocyte-derived dendritic cells. Blood 2005; 105:4120–6.
40. Ramasamy R, Fazekasova H, Lam EW-F, et al. Mesenchymal stem cells inhibit dendritic cell differentiation and function by preventing entry into the cell cycle. Transplantation 2007; 83:71–6.
41. Ishida T, Inaba M, Hisha H, et al. Requirement of donor-derived stromal cells in the bone marrow for successful allogeneic bone marrow transplantation. Complete prevention of recurrence of autoimmune diseases in MRL/MP-lpr/lpr mice by transplantation of bone marrow plus bones (stromal cells) from the same donor. J Immunol 1994; 152:3119–27.
42. Karussis DM, Grigoriadis N, Ben-Hur T, et al. Mesenchymal bone marrow stem cells migrate in CNS lesions in experimental autoimmune encephalomyelitis, differentiate into neuronal and glial line and downregulate EAE (abstract). Neurology 2005; 64(Suppl 1):A407.
43. Karussis D, Kassis I. Use of stem cells for the treatment of multiple sclerosis. Expert Rev Neurotherap. 2007; 7:1189–201.
44. Zhang J, Li Y, Chen J, et al. Human bone marrow stromal cell treatment improves neurological functional recovery in EAE mice. Exp Neurol 2005; 195:16–26.
45. Einstein O, Fainstein N, Vaknin I, et al. Neural precursors attenuate autoimmune encephalomyelitis by peripheral immunosuppression. Ann Neurol 2007; 61:209–18.
46. Klyushnenkova E, Mosca JD, Zernetkina V, et al. T cell responses to allogeneic human mesenchymal stem cells: immunogenicity, tolerance, and suppression. J Biomed Sci 2005; 12:47–57.
47. Rasmusson I, Uhlin M, Le Blanc K, Levitsky V. Mesenchymal stem cells fail to trigger effector functions of cytotoxic T lymphocytes. J Leukoc Biol 2007; 82:887–93.
48. Lazarus HM, Haynesworth SE, Gerson SL, Rosenthal NS, Caplan AI. Ex vivo expansion and subsequent infusion of human bone marrow-derived stromal progenitor cells (mesenchymal progenitor cells): implications for therapeutic use. Bone Marrow Transplant 1995; 16:557–64.
49. Koc ON, Gerson SL, Cooper BW, et al. Rapid hematopoietic recovery after coinfusion of autologous-blood stem cells and culture-expanded marrow mesenchymal stem cells in advanced breast cancer patients receiving high-dose chemotherapy. J Clin Oncol 2000; 18:307–16.
50. Lee ST, Jang JH, Cheong J-W, Kim JS, Maemg H-Y. Treatment of high-risk acute myelogenous leukaemia by myeloablative chemoradiotherapy followed by co-infusion of T cell depleted haematopoietic stem cells and culture-expanded marrow mesenchymal cells from a related donor with one fully mismatched human leucocyte antigen haplotype. Br J Haematol 2002; 118:1128–31.
51. MacMillan ML, Blazar BR, DeFor TE, Wagner JE. Transplantation of ex-vivo culture-expanded parental haploidentical mesenchymal stem cells to promote engraftment in pediatric recipients of unrelated donor umbilical cord blood: results of a phase I-II clinical trial. Bone Marrow Transplant 2009; 43:447–54.
52. Liu K, chen Y, Xu L, et al. A randomized controlled clinical study: co-infusion of mesenchymal stromal cells facilitates platelet recovery without increasing leukemia recurrence in haploidentical hematopoietic stem cell transplantation. Stem Cells Dev 2011;in press.
53. Frassoni F, Labopin M, Bacigalupo A, et al. Expanded mesenchymal stem cells (MSC), co-infused with HLA identical hematopoietic stem cell transplants, reduce acute and chronic graft versus host disease: a matched pair analysis (abstract). Bone Marrow Transplant 2002; 29(Suppl 2):S2.
54. Le Blanc K, Rasmusson I, Sundberg B, et al. Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet 2004; 363:1439–41.
55. Ringden O, Uzunel M, Rasmusson I, et al. Mesenchymal stem cells for treatment of therapy-resistant graft-versus-host disease. Transplantation 2006; 81:1390–7.
56. Ringden O, Uzunel M, Sundberg B, et al. Tissue repair using allogeneic mesenchymal stem cells for hemorrhagic cystitis, pneumomediastinum and perforated colon. Leukemia 2007; 21:2271–6.
