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Progress in Stem Cell Therapy for Major Human Neurological Disorders

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Abstract

Human neurological disorders such as Alzheimer’s disease (AD), Parkinson’s disease, stroke or spinal cord injury are caused by the loss of neurons and glial cells in the brain or spinal cord in the Central Nervous System (CNS). Stem cell technology has become an attractive option to investigate and treat these diseases. Several types of neurons and glial cells have successfully been generated from stem cells, which in some cases, have ameliorated some dysfunctions both in animal models of neurological disorders and in patients at clinical level. Stem cell-based therapies can be beneficial by acting through several mechanisms such as cell replacement, modulation of inflammation and trophic actions. Here we review recent and current remarkable clinical studies involving stem cell-based therapy for AD and stroke and provide an overview of the different types of stem cells available nowadays, their main properties and how they are developing as a possible therapy for neurological disorders.

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References

  1. Lindvall, O., & Kokaia, Z. (2010). Stem cells in human neurodegenerative disorders–time for clinical translation? Journal of Clinical Investigation, 120(1), 29–40.

    PubMed  CAS  Google Scholar 

  2. Lunn, J. S., Sakowski, S. A., Hur, J., & Feldman, E. L. (2011). Stem cell technology for neurodegenerative diseases. Annals of Neurology, 70(3), 353–361.

    PubMed  CAS  Google Scholar 

  3. Nussbaum, R. L., & Ellis, C. E. (2003). Alzheimer’s disease and Parkinson’s disease. The New England Journal of Medicine, 348(14), 1356–1364.

    PubMed  CAS  Google Scholar 

  4. Huang, Y., & Mucke, L. (2012). Alzheimer mechanisms and therapeutic strategies. Cell, 148(6), 1204–1222.

    PubMed  CAS  Google Scholar 

  5. Martinez-Morales, P. L., & Liste, I. (2012). Stem cells as in vitro model of Parkinson’s disease. Stem Cells International, 2012, 980941.

  6. Durnaoglu, S., Genc, S., & Genc, K. (2011). Patient-specific pluripotent stem cells in neurological diseases. Stem Cells International, 2011, 212487.

    PubMed  Google Scholar 

  7. Bongso, A., Fong, C. Y., & Gauthaman, K. (2008). Taking stem cells to the clinic: major challenges. Journal of Cellular Biochemistry, 105(6), 1352–1360.

    PubMed  CAS  Google Scholar 

  8. Thomson, J. A., Itskovitz-Eldor, J., Shapiro, S. S., et al. (1998). Embryonic stem cell lines derived from human blastocysts. Science, 282(5391), 1145–1147.

    PubMed  CAS  Google Scholar 

  9. Kriks, S., Shim, J. W., Piao, J., et al. (2011). Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson’s disease. Nature, 480, 547–551.

    PubMed  CAS  Google Scholar 

  10. Malmersjo, S., Liste, I., Dyachok, O., Tengholm, A., Arenas, E., & Uhlén, P. (2010). Ca2+ and cAMP signaling in human embryonic stem cell-derived dopamine neurons. Stem Cells and Development, 19(9), 1355–1364.

    PubMed  Google Scholar 

  11. Chambers, S. M., Fasano, C. A., Papapetrou, E. P., Tomishima, M., Sadelain, M., & Studer, L. (2009). Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling. Nature Biotechnology, 27(5), 275–280.

    PubMed  CAS  Google Scholar 

  12. Sacchetti, P., Sousa, K. M., Hall, A. C., et al. (2009). Liver X receptors and oxysterols promote ventral midbrain neurogenesis in vivo and in human embryonic stem cells. Cell Stem Cell, 5(4), 409–419.

    PubMed  CAS  Google Scholar 

  13. Hu, B. Y., & Zhang, S. C. (2009). Differentiation of spinal motor neurons from pluripotent human stem cells. Nature Protocols, 4(9), 1295–1304.

    PubMed  CAS  Google Scholar 

  14. Lee, H., Shamy, G. A., Elkabetz, Y., et al. (2007). Directed differentiation and transplantation of human embryonic stem cell-derived motoneurons. Stem Cells, 25(8), 1931–1939.

    PubMed  CAS  Google Scholar 

  15. Krencik, R., Weick, J. P., Liu, Y., Zhang, Z. J., & Zhang, S. C. (2011). Specification of transplantable astroglial subtypes from human pluripotent stem cells. Nature Biotechnology, 29(6), 528–534.

    PubMed  CAS  Google Scholar 

  16. Cho, M. S., Lee, Y. E., Kim, J. Y., et al. (2008). Highly efficient and large-scale generation of functional dopamine neurons from human embryonic stem cells. Proceedings of the National Academy of Sciences of the United States of America, 105(9), 3392–3397.

    PubMed  CAS  Google Scholar 

  17. Koch, P., Opitz, T., Steinbeck, J. A., Ladewig, J., & Brüstle, O. (2009). A rosette-type, self-renewing human ES cell-derived neural stem cell with potential for in vitro instruction and synaptic integration. Proceedings of the National Academy of Sciences of the United States of America, 106(9), 3225–3230.

    PubMed  CAS  Google Scholar 

  18. Liras, A. (2010). Future research and therapeutic applications of human stem cells: general, regulatory, and bioethical aspects. Journal of Translational Medicine, 8, 131.

