Cellular and Molecular Life Sciences

, Volume 70, Issue 20, pp 3871–3882 | Cite as

Mesenchymal stem cells secretome: a new paradigm for central nervous system regeneration?

  • Fábio G. Teixeira
  • Miguel M. Carvalho
  • Nuno Sousa
  • António J. SalgadoEmail author


The low regeneration potential of the central nervous system (CNS) represents a challenge for the development of new therapeutic strategies. Mesenchymal stem cells (MSCs) have been proposed as a possible therapeutic tool for CNS disorders. In addition to their differentiation potential, it is well accepted nowadays that their beneficial actions can also be mediated by their secretome. Indeed, it was already demonstrated, both in vitro and in vivo, that MSCs are able to secrete a broad range of neuroregulatory factors that promote an increase in neurogenesis, inhibition of apoptosis and glial scar formation, immunomodulation, angiogenesis, neuronal and glial cell survival, as well as relevant neuroprotective actions on different pathophysiological contexts. Considering their protective action in lesioned sites, MSCs’ secretome might also improve the integration of local progenitor cells in neuroregeneration processes, opening a door for their future use as therapeutical strategies in human clinical trials. Thus, in this review we analyze the current understanding of MSCs secretome as a new paradigm for the treatment of CNS neurodegenerative diseases.


Mesenchymal stem cells Secretome Neurodegenerative diseases Neuroregeneration 



We thank to the Portuguese Foundation for Science and Technology (FCT) for: Ciência 2007 program (A.J. Salgado), Grant PTDC/SAU-BMA/114059/2009 and, pre-doctoral fellowships to F.G. Teixeira (SFRH/BD/69637/2010) and Miguel Carvalho (SFRH/BD/51061/2010).


  1. 1.
    Gogel S, Gubernator M, Minger SL (2011) Progress and prospects: stem cells and neurological diseases. Gene Ther 18(1):1–6PubMedGoogle Scholar
  2. 2.
    Lindvall O, Kokaia Z (2010) Stem cells in human neurodegenerative disorders—time for clinical translation? J Clin Invest 120(1):29–40PubMedGoogle Scholar
  3. 3.
    Lindvall O, Barker RA, Brustle O et al (2012) Clinical translation of stem cells in neurodegenerative disorders. Cell Stem Cell 10(2):151–155PubMedGoogle Scholar
  4. 4.
    Becerra J, Santos-Ruiz L, Andrades JA et al (2011) The stem cell niche should be a key issue for cell therapy in regenerative medicine. Stem Cell Rev 7(2):248–255PubMedGoogle Scholar
  5. 5.
    Chen FM, Wu LA, Zhang M et al (2011) Homing of endogenous stem/progenitor cells for in situ tissue regeneration: promises, strategies, and translational perspectives. Biomaterials 32(12):3189–3209PubMedGoogle Scholar
  6. 6.
    Chen FM, Zhao YM, Jin Y et al (2012) Prospects for translational regenerative medicine. Biotechnol Adv 30(3):658–672PubMedGoogle Scholar
  7. 7.
    Kassem M, Kristiansen M, Abdallah BM (2004) Mesenchymal stem cells: cell biology and potential use in therapy. Basic Clin Pharmacol Toxicol 95(5):209–214PubMedGoogle Scholar
  8. 8.
    Wang S, Qu X, Zhao RC (2011) Mesenchymal stem cells hold promise for regenerative medicine. Front Med 5(4):372–378PubMedGoogle Scholar
  9. 9.
    Uccelli A, Benvenuto F, Laroni A et al (2011) Neuroprotective features of mesenchymal stem cells. Best Pract Res Clin Haematol 24(1):59–64PubMedGoogle Scholar
  10. 10.
    Uccelli A, Laroni A, Freedman MS (2011) Mesenchymal stem cells for the treatment of multiple sclerosis and other neurological diseases. Lancet Neurol 10(7):649–656PubMedGoogle Scholar
  11. 11.
    Dominici M, Le Blanc K, Mueller I et al (2006) Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8(4):315–317PubMedGoogle Scholar
  12. 12.
    Friedenstein AJ, Deriglasova UF, Kulagina NN et al (1974) Precursors for fibroblasts in different populations of hematopoietic cells as detected by the in vitro colony assay method. Exp Hematol 2(2):83–92PubMedGoogle Scholar
  13. 13.
    Zuk PA, Zuk M, Ashjian P et al (2002) Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell 13(12):4279–4295PubMedGoogle Scholar
  14. 14.
    Zuk PA, Zuk M, Mizuno H et al (2001) Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng 7(2):211–228PubMedGoogle Scholar
  15. 15.
    Gronthos S, Mankani M, Brahim J et al (2000) Postnatal human dental pulp stem cells (DPSCs) in vitro and in vivo. Proc Natl Acad Sci USA 97(25):13625–13630PubMedGoogle Scholar
  16. 16.