57. Ball L, Bredius R, Klankester A, et al. Third party mesenchymal stromal cell infusions fail to induce tissue repair despite successful control of severe grade i.v. acute graft-versus-host disease in a child with juvenile myelo-monocytic leukemia. Leukemia, 2008; 22:1256–7.
58. Le Blanc K, Frassoni F, Ball L, et al. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet 2008; 371:1579–86.
59. Kebriaei P, Isola L, Bahceci E, 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; 15:804–11.
60. Prasad VK, Lucas KG, Kleiner GI, et al. Efficacy and safety of ex-vivo cultured adult mesenchymal stem cells (Prochymal) in pediatric patients with severe refractory acute graft-versus-host disease in a compassionate use study. Biol Blood Marrow Transpl 2011; 17:534–41.
61. Zhou H, Guo M, Bian C, 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; 16:404–12.
62. Arima N, Nakamura F, Fukunaga A, 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; 12:265–8.
63. Fouillard L, Bensidhoum M, Bories D, et al. Engraftment of allogeneic mesenchymal stem cells in the bone marrow of a patient with severe idiopathic aplastic anemia improves stroma. Leukemia 2003; 17:474–6.
64. Assmus B, Schachinger V, Teupe C, et al. Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction (TOPCARE-AMI). Circulation 2002; 106:3009–17.
65. Strauer BE, Brehm M, Zeus T, et al. Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans. Circulation 2002; 106:1913–8.
66. Stamm C, Westphal B, Kleine H-P, et al. Autologous bone-marrow stem-cell transplantation for myocardial regeneration. Lancet 2003; 361:45–6.
67. Chen S-l, Fang W-w, Ye F, et al. Effect on left ventricular function of intracoronary transplantation of autologous bone marrow mesenchymal stem cell in patients with acute myocardial infarction. Am J Cardiol 2004; 94:92–5.
68. Katritsis DG, Sotiropoulou PA, Karvouni E, et al. Transcoronary transplantation of autologous mesenchymal stem cells and endothelial progenitors into infarcted human myocardium. Catheter Cardiovasc Interv 2005; 65:321–9.
69. Hare JM, Traverse JH, Henry TD, et al. A randomized, double-blind, placebo-controlled, dose-escalation study of entravenous adult human mesenchymal stem cells (Prohymal) after acute myocardial infarction. J Am Coll Cardiol 2009; 54:2277–86.
70. Tse H-F, Kwong Y-L, Chan JKF, et al. Angiogenesis in ischaemic myocardium by intramyocardial autologous bone marrow mononuclear cell implantation. Lancet 2003; 361:47–9.
71. Lasala GP, Silva JA, Kusnick BA, Minguell JJ. Combination stem cell therapy for the treatment of medically refractory coronary ischemia: a Phase I study. Cardiovasc Revasc Med 2011; 12:29–34.
72. Tateishi-Yuyama E, Matsubara H, Murohara T, et al. Therapeutic angiogenesis for patients with limb ischaemia by autologous transplantation of bone-marrow cells: a pilot study and a randomised controlled trial. Lancet 2002; 360:427–35.
73. Lasala GP, Silva JA, Gardner PA, Minguell JJ. Combination stem cell therapy for the treatment of severe limb ischemia: safety and efficacy analysis. Angiology 2010; 61:551–6.
74. Guiducci S, Porta F, Saccardi R, et al. Autologous mesenchymal stem cells foster revascularization of ischemic limbs in systemic sclerosis. A case report. Ann Intern Med 2010; 153:650–4.
75. Miyamoto K, Nishigami K, Nagaya N, et al. Unblinded pilot study of autologous transplantation of bone marrow mononuclear cells in patients with thromboangiitis obliterans. Circulation 2006; 114:2679–84.
76. Badiavas EV, Falanga V. Treatment of chronic wounds with bone marrow-derived cells. Arch Dermatol 2003; 139:510–6.
77. Dash NR, Dash SN, Routray P, Mohapatra S, Mohapatra PC. Targeting nonhealing ulcers of lower extremity in human through autologous bone marrow-derived mesenchymal stem cells. Rejuvenation Res 2009; 12:359–66.
78. Quarto R, Mastrogiacomo M, Cancedda R, et al. Repair of large bone defects with the use of autologous bone marrow stromal cells (letter). N Engl J Med 2001; 344:385–6.