    PubMed  Google Scholar 

  19. Condic, M. L., & Rao, M. (2010). Alternative sources of pluripotent stem cells: ethical and scientific issues revisited. Stem Cells and Development, 19, 1121–1129.

    PubMed  Google Scholar 

  20. Baker, M. (2011). Stem-cell pioneer bows out. Nature, 479(7374), 459.

    PubMed  CAS  Google Scholar 

  21. Takahashi, K., Tanabe, K., Ohnuki, M., et al. (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell, 131(5), 861–872.

    PubMed  CAS  Google Scholar 

  22. Yu, J., Vodyanik, M. A., Smuga-Otto, K., et al. (2007). Induced pluripotent stem cell lines derived from human somatic cells. Science, 318(5858), 1917–1920.

    PubMed  CAS  Google Scholar 

  23. Phanstiel, D. H., Brumbaugh, J., Wenger, C. D., et al. (2011). Proteomic and phosphoproteomic comparison of human ES and iPS cells. Nature Methods, 8(10), 821–827.

    PubMed  CAS  Google Scholar 

  24. Lister, R., Pelizzola, M., Kida, Y. S., et al. (2011). Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells. Nature, 471(7336), 68–73.

    PubMed  CAS  Google Scholar 

  25. Hibaoui, Y., & Feki, A. (2012). Human pluripotent stem cells: applications and challenges in neurological diseases. Frontiers in Physiology, 3, 1–22.

    Google Scholar 

  26. Bonnamain, V., Neveu, I., & Naveilhan, P. (2012). Neural stem/progenitor cells as a promising candidate for regenerative therapy of the central nervous system. Frontiers in Cellular Neuroscience, 6, 17.

    PubMed  Google Scholar 

  27. Kallur, T., Darsalia, V., Lindvall, O., & Kokaia, Z. (2006). Human fetal cortical and striatal neural stem cells generate region-specific neurons in vitro and differentiate extensively to neurons after intrastriatal transplantation in neonatal rats. Journal of Neuroscience Research, 84(8), 1630–1644.

    PubMed  CAS  Google Scholar 

  28. Kim, H. J., McMillan, E., Han, F. B., & Svendsen, C. N. (2009). Regionally specified human neural progenitor cells derived from the mesencephalon and forebrain undergo increased neurogenesis following overexpression of ASCL1. Stem Cells, 27(2), 390–398.

    PubMed  CAS  Google Scholar 

  29. Villa, A., Liste, I., Courtois, E. T., et al. (2009). Generation and properties of a new human ventral mesencephalic neural stem cell line. Experimental Cell Research, 315(11), 1860–1874.

    PubMed  CAS  Google Scholar 

  30. Cacci, E., Villa, A., Parmar, M., et al. (2007). Generation of human cortical neurons from a new immortal fetal neural stem cell line. Experimental Cell Research, 313(3), 588–601.

    PubMed  CAS  Google Scholar 

  31. Hicks, C., Stevanato, L., Stroemer, R. P., Tang, E., Richardson, S., & Sinden, J.D. (2012). In vivo and in vitro characterization of the angiogenic effect of CTX0E03 human neural stem cells. Cell Transplantation. doi:10.3727/096368912X657936.

  32. Mack, G. S. (2011). ReNeuron and StemCells get green light for neural stem cell trials. Nature Biotechnology, 29(2), 95–97.

    PubMed  CAS  Google Scholar 

  33. Trounson, A., Thakar, R. G., Lomax, G., Gibbons, D., et al. (2011). Clinical trials for stem cell therapies. BMC Medicine, 9, 52.

    PubMed  Google Scholar 

  34. Achilleos, A., & Trainor, P. A. (2012). Neural crest stem cells: discovery, properties and potential for therapy. Cell Research, 22(2), 288–304.

    PubMed  CAS  Google Scholar 

  35. Krejci, E., & Grim, M. (2010). Isolation and characterization of neural crest stem cells from adult human hair follicles. Folia Biologica (Praha), 56(4), 149–157.

    CAS  Google Scholar 

  36. Fernandes, K. J., Kobayashi, N. R., Gallagher, C. J., et al. (2006). Analysis of the neurogenic potential of multipotent skin-derived precursors. Experimental Neurology, 201(1), 32–48.

    PubMed  Google Scholar 

  37. Crane, J. F., & Trainor, P. A. (2006). Neural crest stem and progenitor cells. Annual Review of Cell Biology, 22, 267–286.

    CAS  Google Scholar 

  38. Trentin, A., Glavieux-Pardanaud, C., Le Douarin, N. M., & Dupin, E. (2004). Self-renewal capacity is a widespread property of various types of neural crest precursor cells. Proceedings of the National Academy of Sciences of the United States of America, 101(13), 4495–4500.

    PubMed  CAS  Google Scholar 

  39. Clewes, O., Narytnyk, A., Gillinder, K. R., Loughney, A. D., Murdoch, A. P., & Sieber-Blum, M. (2011). Human epidermal neural crest stem cells (hEPI-NCSC)–characterization and directed differentiation into osteocytes and melanocytes. Stem Cell Reviews, 7(4), 799–814.

    PubMed  Google Scholar 

  40. Sieber-Blum, M., Grim, M., Hu, Y. F., & Szeder, V. (2004). Pluripotent neural crest stem cells in the adult hair follicle. Developmental Dynamics, 231(2), 258–269.