    Shi S, Gronthos S (2003) Perivascular niche of postnatal mesenchymal stem cells in human bone marrow and dental pulp. J Bone Miner Res 18(4):696–704PubMedGoogle Scholar
  17. 17.
    Fukuchi Y, Nakajima H, Sugiyama D et al (2004) Human placenta-derived cells have mesenchymal stem/progenitor cell potential. Stem Cells 22(5):649–658PubMedGoogle Scholar
  18. 18.
    Abumaree MH, Al Jumah M, Kalionis B et al. (2012) Phenotypic and functional characterization of mesenchymal stem cells from chorionic villi of human term placenta. Stem Cell Rev 9(1):16–31Google Scholar
  19. 19.
    Erices A, Conget P, Minguell JJ (2000) Mesenchymal progenitor cells in human umbilical cord blood. Br J Haematol 109(1):235–242PubMedGoogle Scholar
  20. 20.
    Wang HS, Hung SC, Peng ST et al (2004) Mesenchymal stem cells in the Wharton’s jelly of the human umbilical cord. Stem Cells 22(7):1330–1337PubMedGoogle Scholar
  21. 21.
    Weiss ML, Troyer DL (2006) Stem cells in the umbilical cord. Stem Cell Rev 2(2):155–162PubMedGoogle Scholar
  22. 22.
    Paul G, Ozen I, Christophersen NS et al (2012) The adult human brain harbors multipotent perivascular mesenchymal stem cells. PLoS One 7(4):e35577PubMedGoogle Scholar
  23. 23.
    Chamberlain G, Fox J, Ashton B et al (2007) Concise review: mesenchymal stem cells: their phenotype, differentiation capacity, immunological features, and potential for homing. Stem Cells 25(11):2739–2749PubMedGoogle Scholar
  24. 24.
    Meirelles Lda S, Fontes AM, Covas DT et al (2009) Mechanisms involved in the therapeutic properties of mesenchymal stem cells. Cytokine Growth Factor Rev 20(5–6):419–427PubMedGoogle Scholar
  25. 25.
    Phinney DG (2007) Biochemical heterogeneity of mesenchymal stem cell populations: clues to their therapeutic efficacy. Cell Cycle 6(23):2884–2889PubMedGoogle Scholar
  26. 26.
    Phinney DG, Prockop DJ (2007) Concise review: mesenchymal stem/multipotent stromal cells: the state of transdifferentiation and modes of tissue repair–current views. Stem Cells 25(11):2896–2902PubMedGoogle Scholar
  27. 27.
    Kolf CM, Cho E, Tuan RS (2007) Mesenchymal stromal cells. Biology of adult mesenchymal stem cells: regulation of niche, self-renewal and differentiation. Arthritis Res Ther 9(1):204PubMedGoogle Scholar
  28. 28.
    Mitchell KE, Weiss ML, Mitchell BM et al (2003) Matrix cells from Wharton’s jelly form neurons and glia. Stem Cells 21(1):50–60PubMedGoogle Scholar
  29. 29.
    Alaminos M, Perez-Kohler B, Garzon I et al (2010) Transdifferentiation potentiality of human Wharton’s jelly stem cells towards vascular endothelial cells. J Cell Physiol 223(3):640–647PubMedGoogle Scholar
  30. 30.
    Liqing Y, Jia G, Jiqing C et al (2011) Directed differentiation of motor neuron cell-like cells from human adipose-derived stem cells in vitro. NeuroReport 22(8):370–373PubMedGoogle Scholar
  31. 31.
    Baer PC, Geiger H (2012) Adipose-derived mesenchymal stromal/stem cells: tissue localization, characterization, and heterogeneity. Stem Cells Int 2012:812693PubMedGoogle Scholar
  32. 32.
    Maltman DJ, Hardy SA, Przyborski SA (2011) Role of mesenchymal stem cells in neurogenesis and nervous system repair. Neurochem Int 59(3):347–356PubMedGoogle Scholar
  33. 33.
    Meyerrose T, Olson S, Pontow S et al (2010) Mesenchymal stem cells for the sustained in vivo delivery of bioactive factors. Adv Drug Deliv Rev 62(12):1167–1174PubMedGoogle Scholar
  34. 34.
    Skalnikova H, Motlik J, Gadher SJ et al (2011) Mapping of the secretome of primary isolates of mammalian cells, stem cells and derived cell lines. Proteomics 11(4):691–708PubMedGoogle Scholar
  35. 35.
    Chen L, Tredget EE, Wu PY et al (2008) Paracrine factors of mesenchymal stem cells recruit macrophages and endothelial lineage cells and enhance wound healing. PLoS One 3(4):e1886PubMedGoogle Scholar
  36. 36.