79. Wakitani S, Imoto K, Yamamoto T, et al. Human autologous culture expanded bone marrow mesenchymal cell transplantation for repair of cartilage defects in osteoarthritic knees. Osteoarthritis Cartilage 2002; 10:199–206.
80. Cahill RA, Jones OY, Klemperer M, et al. Replacement of recipient stromal/mesenchymal cells after bone marrow transplantation using bone fragments and cultured osteoblast-like cells. Biol Blood Marrow Transplant 2004; 10:709–17.
81. Whyte MP, Kurtzberg J, McAlister WH, et al. Marrow transplantation for infantile hypophosphatemia. J Bone Miner Res 2003; 18:624–36.
82. Horwitz EM, Prockop DJ, Fitzpatrick LA, et al. Transplantability and therapeutic effects of bone marrow-derived mesenchymal cells in children with osteogenesis imperfecta. Nat Med 1999; 5:309–13.
83. Horwitz EM, Gordon PL, Koo WKK, et al. Isolated allogeneic bone marrow-derived mesenchymal cells engraft and stimulate growth in children with osteogenesis imperfecta: Implications for cell therapy of bone. Proc Natl Acad Sci USA 2002; 99:8932–7.
84. Horwitz EM, Prockop DJ, Gordon PL, et al. Clinical responses to bone marrow transplantation in children with severe osteogenesis perfecta. Blood 2001; 97:1227–31.
85. Koc ON, Day J, Nieder M, et al. Mesenchymal stem cells. Allogeneic mesenchymal stem cell infusion for treatment of metachromatic leukodystrophy (MLD) and Hurler syndrome (MPS-IH). Bone Marrow Transplant 2002; 30:215–22.
86. Kharaziha P, Hellstrom PM, Noorinayer B, et al. Improvement of liver function in live cirrhosis patients after autologous mesenchymal stem cell injection: a phase I-II clinical trial. Eur J Gastroenterol Hepatol 2009; 21:1199–205.
87. Duijvestein M, Vos ACW, Roelofs H, et al. Autologous bone marrow-derived mesenchymal stromal cell treatment for refractory luminal Chrohn's disease: results of a phase I study. Gut 2010; 59:1662–9.
88. Sun L, Wang D, Liang J, et al. Umbilical cord mesenchymal stem cell transplantation in severe and refractroy systemic lupus erythematosus. Arthritis Rheum 2010; 62:2467–75.
89. Liang J, Zhang H, Hua B, et al. Allogenic mesenchymal stem cell transplantation in refractory systemic lupus erythematosus: a pilot clinical study. Ann Rheum Dis 2010; 69:1423–9.
90. Bang OY, Lee JS, Lee PH, Lee G. Autologous mesenchymal stem cell transplantation in stroke patients. Ann Neurol 2005; 57:874–82.
91. Lee JS, Hong JM, Moon GJ, et al. A long-term follow-up study of intravenous autologous mesenchymal stem cell transplantation in patients with ischemic stroke. Stem Cells 2010; 28:1099–106.
92. Moviglia GA, Fernandez Vina R, Brizuela JA, et al. Combined protocol of cell therapy for chronic spinal cord injury. Report on the electrical and functional recovery of two patients. Cytotherapy 2006; 8:202–9.
93. Karussis D, Kassis I, Kurkalli BGS, Slavin S. Immunomodulation and neuroprotection with mesenchymal bone marrow stem cells (MSCs): a proposed treatment for multiple sclerosis and other neuroimmunological/neurodegenerative diseases. J Neurol Sci 2008; 265:131–5.
94. Pal R, Venkataramana NK, Jan M, et al. Ex vivo-expanded autologous bone marrow-derived mesenchymal stromal cells in human spinal cord injury/paraplegia: a pilot study. Cytotherapy 2009; 11:897–911.
95. Kishk NA, Gabr H, Hamdy S, et al. Case control series of intrathecal autologous bone marrow mesenchymal stem cell therapy for chronic spinal cord injury. Neurorehabil Neural Repair 2010; 24:702–8.
96. Zhang Z-X, Guan L-X, Zhang K, Zhang Q, Dai L-J. A combined procedure to deliver autologous mesenchymal stromal cells to patients with traumatic brain injury. Cytotherapy 2008; 10:134–9.
97. Mazzini L, Fagioli F, Boccaletti R, et al. Stem cell therapy in amyotrophic lateral sclerosis: a methodological approach in humans. ALS and other motor neuron disorders. Amyotroph Lateral Scler Other Motor Neuron Diserd 2003; 4:158–61.