    PubMed  CAS  Google Scholar 

  41. Fernandes, K. J., McKenzie, I. A., Mill, P., et al. (2004). A dermal niche for multipotent adult skin-derived precursor cells. Nature Cell Biology, 6(11), 1082–1093.

    PubMed  CAS  Google Scholar 

  42. Hu, Y. F., Gourab, K., Wells, C., Clewes, O., Schmit, B. D., & Sieber-Blum, M. (2010). Epidermal neural crest stem cell (EPI-NCSC)–mediated recovery of sensory function in a mouse model of spinal cord injury. Stem Cell Reviews, 6(2), 186–198.

    PubMed  Google Scholar 

  43. Sieber-Blum, M., Schnell, L., Gim, M., et al. (2006). Characterization of epidermal neural crest stem cell (EPI-NCSC) grafts in the lesioned spinal cord. Molecular and Cellular Neuroscience, 32, 67–81.

    PubMed  CAS  Google Scholar 

  44. Sieber-Blum, M. (2010). Epidermal neural crest stem cells and their use in mouse models of spinal cord injury. Brain Research Bulletin, 83(5), 189–193.

    PubMed  CAS  Google Scholar 

  45. Yu, H., Kumar, S. M., Kossenkov, A. V., Showe, L., & Xu, X. (2010). Stem cells with neural crest characteristics derived from the bulge region of cultured human hair follicles. The Journal of Investigative Dermatology, 130(5), 1227–1236.

    PubMed  CAS  Google Scholar 

  46. Leong, W. K., Henshall, T. L., Arthur, A., et al. (2012). Human adult dental pulp stem cells enhance poststroke functional recovery through non-neural replacement mechanisms. Stem Cells Translational Medicine, 1(3), 177–187.

    PubMed  CAS  Google Scholar 

  47. Arthur, A., Rychkov, G., Shi, S., Koblar, S. A., & Gronthos, S. (2008). Adult human dental pulp stem cells differentiate toward functionally active neurons under appropriate environmental cues. Stem Cells, 26(7), 1787–1795.

    PubMed  CAS  Google Scholar 

  48. Arthur, A., Shi, S., Zannetino, A. C., et al. (2009). Implanted adult human dental pulp stem cells induce endogenous axon guidance. Stem Cells, 27, 2229–2237.

    PubMed  CAS  Google Scholar 

  49. Gronthos, S., Mankani, M., Brahim, J., Robey, P. G., & Shi, S. (2001). Postnatal human dental pulp stem cells (DPSCs) in vitro and in vivo. Proceedings of the National Academy of Sciences of the United States of America, 97(25), 13625–13630.

    Google Scholar 

  50. Kiraly, M., Porcsalmy, B., Pataki, et al. (2009). Simultaneous PKC and cAMP activation induces differentiation of human dental pulp stem cells into functionally active neurons. Neurochemistry International, 55(5), 323–332.

    PubMed  CAS  Google Scholar 

  51. Nosrat, I. V., Widenfalk, J., Olson, L., & Nosrat, C. A. (2001). Dental pulp cells produce neurotrophic factors, interact with trigeminal neurons in vitro, and rescue motoneurons after spinal cord injury. Developmental Biology, 238(1), 120–132.

    PubMed  CAS  Google Scholar 

  52. Yang, K. L., Chen, M. F., Liao, C. H., Pang, C. Y., & Lin, P. Y. (2009). A simple and efficient method for generating Nurr1-positive neuronal stem cells from human wisdom teeth (tNSC) and the potential of tNSC for stroke therapy. (2009). Cytotherapy, 11(5), 606–617.

    PubMed  CAS  Google Scholar 

  53. Barraud, P., Seferiadis, A. A., Tyson, L. D., et al. (2010). Neural crest origin of olfactory ensheathing glia. Proceedings of the National Academy of Sciences of the United States of America, 107(49), 21040–21045.

    PubMed  CAS  Google Scholar 

  54. Barnett, S. C., & Riddell, J. S. (2007). Olfactory ensheathing cell transplantation as a strategy for spinal cord repair–what can it achieve? Nature Clinical Practice Neurology, 3(3), 152–161.

    PubMed  Google Scholar 

  55. Raisman, G., & Li, Y. (2007). Repair of neural pathways by olfactory ensheathing cells. Nature Reviews Neuroscience, 8(4), 312–319.

    PubMed  CAS  Google Scholar 

  56. Ramon-Cueto, A. (2011). Olfactory ensheathing glia for nervous system repair. Experimental Neurology, 229(1), 1.

    PubMed  Google Scholar 

  57. Muñoz-Quiles, C., Santos-Benito, F. F., Llamusi, M. B., & Ramon-Cueto, A. J. (2009). Chronic spinal injury repair by olfactory bulb ensheathing glia and feasibility for autologous therapy. Journal of Neuropathology and Experimental Neurology, 68(12), 1294–1308.

    PubMed  Google Scholar 

  58. Imaizumi, T., Lankford, K. L., Waxman, S. G., Greer, C. A., & Kocsis, J. D. (1998). Transplanted olfactory ensheathing cells remyelinate and enhance axonal conduction in the demyelinated dorsal columns of the rat spinal cord. The Journal of Neuroscience, 18(16), 6176–6185.

    PubMed  CAS  Google Scholar 

  59. Ramon-Cueto, A., & Avila, J. (1998). Olfactory ensheathing glia: properties and function. Brain Research Bulletin, 46(3), 175–187.