    Block GJ, Ohkouchi S, Fung F et al (2009) Multipotent stromal cells are activated to reduce apoptosis in part by upregulation and secretion of stanniocalcin-1. Stem Cells 27(3):670–681PubMedGoogle Scholar
  37. 37.
    Wagner J, Kean T, Young R et al (2009) Optimizing mesenchymal stem cell-based therapeutics. Curr Opin Biotechnol 20(5):531–536PubMedGoogle Scholar
  38. 38.
    Baglio SR, Pegtel DM, Baldini N (2012) Mesenchymal stem cell secreted vesicles provide novel opportunities in (stem) cell-free therapy. Front Physiol 3:359PubMedGoogle Scholar
  39. 39.
    Valadi H, Ekstrom K, Bossios A et al (2007) Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 9(6):654–659PubMedGoogle Scholar
  40. 40.
    Pegtel DM, Cosmopoulos K, Thorley-Lawson DA et al (2010) Functional delivery of viral miRNAs via exosomes. Proc Natl Acad Sci USA 107(14):6328–6333PubMedGoogle Scholar
  41. 41.
    Lai RC, Arslan F, Lee MM et al (2010) Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury. Stem Cell Res 4(3):214–222PubMedGoogle Scholar
  42. 42.
    Chen TS, Arslan F, Yin Y et al (2011) Enabling a robust scalable manufacturing process for therapeutic exosomes through oncogenic immortalization of human ESC-derived MSCs. J Transl Med 9:47PubMedGoogle Scholar
  43. 43.
    Shi Y, Hu G, Su J et al (2010) Mesenchymal stem cells: a new strategy for immunosuppression and tissue repair. Cell Res 20(5):510–518PubMedGoogle Scholar
  44. 44.
    Kode JA, Mukherjee S, Joglekar MV et al (2009) Mesenchymal stem cells: immunobiology and role in immunomodulation and tissue regeneration. Cytotherapy 11(4):377–391PubMedGoogle Scholar
  45. 45.
    Puissant B, Barreau C, Bourin P et al (2005) Immunomodulatory effect of human adipose tissue-derived adult stem cells: comparison with bone marrow mesenchymal stem cells. Br J Haematol 129(1):118–129PubMedGoogle Scholar
  46. 46.
    Lanza C, Morando S, Voci A et al (2009) Neuroprotective mesenchymal stem cells are endowed with a potent antioxidant effect in vivo. J Neurochem 110(5):1674–1684PubMedGoogle Scholar
  47. 47.
    Caplan AI, Dennis JE (2006) Mesenchymal stem cells as trophic mediators. J Cell Biochem 98(5):1076–1084PubMedGoogle Scholar
  48. 48.
    Crigler L, Robey RC, Asawachaicharn A et al (2006) Human mesenchymal stem cell subpopulations express a variety of neuro-regulatory molecules and promote neuronal cell survival and neuritogenesis. Exp Neurol 198(1):54–64PubMedGoogle Scholar
  49. 49.
    Nakano N, Nakai Y, Seo TB et al (2010) Characterization of conditioned medium of cultured bone marrow stromal cells. Neurosci Lett 483(1):57–61PubMedGoogle Scholar
  50. 50.
    Wilkins A, Kemp K, Ginty M et al (2009) Human bone marrow-derived mesenchymal stem cells secrete brain-derived neurotrophic factor which promotes neuronal survival in vitro. Stem Cell Res 3(1):63–70PubMedGoogle Scholar
  51. 51.
    Ribeiro CA, Salgado AJ, Fraga JS et al (2011) The secretome of bone marrow mesenchymal stem cells—conditioned media varies with time and drives a distinct effect on mature neurons and glial cells (primary cultures). J Tissue Eng Regen Med 5(8):668–672PubMedGoogle Scholar
  52. 52.
    Cova L, Armentero MT, Zennaro E et al (2010) Multiple neurogenic and neurorescue effects of human mesenchymal stem cell after transplantation in an experimental model of Parkinson’s disease. Brain Res 1311:12–27PubMedGoogle Scholar
  53. 53.
    Nicaise C, Mitrecic D, Pochet R (2011) Brain and spinal cord affected by amyotrophic lateral sclerosis induce differential growth factors expression in rat mesenchymal and neural stem cells. Neuropathol Appl Neurobiol 37(2):179–188PubMedGoogle Scholar
  54. 54.
    Rehman J, Traktuev D, Li J et al (2004) Secretion of angiogenic and antiapoptotic factors by human adipose stromal cells. Circulation 109(10):1292–1298PubMedGoogle Scholar
  55. 55.
    Salgado AJ, Reis RL, Sousa NJ et al (2010) Adipose tissue derived stem cells secretome: soluble factors and their roles in regenerative medicine. Curr Stem Cell Res Ther 5(2):103–110PubMedGoogle Scholar
  56. 56.