98. Mazzini L, Mareschi K, Ferrero I, et al. Autologous mesenchymal stem cells: clinical applications in amyotrophic lateral sclerosis. Neurol Res 2006; 28:523–6.
99. Mazzini L, Ferrero I, Luparello V, et al. Mesenchymal stem cell transplantation in amyotrophic lateral sclerosis: a Phase I clinical trial. Exp Neurol 2010; 223:229–37.
100. Karussis D, Karageorgiou C, Vaknin-Dembinsky A, et al. Safety and immunologic effects of mesenchymal stem cell transplantation in patients with multiple sclerosis and amyotrophic lateral sclerosis. Arch Neurol 2010; 67:1187–94.
101. Venkataramana NK, Kumar SKV, Balaraju S, et al. Open-labeled study of unilateral autologous bone-marrow-derived mesenchymal stem cell transplantation in Parkinson's disease. Translational Res 2010; 155:62–70.
102. Brass LM. Bone marrow for the brain? Exp Neurol. 2006; 199:16–19.
103. Bliss T, Guzman R, Daadi M, Steinberg GK. Cell transplantation therapy for stroke. Stroke 2007; 38:817–26.
104. Phinney DG, Isakova I. Plasticity and therapeutic potential of mesenchymal stem cells in the nervous system. Curr Pharm Des 2005; 11:1255–65.
105. English D, Klasko SK, Sanberg PR. Elusive mechanisms of “stem-cell”-mediated repair of cerebral damage. Exp Neurol 2006; 199:10–15.
106. Phinney DG, Prockop DJ. Mesenchymal stem/multipotent stromal cells: the state of transdifferentiation and modes of tissue repair – current views. Stem Cells 2007; 25:2896–902.
107. Chopp M, Li Y, Zhang J. Plasticity and remodeling of brain. J Neurol Sci 2008; 265:97–101.
108. Dharmasaroja P. Bone marrow-derived mesenchymal stem cells for the treatment of ischemic stroke. J Clin Neurosci. 2009; 16:12–20.
109. Munoz JR, Stoutenger BR, Robinson AP, Spees JL, Prockop DJ. Human stem/progenitor cells from bone marrow promote neurogenesis of endogenous neural stem cells in the hippocampus of mice. Proc Natl Acad Sci USA 2005; 102:18171–6.
110. Rivera F, Couillard-Despres S, Pedre X, et al. Mesenchymal stem cells instruct oligodrogenic fate decision on adult neural stem cells. Stem Cells 2006; 24:2209–19.
111. Akiyama Y, Radtke C, Honmou O, Kocsis JD. Remyelination of the spinal cord following intravenous delivery of bone marrow cells. Glia 2002; 39:229–36.
112. Dezawa M, Takahashi I, Esaki M, Takano M, Sawada H. Sciatic nerve regeneration in rats induced by transplantation of in vitro differentiated bone-marrow stromal cells. Eur J Neurosci 2001; 14:1771–6.
113. Zhao C-P, Zhang C, Zhou S-N, et al. Human mesenchymal stromal cells ameliorate the phenotype of SOD1-G93A ALS mice. Cytotherapy 2007; 9:414–26.
114. Zhang C, Zhou C, Teng J-J, Zhao R-L, Song Y-Q. Multiple administrations of human marrow stromal cells through cerebrospinal fluid prolong survival in a transgenic mouse model of amyotrophic lateral sclerosis. Cytotherapy 2009; 11:299–306.
115. Li Y, Chen J, Wang L, et al. Intracerebral transplantation of bone marrow stromal cells in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease. Neurosci Lett 2001; 315:67–70.
116. Sadan O, Shemesh N, Barzilay R, et al. Migration of neurotrophic factor-secreting mesenchymal stem cells toward a quinolinic acid lesion as viewed by magnetic resonance imaging. Stem Cells 2008; 26:2542–51.
117. Mahmood A, Lu D, Wang L, et al. Treatment of traumatic brain injury in female rats with intravenous administration of bone marrow stromal cells. Neurosurgery 2001; 49:1196–204.
118. Lu P, Tuszynski MH. Can bone marrow-derived stem cells differentiate into functional neurons? Exp Neurol 2005; 193:273–8.