    PubMed  CAS  Google Scholar 

  60. Ramon-Cueto, A., Cordero, M. I., Santos-Benito, F. F., & Avila, J. (2000). Functional recovery of paraplegic rats and motor axon regeneration in their spinal cords by olfactory ensheathing glia. Neuron, 25(2), 425–435.

    PubMed  CAS  Google Scholar 

  61. Deumens, R., Koopmans, G. C., Honig, W. M., et al. (2006). Chronically injured corticospinal axons do not cross large spinal lesion gaps after a multifactorial transplantation strategy using olfactory ensheathing cell/olfactory nerve fibroblast-biomatrix bridges. Journal of Neuroscience Research, 83(5), 811–820.

    PubMed  CAS  Google Scholar 

  62. Li, Y., Field, P. M., & Raisman, G. (1998). Regeneration of adult rat corticospinal axons induced by transplanted olfactory ensheathing cells. The Journal of Neuroscience, 18(24), 10514–10524.

    PubMed  CAS  Google Scholar 

  63. Lopez-Vales, R., Garcia-Alias, G., Fores, J., Navarro, X., & Verdu, E. (2004). Increased expression of cyclo-oxygenase 2 and vascular endothelial growth factor in lesioned spinal cord by transplanted olfactory ensheathing cells. Journal of Neurotrauma, 21(8), 1031–1043.

    PubMed  Google Scholar 

  64. 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. Molecular Therapy, 11(1), 96–104.

    PubMed  CAS  Google Scholar 

  65. Wu, J., Sun, T., Ye, C., Yao, J., Zhu, B., & He, H. (2012). Clinical observation of fetal olfactory ensheathing glia transplantation (OEGT) in patients with complete chronic spinal cord injury. Cell Transplantation, 21(Suppl 1), S33–S37.

    PubMed  Google Scholar 

  66. Huang, H., Chen, L., Xi, H., et al. (2008). Fetal olfactory ensheathing cells transplantation in amyotrophic lateral sclerosis patients: a controlled pilot study. Clinical Transplantation, 22(6), 710–718.

    PubMed  Google Scholar 

  67. Shyu, W. C., Liu, D., Lin, S. Z., et al. (2008). Implantation of olfactory ensheathing cells promotes neuroplasticity in murine models of stroke. Journal of Clinical Investigation, 118, 2482–2495.

    PubMed  CAS  Google Scholar 

  68. Joyce, N., Annett, G., Wirthlin, L., Olson, S., Bauer, G., & Nolta, J. A. (2010). Mesenchymal stem cells for the treatment of neurodegenerative disease. Regenerative Medicine, 5(6), 933–946.

    PubMed  Google Scholar 

  69. Zhang, L., Tan, X., Dong, C., et al. (2012). In vitro differentiation of human umbilical cord mesenchymal stem cells (hUCMSCs), derived from Wharton’s jelly, into choline acetyltransferase (ChAT)-positive cells. International Journal of Developmental Neuroscience, 30(6), 471–477.

    PubMed  CAS  Google Scholar 

  70. Chen, L., He, D. M., & Zhang, Y. (2009). The differentiation of human placenta-derived mesenchymal stem cells into dopaminergic cells in vitro. Cellular and Molecular Biology Letters, 14(3), 528–536.

    PubMed  CAS  Google Scholar 

  71. Barzilay, R., Kan, I., Ben-Zur, T., Bulvik, S., Melamed, E., & Offen, D. (2008). Induction of human mesenchymal stem cells into dopamine-producing cells with different differentiation protocols. Stem Cells and Development, 17(3), 547–554.

    PubMed  CAS  Google Scholar 

  72. Satija, N. K., Singh, V. K., Verma, Y. K., et al. (2009). Mesenchymal stem cell-based therapy: a new paradigm in regenerative medicine. Journal of Cellular and Molecular Medicine, 13(11–12), 4385–4402.

    PubMed  CAS  Google Scholar 

  73. Ylostalo, J. H., Bartosh, T. J., Coble, K., & Prockop, D. J. (2012). Human mesenchymal stem/stromal cells (hMSCs) cultured as spheroids are self-activated to produce prostaglandin E2 (PGE2) that directs stimulated macrophages into an anti-inflammatory phenotype. Stem Cells, 30(10), 2283–2296.

    PubMed  CAS  Google Scholar 

  74. Chamberlain, G., Fox, J., Ashton, B., & Middleton, J. (2007). Concise review: mesenchymal stem cells: their phenotype, differentiation capacity, immunological features, and potential for homing. Stem Cells, 25(11), 2739–2749.

    PubMed  CAS  Google Scholar 

  75. Hoch, A. I., Binder, B. Y., Genetos, D. C., & Leach, J. K. (2012). Differentiation-dependent secretion of proangiogenic factors by mesenchymal stem cells. PLoS One, 7(4), e35579.

    PubMed  CAS  Google Scholar 

  76. Park, H. W., Lim, M. J., Jung, H., Lee, S. P., Paik, K. S., & Chang, M. S. (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), 1118–1132.

    PubMed  Google Scholar 

  77. Park, K. S., Kim, Y. S., Kim, J. H., et al. (2010). Trophic molecules derived from human mesenchymal stem cells enhance survival, function, and angiogenesis of isolated islets after transplantation. Transplantation, 89(5), 509–517.

    PubMed  CAS  Google Scholar 

  78. Chen, N., Kamath, S., Newcomb, J., et al. (2007). Trophic factor induction of human umbilical cord blood cells in vitro and in vivo. Journal of Neural Engineering, 4(2), 130–145.