    Lu S, Lu C, Han Q et al (2011) Adipose-derived mesenchymal stem cells protect PC12 cells from glutamate excitotoxicity-induced apoptosis by upregulation of XIAP through PI3-K/Akt activation. Toxicology 279(1–3):189–195PubMedGoogle Scholar
  57. 57.
    Tan B, Luan Z, Wei X et al (2011) AMP-activated kinase mediates adipose stem cell-stimulated neuritogenesis of PC12 cells. Neuroscience 181:40–47PubMedGoogle Scholar
  58. 58.
    Wei X, Du Z, Zhao L et al (2009) IFATS collection: the conditioned media of adipose stromal cells protect against hypoxia-ischemia-induced brain damage in neonatal rats. Stem Cells 27(2):478–488PubMedGoogle Scholar
  59. 59.
    Ribeiro CA, Fraga JS, Graos M et al (2012) The secretome of stem cells isolated from the adipose tissue and Wharton jelly acts differently on central nervous system derived cell populations. Stem Cell Res Ther 3(3):18PubMedGoogle Scholar
  60. 60.
    Arboleda D, Forostyak S, Jendelova P et al (2011) Transplantation of predifferentiated adipose-derived stromal cells for the treatment of spinal cord injury. Cell Mol Neurobiol 31(7):1113–1122PubMedGoogle Scholar
  61. 61.
    Egashira Y, Sugitani S, Suzuki Y et al (2012) The conditioned medium of murine and human adipose-derived stem cells exerts neuroprotective effects against experimental stroke model. Brain Res 1461:87–95PubMedGoogle Scholar
  62. 62.
    Lopatina T, Kalinina N, Karagyaur M et al (2011) Adipose-derived stem cells stimulate regeneration of peripheral nerves: BDNF secreted by these cells promotes nerve healing and axon growth de novo. PLoS One 6(3):e17899PubMedGoogle Scholar
  63. 63.
    Koh SH, Kim KS, Choi MR et al (2008) Implantation of human umbilical cord-derived mesenchymal stem cells as a neuroprotective therapy for ischemic stroke in rats. Brain Res 1229:233–248PubMedGoogle Scholar
  64. 64.
    Salgado AJ, Fraga JS, Mesquita AR et al (2010) Role of human umbilical cord mesenchymal progenitors conditioned media in neuronal/glial cell densities, viability, and proliferation. Stem Cells Dev 19(7):1067–1074PubMedGoogle Scholar
  65. 65.
    Ding DC, Shyu WC, Chiang MF et al (2007) Enhancement of neuroplasticity through upregulation of beta1-integrin in human umbilical cord-derived stromal cell implanted stroke model. Neurobiol Dis 27(3):339–353PubMedGoogle Scholar
  66. 66.
    Abe K, Yamashita T, Takizawa S et al (2012) Stem cell therapy for cerebral ischemia: from basic science to clinical applications. J Cereb Blood Flow Metab 32(7):1317–1331PubMedGoogle Scholar
  67. 67.
    Pal R, Gopinath C, Rao NM et al (2010) Functional recovery after transplantation of bone marrow-derived human mesenchymal stromal cells in a rat model of spinal cord injury. Cytotherapy 12(6):792–806PubMedGoogle Scholar
  68. 68.
    Kim HJ, Kim HJ, Lee JY et al (2011) Phenotype analysis in patients with early onset Parkinson’s disease with and without parkin mutations. J Neurol 258(12):2260–2267PubMedGoogle Scholar
  69. 69.
    Chung YC, Ko HW, Bok E et al (2010) The role of neuroinflammation on the pathogenesis of Parkinson’s disease. BMB Rep 43(4):225–232PubMedGoogle Scholar
  70. 70.
    Anisimov SV (2009) Cell-based therapeutic approaches for Parkinson’s disease: progress and perspectives. Rev Neurosci 20(5–6):347–381PubMedGoogle Scholar
  71. 71.
    Singh N, Pillay V, Choonara YE (2007) Advances in the treatment of Parkinson’s disease. Prog Neurobiol 81(1):29–44PubMedGoogle Scholar
  72. 72.
    Muller T, Hefter H, Hueber R et al (2004) Is levodopa toxic? J Neurol 251(Suppl 6):VI/44–VI/46Google Scholar
  73. 73.
    Muller T, Renger K, Kuhn W (2004) Levodopa-associated increase of homocysteine levels and sural axonal neurodegeneration. Arch Neurol 61(5):657–660PubMedGoogle Scholar
  74. 74.
    Weiner WJ (2006) Advances in the diagnosis, treatment, and understanding of Parkinson’s disease and parkinsonism. Rev Neurol Dis 3(4):191–194PubMedGoogle Scholar
  75. 75.