119. Chopp M, Zhang XH, Li Y, et al. Spinal cord injury in rat: treatment with bone marrow stromal cell transplantation. Neuroreport 2000; 11:3001–5.
120. Hofstetter CP, Schwarz EJ, Hess D, et al. Marrow stromal cells form guiding strands in the injured spinal cord and promote recovery. Proc Natl Acad Sci USA 2002; 99:2199–204.
121. Wu S, Suzuki Y, Ejiri Y, et al. Bone marrow stromal cells enhance differentiation of cocultured neurosphere cells and promote regeneration of injured spinal cord. J Neurosci Res 2003; 72:343–51.
122. Orlic D, Kajstura J, Chimenti S, et al. Mobilized bone marrow cells repair the infarcted heart, improving function and survival. Proc Natl Acad Sci USA 2001; 98:10344–9.
123. Wang J-S, Shum-Tim D, Chedrawy E, Chiu RC-J. The coronary delivery of marrow stromal cells for myocardial regeneration: Pathophysiologic and therapeutic implications. J Thorac Cardiovasc Surg 2001;122(699–705).
124. Martin B, Caparelli D, Kuang J-Q, et al. Implantation of allogeneic mesenchymal stem cells results in improved cardiac performance in a swine model of myocardial infarction (abstract). Bone Marrow Transplant 2002; 29(Suppl 2):S2.
125. Tomita S, Mickle DAG, Weisel RD, et al. Improved heart function with myogenesis and angiogenesis after autologus porcine bone marrow stromal cell transplantation. J Thorac Cardiovasc Surg 2002; 123:1132–40.
126. Kawada H, Fujita J, Kinjo K, et al. Nonhematopoietic mesenchymal stem cells can be mobilized and differentiate into cardiomyocytes after myocardial infarction. Blood 2004; 104:3581–7.
127. Breitbach M, Bostani T, Roell W, et al. Potential risks of bone marrow cell transplantation into infarcted hearts. Blood 2007; 110:1362–9.
128. Van't Hof W, Mal N, Huang Y, et al. Direct delivery of syngeneic and allogeneic large-scale expanded multipotent adult progenitor cells improves cardiac function after myocardial infarct. Cytotherapy 2007; 9:477–87.
129. Mirotsou M, Zhang Z, Deb A, et al. Secreted frizzled related protein 2 (sfrp2) is the key Akt-mesenchymal stem cell-released paracrine factor mediating myocardial survival and repair. Proc Nat Acad Sci USA 2007; 104:1643–8.
130. Ortiz LA, Gambelli F, McBride C, et al. Mesenchymal stem cell engraftment in lung is enhanced in response to bleomycin exposure and ameliorates its fibrotic effects. Proc Natl Acad Sci USA 2003; 100:8407–11.
131. Ortiz LA, DuTreil M, Fattman C, et al. Interleukin 1 receptor antagonist mediates the antiinflammatory and antifibrotic effect of mesenchymal stem cells during lung injury. Proc Nat Acad Sci USA 2007; 104:11002–7.
132. Gupta N, Su X, Popov B, et al. Intrapulmonary delivery of bone marrow-derived mesenchymal stem cells improves survival and attenuates endotoxin-induced acute lung injury in mice. J Immunol 2007; 179:1855–63.
133. Togel F, Hu Z, Weiss K, et al. Administered mesenchymal stem cells protect against ischemic acute renal failure through differentiation-independent mechanisms. Am J Physiol Renal Physiol 2005; 289:F31–F42.
134. Kunter U, Rong S, Djuric Z, et al. Transplanted mesenchymal stem cells accelerate glomerular healing in experimental glomerulonephritis. J Am Soc Nephrol 2006; 17:2202–12.
135. Morigi M, Introna M, Imberti B, et al. Human bone marrow mesenchymal stem cells accelerate recovery of acute renal injury and prolong survival in mice. Stem Cells 2008; 26:2075–82.
136. Imberti B, Morigi M, Tomasoni S, et al. Insulin-like growth factor-1 sustains stem cell-mediated renal repair. J Am Soc Nephrol 2007; 18:2921–8.
137. Parekkadan B, van Poll D, Suganuma K, et al. Mesenchymal stem-derived molecules reverse fulminant hepatic failure. PLoS ONE 2007; 2:e941.
138. Carvalho AB, Quintanilha LF, Dias JV, et al. Bone marrow multipotent mesenchymal stromal cells do not reduce fibrosis or improve function in a rat model of severe chronic liver injury. Stem Cells 2008; 26:1307–14.