    PubMed  Google Scholar 

  79. Tang, Y., Yasuhara, T., Hara, K., et al. (2007). Transplantation of bone marrow-derived stem cells: a promising therapy for stroke. Cell Transplantation, 16(2), 159–169.

    PubMed  Google Scholar 

  80. Chen, J., Sanberg, P. R., Li, Y., et al. (2001). Intravenous administration of human umbilical cord blood reduces behavioral deficits after stroke in rats. Stroke, 32(11), 2682–2688.

    PubMed  CAS  Google Scholar 

  81. Bang, O. Y., Lee, J. S., Lee, P. H., & Lee, G. (2005). Autologous mesenchymal stem cell transplantation in stroke patients. Annals of Neurology, 57(6), 874–882.

    PubMed  Google Scholar 

  82. Lee, J. S., Hong, J. M., Moon, G. J., 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), 1099–1106.

    PubMed  Google Scholar 

  83. Shen, L. H., Li, Y., Chen, J., et al. (2007). Therapeutic benefit of bone marrow stromal cells administered 1 month after stroke. Journal of Cerebral Blood Flow and Metabolism, 27(1), 6–13.

    PubMed  Google Scholar 

  84. Chen, J., & Chopp, M. (2006). Neurorestorative treatment of stroke: cell and pharmacological approaches. The Journal of the American Society for Experimental NeuroTherapeutics, 3(4), 466–473.

    CAS  Google Scholar 

  85. Zhang, J., Li, Y., Chen, J., et al. (2004). Expression of insulin-like growth factor 1 and receptor in ischemic rats treated with human marrow stromal cells. Brain Research, 1030(1), 19–27.

    PubMed  CAS  Google Scholar 

  86. Teo, G. S., Ankrum, J. A., Martinelli, R., et al. (2012). Mesenchymal stem cells transmigrate between and directly through tumor necrosis factor-α-activated endothelial cells via both leukocyte-like and novel mechanisms. Stem Cells, 30(11), 2472–2486.

    PubMed  CAS  Google Scholar 

  87. Kang, S. K., Shin, I. S., Ko, M. S., Jo, J. Y., & Ra, J. C. (2012). Journey of mesenchymal stem cells for homing: strategies to enhance efficacy and safety of stem cell therapy. Stem Cells International, 2012, 342968.

  88. Karp, J. M., & Leng Teo, G. S. (2009). Mesenchymal stem cell homing: the devil is in the details. Cell Stem Cell, 4(3), 206–216.

    PubMed  CAS  Google Scholar 

  89. Chapel, A., Bertho, J. M., Bensidhoum, M., et al. (2003). Mesenchymal stem cells home to injured tissues when co-infused with hematopoietic cells to treat a radiation-induced multi-organ failure syndrome. The Journal of Gene Medicine, 5(12), 1028–1038.

    PubMed  Google Scholar 

  90. Liu, R., Zhang, Z., Lu, Z., et al. (2013). Human Umbilical Cord Stem Cells Ameliorate Experimental Autoimmune Encephalomyelitis by Regulating Immunoinflammation and Remyelination. Stem Cells and Development, 22, 1053–1062.

    Google Scholar 

  91. Kondo, M., Wagers, A. J., Manz, M. G., et al. (2003). Biology of hematopoietic stem cells and progenitors: implications for clinical application. Annual Review of Immunology, 21, 759–806.

    PubMed  CAS  Google Scholar 

  92. Borlongan, C. V., Glover, L. E., Tajiri, N., Kaneko, Y., & Freeman, T. B. (2011). The great migration of bone marrow-derived stem cells toward the ischemic brain: therapeutic implications for stroke and other neurological disorders. Progress in Neurobiology, 95(2), 213–228.

    PubMed  CAS  Google Scholar 

  93. Seita, J., & Weissman, I. L. (2010). Hematopoietic stem cell: self-renewal versus differentiation. Wiley Interdisciplinary Reviews: Systems Biology and Medicine, 2(6), 640–653.

    PubMed  CAS  Google Scholar 

  94. Nervi, B., Link, D. C., & DiPersio, J. F. (2006). Cytokines and hematopoietic stem cell mobilization. Journal of Cellular Biochemistry, 99(3), 690–705.

    PubMed  CAS  Google Scholar 

  95. Welte, K., Platzer, E., Lu, L., et al. (1985). Purification and biochemical characterization of human pluripotent hematopoietic colony-stimulating factor. Proceedings of the National Academy of Sciences of the United States of America, 82(5), 1526–1530.

    PubMed  CAS  Google Scholar 

  96. Minnerup, J., Heidrich, J., Wellmann, J., Rogalewski, A., Schneider, A., & Schabitz, W. R. (2008). Meta-analysis of the efficacy of granulocyte-colony stimulating factor in animal models of focal cerebral ischemia. Stroke, 39(6), 1855–1861.

    PubMed  CAS  Google Scholar 

  97. Gibson, C. L., Bath, P. M., & Murphy, S. P. (2005). G-CSF reduces infarct volume and improves functional outcome after transient focal cerebral ischemia in mice. Journal of Cerebral Blood Flow and Metabolism, 25(4), 431–439.