    Lindvall O, Brundin P, Widner H et al (1990) Grafts of fetal dopamine neurons survive and improve motor function in Parkinson’s disease. Science 247(4942):574–577PubMedGoogle Scholar
  76. 76.
    Lindvall O, Rehncrona S, Brundin P et al (1989) Human fetal dopamine neurons grafted into the striatum in two patients with severe Parkinson’s disease. A detailed account of methodology and a 6-month follow-up. Arch Neurol 46(6):615–631PubMedGoogle Scholar
  77. 77.
    Lindvall O, Widner H, Rehncrona S et al (1992) Transplantation of fetal dopamine neurons in Parkinson’s disease: one-year clinical and neurophysiological observations in two patients with putaminal implants. Ann Neurol 31(2):155–165PubMedGoogle Scholar
  78. 78.
    Sawle GV, Bloomfield PM, Bjorklund A et al (1992) Transplantation of fetal dopamine neurons in Parkinson’s disease: PET [18F]6-L-fluorodopa studies in two patients with putaminal implants. Ann Neurol 31(2):166–173PubMedGoogle Scholar
  79. 79.
    Azari MF, Mathias L, Ozturk E et al (2010) Mesenchymal stem cells for treatment of CNS injury. Curr Neuropharmacol 8(4):316–323PubMedGoogle Scholar
  80. 80.
    Wang Y, Chen S, Yang D et al (2007) Stem cell transplantation: a promising therapy for Parkinson’s disease. J Neuroimmune Pharmacol 2(3):243–250PubMedGoogle Scholar
  81. 81.
    Bouchez G, Sensebe L, Vourc’h P et al (2008) Partial recovery of dopaminergic pathway after graft of adult mesenchymal stem cells in a rat model of Parkinson’s disease. Neurochem Int 52(7):1332–1342PubMedGoogle Scholar
  82. 82.
    Levy YS, Bahat-Stroomza M, Barzilay R et al (2008) Regenerative effect of neural-induced human mesenchymal stromal cells in rat models of Parkinson’s disease. Cytotherapy 10(4):340–352PubMedGoogle Scholar
  83. 83.
    Jin GZ, Cho SJ, Lee YS et al (2010) Intrastriatal grafts of mesenchymal stem cells in adult intact rats can elevate tyrosine hydroxylase expression and dopamine levels. Cell Biol Int 34(1):135–140Google Scholar
  84. 84.
    McCoy MK, Martinez TN, Ruhn KA et al (2008) Autologous transplants of Adipose-Derived Adult Stromal (ADAS) cells afford dopaminergic neuroprotection in a model of Parkinson’s disease. Exp Neurol 210(1):14–29PubMedGoogle Scholar
  85. 85.
    Fu YS, Cheng YC, Lin MY et al (2006) Conversion of human umbilical cord mesenchymal stem cells in Wharton’s jelly to dopaminergic neurons in vitro: potential therapeutic application for Parkinsonism. Stem Cells 24(1):115–124PubMedGoogle Scholar
  86. 86.
    Kan I, Ben-Zur T, Barhum Y et al (2007) Dopaminergic differentiation of human mesenchymal stem cells—utilization of bioassay for tyrosine hydroxylase expression. Neurosci Lett 419(1):28–33PubMedGoogle Scholar
  87. 87.
    Chao YX, He BP, Tay SS (2009) Mesenchymal stem cell transplantation attenuates blood brain barrier damage and neuroinflammation and protects dopaminergic neurons against MPTP toxicity in the substantia nigra in a model of Parkinson’s disease. J Neuroimmunol 216(1–2):39–50PubMedGoogle Scholar
  88. 88.
    Thomas MG, Stone L, Evill L et al (2011) Bone marrow stromal cells as replacement cells for Parkinson’s disease: generation of an anatomical but not functional neuronal phenotype. Transl Res 157(2):56–63PubMedGoogle Scholar
  89. 89.
    Wang F, Yasuhara T, Shingo T et al (2010) Intravenous administration of mesenchymal stem cells exerts therapeutic effects on parkinsonian model of rats: focusing on neuroprotective effects of stromal cell-derived factor-1alpha. BMC Neurosci 11:52PubMedGoogle Scholar
  90. 90.
    Weiss ML, Medicetty S, Bledsoe AR et al (2006) Human umbilical cord matrix stem cells: preliminary characterization and effect of transplantation in a rodent model of Parkinson’s disease. Stem Cells 24(3):781–792PubMedGoogle Scholar
  91. 91.
    Sadan O, Bahat-Stromza M, Barhum Y et al (2009) Protective effects of neurotrophic factor-secreting cells in a 6-OHDA rat model of Parkinson disease. Stem Cells Dev 18(8):1179–1190PubMedGoogle Scholar
  92. 92.