139. Wakitani S, Yamamoto T. Response of the donor and recipient cells in mesenchymal cell transplantation to cartilage defect. Microsc Res Tech 2002; 58:14–18.
140. Uejima S, Okada K, Kagami H, Taguchi A, Ueda M. Bone marrow stromal cell therapy improves femoral bone mineral density and mechanical strength in ovariectomized rats. Cytotherapy 2008; 10:479–89.
141. Oh JY, Kim MK, Shin MS, et al. The anti-inflammatory and anti-angiogenic role of mesenchymal stem cells in corneal wound healing following chemical injury. Stem Cells 2008; 26:1047–55.
142. Chang C, Niu D, Zhou H, et al. Mesenchymal stroma cells improve hyperglycemia and insulin deficiency in the diabetic porcine pancreatic microenvironment. Cytotherapy 2008; 10:796–805.
143. Fu X, He Y, Kie C, Liu W. Bone marrow mesenchymal stem cell transplantation improves ovarian function and structure in rats with chemotherapy-induced ovarian failure. Cytotherapy 2008; 10:353–63.
144. Chapel A, Bertho JM, Bensidhoum M, et al. Mesenchymal stem cells home to injured tissues when co-infused with hematopoietic cells to treat a radiation-induced multi-organ failure syndrome. J Gene Med 2003; 5:1028–38.
145. Pereira RF, O’Hara MD, Laptev AV, et al. Marrow stromal cells as a source of progenitor cells for nonhematopoietic tissues in transgenic mice with a phenotype of osteogenesis imperfecta. Proc Natl Acad Sci USA 1998; 95:1142–7.
146. Pereira RF, Halford KW, O’Hara 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; 92:4857–61.
147. Li Y, Hisha H, Inaba M. Evidence for migration of donor bone marrow stromal cells into recipient thymus after bone marrow transplantation plus bone grafts: A role of stromal cells in positive selection. Exp Hematol 2000; 28:950–60.
148. Chen J, Li Y, Wang L, et al. Therapeutic benefit of intravenous administration of bone marrow stromal cells after cerebral ischemia in rats. Stroke 2001; 32:1005–11.
149. Devine SM, Bartholomew AM, Mahmud N, et al. Mesenchymal stem cells are capable of homing to the bone marrow of non-human primates following systemic infusion. Exp Hematol 2001; 29:244–55.
150. Gao J, Dennis JE, Muzic RF, Lundberg M, Caplan AI. The dynamic in vivo distribution of bone marrow-derived mesenchymal stem cells after infusion. Cells Tissues Organs 2001; 169:12–20.
151. Wu GD, Nolta JA, Jin Y-S, et al. Migration of mesenchymal stem cells to heart allografts during chronic rejection. Transplantation 2003; 75:679–85.
152. Allers C, Sierralta WD, Neubauer S, et al. Dynamic of distribution of human bone marrow-derived mesenchymal stem cells after transplantation into adult unconditioned mice. Transplantation. 2004; 78:503–8.
153. Niemeyer P, Vohrer J, Schmal H, et al. Survival of human mesenchymal stromal cells from bone marrow and adipose tissue after xenogenic transplantation in immunocompetent mice. Cytotherapy 2008; 10:784–95.
154. Sokolova IB, Zin'kova NN, Shvedova EV, Kruglyakov PV, Polyntsev DG. Distribution of mesenchymal stem cells in the area of tissue inflammation after transplantation of the cell material via different routes. Bull Exp Biol Med 2007; 143:143–6.
155. Inoue M, Honmou O, Oka S, et al. Comparative analysis of remyelinating potential of focal and intravenous administration of autologous bone marrow cells into the rat demyelinated spinal cord. Glia 2003; 44:111–8.
156. Nakamizo A, Marini F, Amano T, et al. Human bone marrow-derived mesenchymal stem cells in the treatment of gliomas. Cancer Res 2005; 65:3307–18.
157. Koc ON, Peters C, Auborg P, et al. Bone marrow-derived mesenchymal stem cells remain host-derived despite successful hematopoietic engraftment after allogeneic transplantation in patients with lysosomal and peroxisomal storage diseases. Exp Hematol 1999; 27:1675–81.
158. Bacigalupo A, Valle M, Podesta M, et al. T-cell suppression mediated by mesenchymal stem cells is deficient in patients with severe aplastic anemia. Exp Hematol 2005; 33:819–27.