    PubMed  CAS  Google Scholar 

  98. Sprigg, N., Bath, P. M., Zhao, L., et al. (2006). Granulocyte-colony-stimulating factor mobilizes bone marrow stem cells in patients with subacute ischemic stroke: the Stem cell Trial of recovery EnhanceMent after Stroke (STEMS) pilot randomized, controlled trial (ISRCTN 16784092). Stroke, 37(12), 2979–2983.

    PubMed  CAS  Google Scholar 

  99. Boy, S., Sauerbruch, S., Kraemer, M., et al. (2011). Mobilisation of hematopoietic CD34+ precursor cells in patients with acute stroke is safe–results of an open-labeled non randomized phase I/II trial. PLoS One, 6(8), e23099.

    PubMed  CAS  Google Scholar 

  100. Taguchi, A., Soma, T., Tanaka, H., et al. (2004). Administration of CD34+ cells after stroke enhances neurogenesis via angiogenesis in a mouse model. The Journal of Clinical Investigation, 114(3), 330–338.

    PubMed  CAS  Google Scholar 

  101. Nishio, Y., Koda, M., Kamada, T., et al. (2006). The use of hemopoietic stem cells derived from human umbilical cord blood to promote restoration of spinal cord tissue and recovery of hindlimb function in adult rats. Journal of Neurosurgery: Spine, 5(5), 424–433.

    PubMed  Google Scholar 

  102. Nikolic, W. V., Hou, H., Town, T., et al. (2008). Peripherally administered human umbilical cord blood cells reduce parenchymal and vascular beta-amyloid deposits in Alzheimer mice. Stem Cells and Development, 17(3), 423–439.

    PubMed  CAS  Google Scholar 

  103. Reitz, C., Brayne, C., & Mayeux, R. (2011). Epidemiology of Alzheimer disease. Nature Reviews. Neurology, 7(3), 137–152.

    PubMed  Google Scholar 

  104. Burns, A., Byrne, E. J., & Maurer, K. (2002). Alzheimer’s disease. Lancet, 360(9327), 163–165.

    PubMed  Google Scholar 

  105. Allen, S. J., Watson, J. J., & Dawbarn, D. (2011). The neurotrophins and their role in Alzheimer’s disease. Current Neuropharmacology, 9(4), 559–573.

    PubMed  CAS  Google Scholar 

  106. Eckman, C. B., & Eckman, E. A. (2007). An update on the amyloid hypothesis. Neurologic Clinics, 25(3), 669–682.

    PubMed  Google Scholar 

  107. Kim, J. Y., Kim, D. H., Kim, J. H., et al. (2012). Soluble intracellular adhesion molecule-1 secreted by human umbilical cord blood-derived mesenchymal stem cell reduces amyloid-β plaques. Cell Death and Differentiation, 19(4), 680–691.

    PubMed  CAS  Google Scholar 

  108. Lee, H. J., Lee, J. K., Lee, H., et al. (2012). Human umbilical cord blood-derived mesenchymal stem cells improve neuropathology and cognitive impairment in an Alzheimer’s disease mouse model through modulation of neuroinflammation. Neurobiology of Aging, 33(3), 588–602.

    PubMed  CAS  Google Scholar 

  109. Schliebs, R., & Arendt, T. (2011). The cholinergic system in aging and neuronal degeneration. Behavioural Brain Research, 221(2), 555–563.

    PubMed  CAS  Google Scholar 

  110. Nyakas, C., Granic, I., & Halmy, L. G. (2011). The basal forebrain cholinergic system in aging and dementia. Rescuing cholinergic neurons from neurotoxic amyloid-β42 with memantine. Behavioural Brain Research, 221(2), 594–603.

    PubMed  CAS  Google Scholar 

  111. Mufson, E. J., Counts, S. E., Perez, S. E., & Ginsberg, S. D. (2008). Cholinergic system during the progression of Alzheimer’s disease: therapeutic implications. Expert Review of Neurotherapeutics, 8(11), 1703–1718.

    PubMed  CAS  Google Scholar 

  112. Raiteri, M. (2006). Functional pharmacology in human brain. Pharmacological Reviews, 58(2), 162–193.

    PubMed  CAS  Google Scholar 

  113. Bartus, R. T., Dean, R. L., & Beer, B. (1982). The cholinergic hypothesis of geriatric memory dysfunction. Science, 217(4558), 408–414.

    PubMed  CAS  Google Scholar 

  114. Howard, R., McShare, R., Lindesay, J., et al. (2012). Donepezil and memantine for moderate-to-severe Alzheimer’s disease. The New England Journal of Medicine, 366(10), 893–903.

    PubMed  CAS  Google Scholar 

  115. Wilkinson, D. G., Francis, P. T., Schwam, E., & Payne-Parrish, J. (2004). Cholinesterase inhibitors used in the treatment of Alzheimer’s disease: the relationship between pharmacological effects and clinical efficacy. Drugs & Aging, 21(7), 453–478.

    CAS  Google Scholar 

  116. Bernard, V., Décossas, M., Liste, I., & Bloch, B. (2006). Intraneuronal trafficking of G-protein-coupled receptors in vivo. Trends Neuroscience, 29(3), 140–147.

    CAS  Google Scholar 

  117. Liste, I., Bernard, V., & Bloch, B. (2002). Acute and chronic acetylcholinesterase inhibition regulates in vivo the localization and abundance of muscarinic receptors m2 and m4 at the cell surface and in the cytoplasm of striatal neurons. Molecular and Cellular Neuroscience, 20(2), 244–256.