    Sadan O, Shemesh N, Cohen Y et al (2009) Adult neurotrophic factor-secreting stem cells: a potential novel therapy for neurodegenerative diseases. Isr Med Assoc J 11(4):201–204PubMedGoogle Scholar
  93. 93.
    Blandini F, Cova L, Armentero MT et al (2010) Transplantation of undifferentiated human mesenchymal stem cells protects against 6-hydroxydopamine neurotoxicity in the rat. Cell Transplant 19(2):203–217PubMedGoogle Scholar
  94. 94.
    Olanow CW (2008) Levodopa/dopamine replacement strategies in Parkinson’s disease–future directions. Mov Disord 23(Suppl 3):S613–S622PubMedGoogle Scholar
  95. 95.
    Moloney TC, Rooney GE, Barry FP et al (2010) Potential of rat bone marrow-derived mesenchymal stem cells as vehicles for delivery of neurotrophins to the Parkinsonian rat brain. Brain Res 1359:33–43PubMedGoogle Scholar
  96. 96.
    Mortazavi MM, Verma K, Tubbs RS et al (2011) Cellular and paracellular transplants for spinal cord injury: a review of the literature. Childs Nerv Syst 27(2):237–243PubMedGoogle Scholar
  97. 97.
    Watson RA, Yeung TM (2011) What is the potential of oligodendrocyte progenitor cells to successfully treat human spinal cord injury? BMC Neurol 11:113PubMedGoogle Scholar
  98. 98.
    Rabchevsky AG, Patel SP, Springer JE (2011) Pharmacological interventions for spinal cord injury: where do we stand? How might we step forward? Pharmacol Ther 132(1):15–29PubMedGoogle Scholar
  99. 99.
    Shang AJ, Hong SQ, Xu Q et al (2011) NT-3-secreting human umbilical cord mesenchymal stromal cell transplantation for the treatment of acute spinal cord injury in rats. Brain Res 1391:102–113PubMedGoogle Scholar
  100. 100.
    Zurita M, Vaquero J (2006) Bone marrow stromal cells can achieve cure of chronic paraplegic rats: functional and morphological outcome one year after transplantation. Neurosci Lett 402(1–2):51–56PubMedGoogle Scholar
  101. 101.
    Ide C, Nakai Y, Nakano N et al (2010) Bone marrow stromal cell transplantation for treatment of sub-acute spinal cord injury in the rat. Brain Res 1332:32–47PubMedGoogle Scholar
  102. 102.
    Yang CC, Shih YH, Ko MH et al (2008) Transplantation of human umbilical mesenchymal stem cells from Wharton’s jelly after complete transection of the rat spinal cord. PLoS One 3(10):e3336PubMedGoogle Scholar
  103. 103.
    Vaquero J, Zurita M (2009) Bone marrow stromal cells for spinal cord repair: a challenge for contemporary neurobiology. Histol Histopathol 24(1):107–116PubMedGoogle Scholar
  104. 104.
    Wright KT, El Masri W, Osman A et al (2011) Concise review: bone marrow for the treatment of spinal cord injury: mechanisms and clinical applications. Stem Cells 29(2):169–178PubMedGoogle Scholar
  105. 105.
    Wright KT, El Masri W, Osman A et al (2007) Bone marrow stromal cells stimulate neurite outgrowth over neural proteoglycans (CSPG), myelin associated glycoprotein and Nogo-A. Biochem Biophys Res Commun 354(2):559–566PubMedGoogle Scholar
  106. 106.
    Lu P, Jones LL, Tuszynski MH (2005) BDNF-expressing marrow stromal cells support extensive axonal growth at sites of spinal cord injury. Exp Neurol 191(2):344–360PubMedGoogle Scholar
  107. 107.
    Neuhuber B, Timothy Hilmes B, Shumsky JS et al (2005) Axon growth and recovery of function supported by human bone marrow stromal cells in the injured spinal cord exhibit donor variations. Brain Res 1035(1):73–85PubMedGoogle Scholar
  108. 108.
    Gu W, Zhang F, Xue Q et al (2010) Transplantation of bone marrow mesenchymal stem cells reduces lesion volume and induces axonal regrowth of injured spinal cord. Neuropathology 30(3):205–217PubMedGoogle Scholar
  109. 109.
    Park HW, Lim MJ, Jung H et al (2010) Human mesenchymal stem cell-derived Schwann cell-like cells exhibit neurotrophic effects, via distinct growth factor production, in a model of spinal cord injury. Glia 58(9):1118–1132PubMedGoogle Scholar
  110. 110.
    Zhang L, Zhang HT, Hong SQ et al (2009) Cografted Wharton’s jelly cells-derived neurospheres and BDNF promote functional recovery after rat spinal cord transection. Neurochem Res 34(11):2030–2039PubMedGoogle Scholar
  111. 111.