159. Murphy JM, Dixon K, Beck S, et al. Reduced chondrogenic and adipogenic activity of mesenchymal stem cells from patients with advanced osteoarthritis. Arthritis Rheum 2002; 46:704–13.
160. Del Papa N, Quirici N, Soligo D, et al. Bone marrow endothelial progenitors are defective in systemic sclerosis. Arthritis Rheum 2006; 54:2605–15.
161. Kastrinaki M-C, Sidiropoulos P, Roche S, et al. Functional, molecular and proteomic characterisation of bone marrow mesenchymal stem cells in rheumatoid arthritis. Ann Rheum Dis 2008; 67:741–9.
162. Bocelli-Tyndall C, Bracci L, Spagnoli G, et al. Bone marrow mesenchymal stromal cells (BM-MSCs) from healthy donors and auto-immune disease patients reduce the proliferation of autologous- and allogeneic-stimulated lymphocytes in vitro. Rheumatology (Oxf) 2007; 46:403–8.
163. Larghero J, Farge D, Braccini A, et al. Phenotypical and functional characteristics of in vitro expanded bone marrow mesenchymal stem cells from patients with systemic sclerosis. Ann Rheum Dis 2008; 67:443–9.
164. Papadaki HA, Tsagournisakis M, Mastorodemos V, et al. Normal bone marrow hematopoietic stem cell reserves and normal stromal cell function support the use of autologous stem cell transplantation in patients with multiple sclerosis. Bone Marrow Transplant 2005; 36:1053–63.
165. Mallam E, Kemp K, Wilkins A, Rice C, Scolding N. Characterization of in vitro expanded bone marrow-derived mesenchymal stem cells from patients with multiple sclerosis. Mult Scler 2010; 16:909–18.
166. Mazzanti B, Aldinucci A, Biagioli T, et al. Differences in mesenchymal stem cell cytokine profiles between MS patients and healthy donors: Implications for assessment of disease activity and treatment. J Neuroimmunol 2008; 199:142–50.
167. Ho AD, Wagner W, Franke W. Heterogeneity of mesenchymal stromal cell preparations. Cytotherapy 2008; 10:320–30.
168. Haack-Sorensen M, Bindslev L, Mortensen S, Friis T, Kastrup J. The influence of freezing and storage on the characteristics and functions of human mesenchymal stromal cells isolated for clinical use. Cytotherapy 2007; 9:328–37.
169. Samuelsson H, Ringden O, Lonnies H, Le Blanc K. Optimizing in vitro conditions for immunomodulation and expansion of mesenchymal stromal cells. Cytotherapy 2009; 11:129–36.
170. Agashi K, Chau DYS, Shakesheff KM. The effect of delivery via narrow-bore needles on mesenchymal cells. Regenerat Med 2009; 4:49–64.
171. Scolding N, Marks D, Rice C. Autologous mesenchymal bone marrow stem cells: practical considerations. J Neurol Sci 2008; 265:111–5.
172. Riordan NH, Ichim TE, Min W-P, et al. Non-expanded adipose stromal vascular fraction cell therapy for multiple sclerosis. J Translat Med 2009:7:29.
173. Liang J, Zhang H, JHua B, et al. Allogeneic mesenchymal stem cells transplantation in treatment of multiple sclerosis. Mult Scler 2009; 15:644–6.
174. Chandran S, Hunt D, Joannides A. Myelin repair: the role of stem and precursor cells in multiple sclerosis. Phil Trans R Soc Lond B Biol Sci 2008; 363:171–83.
175. Moyeddin Bonab M, Yazdanbakhsh S, Loft J, et al. Does mesenchymal stem cell therapy help multiple sclerosis patients? Iran J Immunol 2007; 4:50–7.
176. Yamout B, Hourani R, Salti H, et al. bone marrow mesenchymal stem cell transplantation in patients with multiple sclerosis: A pilot study. J Neuroimmunol 2010; 227:185–9.
177. Chen-Plotkin AS, Vossel KA, Samuels MA, Chen MH. Encephalopathy, stroke and myocardial infarction with DMSO use in stem cell transplantation. Neurology 2007; 68:859–61.
178. Sundin M, Ringden O, Sundberg B, et al. No alloantibodies against mesenchymal stromal cells, but presence of anti-fetal calf serum antibodies, after transplantation in allogeneic hematopoietic stem cell recipients. Haematologia (Budap) 2007; 92:1208–15.