    PubMed  CAS  Google Scholar 

  118. Liste, I., García-García, E., Bueno, C., & Martínez-Serrano, A. (2007). Bcl-XL modulates the differentiation of immortalized human neural stem cells. Cell Death and Differentiation, 14(11), 1880–1892.

    PubMed  CAS  Google Scholar 

  119. Nilsson, O. G., Brundin, P., Widner, H., Strecker, R. E., & Björklund, A. (1988). Human fetal basal forebrain neurons grafted to the denervated rat hippocampus produce an organotypic cholinergic reinnervation pattern. Brain Research, 456(1), 193–198.

    PubMed  CAS  Google Scholar 

  120. Cassel, J. C., Gaurivaud, M., Lazarus, C., Bertrand, F., Galani, R., & Jeltsch, H. (2002). Grafts of fetal septal cells after cholinergic immunotoxic denervation of the hippocampus: a functional dissociation between dorsal and ventral implantation sites. Neuroscience, 113(4), 871–882.

    PubMed  CAS  Google Scholar 

  121. Bissonnette, C. J., Lyass, L., & Bhattacharya, B. J. (2011). The controlled generation of functional basal forebrain cholinergic neurons from human embryonic stem cells. Stem Cells, 29(5), 802–811.

    PubMed  Google Scholar 

  122. Appel, S. H. (1981). A unifying hypothesis for the cause of amyotrophic lateral sclerosis, Parkinsonism, and Alzheimer disease. Annals of Neurology, 10(6), 499–505.

    PubMed  CAS  Google Scholar 

  123. Tuszynski, M. H. (2007). Nerve growth factor gene therapy in Alzheimer disease. Alzheimer Disease and Associated Disorders, 21(2), 179–189.

    PubMed  CAS  Google Scholar 

  124. Tuszynski, M. H., Thal, L., Pay, M., et al. (2005). A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease. Nature Medicine, 11(5), 551–555.

    PubMed  CAS  Google Scholar 

  125. Wahlberg, L. U., Lind, G., Almqvist, P. M., et al. (2012). Targeted delivery of nerve growth factor via encapsulated cell biodelivery in Alzheimer disease: a technology platform for restorative neurosurgery. Journal of Neurosurgery, 117(2), 340–347.

    PubMed  Google Scholar 

  126. Eriksdotter-Jönhagen, M., Linderoth, B., Lind, G., Aladellie, L., et al. (2012). Encapsulated cell biodelivery of nerve growth factor to the Basal forebrain in patients with Alzheimer’s disease. Dementia and Geriatric of Cognitie Disorders, 33(1), 18–28.

    Google Scholar 

  127. Li, G., Peskind, E. R., Millard, S. P., et al. (2009). Cerebrospinal fluid concentration of brain-derived neurotrophic factor and cognitive function in non-demented subjects. PLoS One, 4(5), e5424.

    PubMed  Google Scholar 

  128. Connor, B., Beilharz, E. J., Williams, C., et al. (1997). Insulin-like growth factor-I (IGF-I) immunoreactivity in the Alzheimer’s disease temporal cortex and hippocampus. Brain Research. Molecular Brain Research, 49(1–2), 283–290.

    PubMed  CAS  Google Scholar 

  129. Nagahara, A. H., Merrill, D. A., Coppola, G., et al. (2009). Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer’s disease. Nature Medicine, 15(3), 331–337.

    PubMed  CAS  Google Scholar 

  130. Blurton-Jones, M., Kitazawa, M., Martínez-Coria, H., et al. (2009). Neural stem cells improve cognition via BDNF in a transgenic model of Alzheimer disease. Proceedings of the National Academy of Sciences of the United States of America, 106(32), 13594–13599.

    PubMed  CAS  Google Scholar 

  131. Mu, Y., & Gage, F. H. (2011). Adult hippocampal neurogenesis and its role in Alzheimer’s disease. Molecular Neurodegeneration, 6, 85.

    PubMed  Google Scholar 

  132. Murray, C. J., & López, A. D. (1997). Mortality by cause for eight regions of the world: global burden of disease study. Lancet, 349(9061), 1269–1276.

    PubMed  CAS  Google Scholar 

  133. Smith, H. K., & Gavins, F. N. (2012). The potential of stem cell therapy for stroke: is PISCES the sign? The FASEB Journal, 26(6), 2239–2252.

    CAS  Google Scholar 

  134. Luo, Y. (2011). Cell-based therapy for stroke. Journal of Neural Transmission, 118(1), 61–74.

    PubMed  Google Scholar 

  135. Donnan, G. A., Fisher, M., Macleod, M., & Davis, S. M. (2008). Stroke. Lancet, 371(9624), 1612–1623.

    PubMed  CAS  Google Scholar 

  136. Nakatomi, H., Kuriu, T., Okabe, S., et al. (2002). Regeneration of hippocampal pyramidal neurons after ischemic brain injury by recruitment of endogenous neural progenitors. Cell, 110(4), 429–441.

    PubMed  CAS  Google Scholar 

  137. Li, J., Siegel, M., Yuan, M., et al. (2011). Estrogen enhances neurogenesis and behavioral recovery after stroke. Journal of Cerebral Blood Flow and Metabolism, 31(2), 413–425.

    PubMed  CAS  Google Scholar 

  138. Jin, K., Xie, L., Mao, X., et al. (2011). Effect of human neural precursor cell transplantation on endogenous neurogenesis after focal cerebral ischemia in the rat. Brain Research, 1374, 56–62.