    Kim KN, Oh SH, Lee KH et al (2006) Effect of human mesenchymal stem cell transplantation combined with growth factor infusion in the repair of injured spinal cord. Acta Neurochir Suppl 99:133–136PubMedGoogle Scholar
  112. 112.
    Karamouzian S, Nematollahi-Mahani SN, Nakhaee N et al (2012) Clinical safety and primary efficacy of bone marrow mesenchymal cell transplantation in subacute spinal cord injured patients. Clin Neurol Neurosurg 114(7):935–939PubMedGoogle Scholar
  113. 113.
    Saito F, Nakatani T, Iwase M et al (2008) Spinal cord injury treatment with intrathecal autologous bone marrow stromal cell transplantation: the first clinical trial case report. J Trauma 64(1):53–59PubMedGoogle Scholar
  114. 114.
    Saito F, Nakatani T, Iwase M et al (2012) Administration of cultured autologous bone marrow stromal cells into cerebrospinal fluid in spinal injury patients: a pilot study. Restor Neurol Neurosci 30(2):127–136PubMedGoogle Scholar
  115. 115.
    Hawryluk GW, Mothe A, Wang J et al (2012) An in vivo characterization of trophic factor production following neural precursor cell or bone marrow stromal cell transplantation for spinal cord injury. Stem Cells Dev 21(12):2222–2238PubMedGoogle Scholar
  116. 116.
    Fehlings MG, Vawda R (2011) Cellular treatments for spinal cord injury: the time is right for clinical trials. Neurotherapeutics 8(4):704–720PubMedGoogle Scholar
  117. 117.
    Yazdani SO, Pedram M, Hafizi M et al (2012) A comparison between neurally induced bone marrow derived mesenchymal stem cells and olfactory ensheathing glial cells to repair spinal cord injuries in rat. Tissue Cell 44(4):205–213PubMedGoogle Scholar
  118. 118.
    Lindvall O, Bjorklund A (2004) Cell replacement therapy: helping the brain to repair itself. NeuroRx 1(4):379–381PubMedGoogle Scholar
  119. 119.
    Ahmad M, Graham SH (2010) Inflammation after stroke: mechanisms and therapeutic approaches. Transl Stroke Res 1(2):74–84PubMedGoogle Scholar
  120. 120.
    Shafi N, Kasner SE (2011) Treatment of acute ischemic stroke: beyond thrombolysis and supportive care. Neurotherapeutics 8(3):425–433PubMedGoogle Scholar
  121. 121.
    Locatelli F, Bersano A, Ballaio E et al (2009) Stem cell therapy in stroke. Cell Mol Life Sci 66(5):757–772PubMedGoogle Scholar
  122. 122.
    Komatsu K, Honmou O, Suzuki J et al (2010) Therapeutic time window of mesenchymal stem cells derived from bone marrow after cerebral ischemia. Brain Res 1334:84–92PubMedGoogle Scholar
  123. 123.
    Keimpema E, Fokkens MR, Nagy Z et al (2009) Early transient presence of implanted bone marrow stem cells reduces lesion size after cerebral ischaemia in adult rats. Neuropathol Appl Neurobiol 35(1):89–102PubMedGoogle Scholar
  124. 124.
    Zheng W, Honmou O, Miyata K et al (2010) Therapeutic benefits of human mesenchymal stem cells derived from bone marrow after global cerebral ischemia. Brain Res 1310:8–16PubMedGoogle Scholar
  125. 125.
    Kurozumi K, Nakamura K, Tamiya T et al (2005) Mesenchymal stem cells that produce neurotrophic factors reduce ischemic damage in the rat middle cerebral artery occlusion model. Mol Ther 11(1):96–104PubMedGoogle Scholar
  126. 126.
    Wang Y, Deng Y, Zhou GQ (2008) SDF-1alpha/CXCR4-mediated migration of systemically transplanted bone marrow stromal cells towards ischemic brain lesion in a rat model. Brain Res 1195:104–112PubMedGoogle Scholar
  127. 127.
    Wakabayashi K, Nagai A, Sheikh AM et al (2010) Transplantation of human mesenchymal stem cells promotes functional improvement and increased expression of neurotrophic factors in a rat focal cerebral ischemia model. J Neurosci Res 88(5):1017–1025PubMedGoogle Scholar
  128. 128.
    Leu S, Lin YC, Yuen CM et al (2010) Adipose-derived mesenchymal stem cells markedly attenuate brain infarct size and improve neurological function in rats. J Transl Med 8:63PubMedGoogle Scholar
  129. 129.
    Tang YL, Zhao Q, Qin X et al (2005) Paracrine action enhances the effects of autologous mesenchymal stem cell transplantation on vascular regeneration in rat model of myocardial infarction. Ann Thorac Surg 80(1):229–236 discussion 236-7PubMedGoogle Scholar
  130. 130.