179. Brooke G, Cook M, Blair C, et al. Therapeutic applications of mesenchymal stromal cells. Semin Cell Dev Biol 2007; 18:846–58.
180. Le Blanc K, Samuelsson H, Gustafsson B, et al. Transplantation of mesenchymal stem cells to enhance engraftment of hematopoietic stem cells. Leukemia 2007; 21:1733–8.
181. Sundin M, Orvell C, Rasmusson I, et al. Mesenchymal stem cells are susceptible to human herpesviruses, but viral DNA cannot be detected in the healthy seropositive individual. Bone Marrow Transplant 2006; 37:1051–9.
182. Karlsson H, Samarasinghe S, Ball LM, et al. Mesenchymal stem cells exert differential effects on alloantigen and virus-specific T-cell responses. Blood 2008; 112:532–41.
183. Ning H, Yang F, Jiang M, 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; 22:593–9.
184. Prindull G, Zipori D. Environmental guidance of normal and tumor cell plasticity: epithelial mesenchymal transitions as a paradigm. Blood 2004; 103:2892–9.
185. Serakinci N, Guldberg P, Burns JS, et al. Adult human mesenchymal stem cell as a target for neoplastic transformation. Oncogene 2004; 23:5095–8.
186. Greaves M. Molecular genetics, natural history and the demise of childhood leukaemia. Eur J Cancer 1999; 35:1941–53.
187. Houghton JM, Stoicov C, Nomura S, et al. Gastric cancer originating from bone marrow-derived cells. Science 2004; 306:1568–1571.
188. Tolar J, Nauta AJ, Osborn MJ, et al. Sarcoma derived from cultured mesenchymal stem cells. Stem Cells 2007; 25:371–9.
189. Bernardo ME, Zaffaroni N, Novara F, et al. Human bone marrow-derived mesenchymal stem cells do not undergo transformation after long-term in vitro culture and do not exhibit telomere maintenance mechanisms. Cancer Res 2007; 67:9142–9.
190. Wang Y, Huso DL, Harrington J, et al. Outgrowth of a transformed cell population derived from normal human BM mesenchymal stem cell culture. Cytotherapy 2005; 7:509–19.
191. Rubio D, Garcia-Castro J, Martin MC, et al. Spontaneous human adult stem cell transformation. Cancer Res 2005; 65:3035–9.
192. Kim J, Kang JW, Park JH, et al. Biological characterization of long-term cultured human mesenchymal stem cells. Arch Pharm Res 2008; 32:117–26.
193. Rosland GV, Svendsen A, Torsvik A, et al. Long-term cultures of bone marrow-derived human mesenchymal stem cells frequently undergo spontaneous malignant transformation. Cancer Res. 2009; 69:5331–9.
194. Kidd S, Spaeth E, Klopp A, et al. The (in)auspicious role of mesenchymal stromal cells in cancer: be it friend or foe. Cytotherapy 2008; 10:657–67.
195. Tabe Y, Konopleva M, Munsell MF, et al. PML-RARα is associated with leptin-receptor induction: the role of mesenchymal stem cell-derived adipocytes in APL survival. Blood 2004; 103:1815–22.
196. Karnoub AE, Dash AB, Vo AP, et al. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 2007; 449:557–65.
197. Coles AJ, The CAMMS223 Study Group. Efficacy of alemtuzumab in treatment-naive relapsing-remitting multiple sclerosis: analysis after two years of study CAMMS223 (S12.004). Neurology 2007; 68(Suppl 1):A100.
198. The Lenercept Multiple Sclerosis Study Group, The University of British Columbia MS/MRI Analysis Group. TNF neutralization in MS. Results of a randomized, placebo-controlled multicenter study. Neurology 1999; 53:457–65.
199. Barkhof F, Rocca M, Francis G, et al. Validation of diagnostic magnetic resonance imaging criteria for multiple sclerosis and response to interferon β1a. Ann Neurol 2003; 53:718–24.
200. Tintore M, Rovira M, Rio J, et al. New diagnostic criteria for multiple sclerosis. Application in first demyelinating episode. Neurology 2003; 60:27–30.
201. Freedman MS, Bar-Or A, Atkins HL, et al. The therapeutic potential of mesenchymal stem cell transplantation as a treatment for multiple sclerosis: consensus report of the International MSCT Study Group. Mult Scler 2010; 16:503–10.