    Banas A, Teratani T, Yamamoto Y et al (2008) IFATS collection: in vivo therapeutic potential of human adipose tissue mesenchymal stem cells after transplantation into mice with liver injury. Stem Cells 26(10):2705–2712PubMedGoogle Scholar
  131. 131.
    Chen JR, Cheng GY, Sheu CC et al (2008) Transplanted bone marrow stromal cells migrate, differentiate and improve motor function in rats with experimentally induced cerebral stroke. J Anat 213(3):249–258PubMedGoogle Scholar
  132. 132.
    Bang OY, Lee JS, Lee PH et al (2005) Autologous mesenchymal stem cell transplantation in stroke patients. Ann Neurol 57(6):874–882PubMedGoogle Scholar
  133. 133.
    Lee JS, Hong JM, Moon GJ et al (2010) A long-term follow-up study of intravenous autologous mesenchymal stem cell transplantation in patients with ischemic stroke. Stem Cells 28(6):1099–1106PubMedGoogle Scholar
  134. 134.
    Roh JK, Jung KH, Chu K (2008) Adult stem cell transplantation in stroke: its limitations and prospects. Curr Stem Cell Res Ther 3(3):185–196PubMedGoogle Scholar
  135. 135.
    Lanfranconi S, Locatelli F, Corti S et al (2011) Growth factors in ischemic stroke. J Cell Mol Med 15(8):1645–1687PubMedGoogle Scholar
  136. 136.
    Bonfield TL, Nolan Koloze MT, Lennon DP et al (2010) Defining human mesenchymal stem cell efficacy in vivo. J Inflamm (Lond) 7:51Google Scholar
  137. 137.
    Joyce N, Annett G, Wirthlin L et al (2010) Mesenchymal stem cells for the treatment of neurodegenerative disease. Regen Med 5(6):933–946PubMedGoogle Scholar
  138. 138.
    Momin EN, Mohyeldin A, Zaidi HA et al (2010) Mesenchymal stem cells: new approaches for the treatment of neurological diseases. Curr Stem Cell Res Ther 5(4):326–344PubMedGoogle Scholar
  139. 139.
    Lee PH, Park HJ (2009) Bone marrow-derived mesenchymal stem cell therapy as a candidate disease-modifying strategy in Parkinson’s disease and multiple system atrophy. J Clin Neurol 5(1):1–10PubMedGoogle Scholar
  140. 140.
    Roobrouck VD, Clavel C, Jacobs SA et al (2011) Differentiation potential of human postnatal mesenchymal stem cells, mesoangioblasts, and multipotent adult progenitor cells reflected in their transcriptome and partially influenced by the culture conditions. Stem Cells 29(5):871–882PubMedGoogle Scholar
  141. 141.
    Ranganath SH, Levy O, Inamdar MS et al (2012) Harnessing the mesenchymal stem cell secretome for the treatment of cardiovascular disease. Cell Stem Cell 10(3):244–258PubMedGoogle Scholar
  142. 142.
    Dharmasaroja P (2009) Bone marrow-derived mesenchymal stem cells for the treatment of ischemic stroke. J Clin Neurosci 16(1):12–20PubMedGoogle Scholar
  143. 143.
    Liu Z, Li Z, Zhang X et al (2008) Contralesional axonal remodeling of the corticospinal system in adult rats after stroke and bone marrow stromal cell treatment. Stroke 39(9):2571–2577PubMedGoogle Scholar
  144. 144.
    Choi YJ, Li WY, Moon GJ et al (2010) Enhancing trophic support of mesenchymal stem cells by ex vivo treatment with trophic factors. J Neurol Sci 298(1–2):28–34PubMedGoogle Scholar
  145. 145.
    Li WY, Choi WJ, Lee PH et al (2008) Mesenchymal stem cells for ischemic stroke: changes in effects after ex vivo culturing. Cell Transplant 17(9):1045–1059PubMedGoogle Scholar
  146. 146.
    Rivera FJ, Siebzehnrubi FA, Kandasamy M et al (2009) Mesenchymal stem cells promote oligodendroglial differentiation in hippocampal slice cultures. Cell Physiol Biochem 24(3–4):317–324PubMedGoogle Scholar
  147. 147.
    English K, French A, Wood KJ (2010) Mesenchymal stromal cells: facilitators of successful transplantation? Cell Stem Cell 7(4):431–442PubMedGoogle Scholar

Copyright information

© Springer Basel 2013

Authors and Affiliations

  • Fábio G. Teixeira
    • 1
    • 2
  • Miguel M. Carvalho
    • 1
    • 2
  • Nuno Sousa
    • 1
    • 2
  • António J. Salgado
    • 1
    • 2
    Email author
  1. 1.Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of MinhoBragaPortugal
  2. 2.ICVS/3B’sPT Government Associate LaboratoryBraga/GuimarãesPortugal

Personalised recommendations