    PubMed  CAS  Google Scholar 

  139. Jin, K., Wang, X., Xie, L., et al. (2006). Evidence for stroke-induced neurogenesis in the human brain. Proceedings of the National Academy of Sciences of the United States of America, 103(35), 13198–13202.

    PubMed  CAS  Google Scholar 

  140. Arvidsson, A., Collin, T., Kirik, D., Kokaia, Z., & Lindvall, O. (2002). Neuronal replacement from endogenous precursors in the adult brain after stroke. Nature Medicine, 8(9), 963–970.

    PubMed  CAS  Google Scholar 

  141. Ohab, J. J., Fleming, S., Blesch, A., & Carmichael, S. T. (2006). A neurovascular niche for neurogenesis after stroke. Journal of Neuroscience, 26(50), 13007–13016.

    PubMed  CAS  Google Scholar 

  142. Schneider, A., Krüger, C., Steigleder, T., et al. (2005). The hematopoietic factor G-CSF is a neuronal ligand that counteracts programmed cell death and drives neurogenesis. Journal of Clinical Investigation, 115(8), 2083–2098.

    PubMed  CAS  Google Scholar 

  143. Gibson, C. L., Jones, N. C., Prior, M. J., Bath, P. M., & Murphy, S. P. (2005). G-CSF suppresses edema formation and reduces interleukin-1 beta expression after cerebral ischemia in mice. Journal of Neuropathology and Experimental Neurology, 64(9), 763–769.

    PubMed  CAS  Google Scholar 

  144. Kelly, S., Bliss, T. M., Shah, A. K., et al. (2004). Transplanted human fetal neural stem cells survive, migrate, and differentiate in ischemic rat cerebral cortex. Proceedings of the National Academy of Sciences of the United States of America, 101(32), 11839–11844.

    PubMed  CAS  Google Scholar 

  145. Darsalia, V., Kallur, T., & Kokaia, Z. (2007). Survival, migration and neuronal differentiation of human fetal striatal and cortical neural stem cells grafted in stroke-damaged rat striatum. European Journal of Neuroscience, 26(3), 605–614.

    PubMed  Google Scholar 

  146. Kondziolka, D., & Wechsler, L. (2008). Stroke repair with cell transplantation: neuronal cells, neuroprogenitor cells, and stem cells. Neurosurgical Focus, 24(3–4), E13.

    PubMed  Google Scholar 

  147. Kondziolka, D., Steinberg, G. K., Wechsler, L., et al. (2005). Neurotransplantation for patients with subcortical motor stroke: a phase 2 randomized trial. Journal of Neurosurgery, 103(1), 38–45.

    PubMed  Google Scholar 

  148. Lin, Y. C., Ko, T. L., Shih, Y. H., et al. (2011). Human umbilical mesenchymal stem cells promote recovery after ischemic stroke. Stroke, 42(7), 2045–2053.

    PubMed  Google Scholar 

  149. Lim, J. Y., Jeong, C. H., Jun, J. A., et al. (2011). Therapeutic effects of human umbilical cord blood-derived mesenchymal stem cells after intrathecal administration by lumbar puncture in a rat model of cerebral ischemia. Stem Cell Research and Therapy, 2(5), 38.

    PubMed  CAS  Google Scholar 

  150. Chen, X., Li, Y., Wang, L., et al. (2002). Ischemic rat brain extracts induce human marrow stromal cell growth factor production. Neuropathology, 22(4), 275–279.

    PubMed  Google Scholar 

  151. Toyama, K., Honmou, O., Harada, K., et al. (2009). Therapeutic benefits of angiogenetic gene-modified human mesenchymal stem cells after cerebral ischemia. Experimental Neurology, 216(1), 47–55.

    PubMed  CAS  Google Scholar 

  152. Chen, J., Li, Y., Katakowski, M., et al. (2003). Intravenous bone marrow stromal cell therapy reduces apoptosis and promotes endogenous cell proliferation after stroke in female rat. Journal of Neuroscience Research, 73(6), 778–786.

    PubMed  CAS  Google Scholar 

  153. Honmou, O., Onodera, R., Sasaki, M., et al. (2012). Mesenchymal stem cells: therapeutic outlook for stroke. Trends in Molecular Medicine, 18(5), 292–297.

    PubMed  CAS  Google Scholar 

  154. Shyu, W. C., Lin, S. Z., Chiang, M. F., Su, C. Y., & Li, H. (2006). Intracerebral peripheral blood stem cell (CD34+) implantation induces neuroplasticity by enhancing beta1 integrin-mediated angiogenesis in chronic stroke rats. Journal of Neuroscience, 26(13), 3444–3453.

    PubMed  CAS  Google Scholar 

  155. Banerjee, S., Williamson, D., Habib, N., Gordon, M., & Chataway, J. (2011). Human stem cell therapy in ischaemic stroke: a review. Age and Ageing, 40, 7–13.

    PubMed  Google Scholar 

  156. Guzman, R., Raymond Choi, M. D., Atul Gera, B. S., De Los Angeles, A., Andres, R. H., & Steinberg, G. K. (2008). Intravascular cell replacement therapy for stroke. Neurosurgical Focus, 24, 1–10.

    Google Scholar 

  157. Dirnagl, U., Iadecola, C., & Moskowitz, M. A. (1999). Pathobiology of ischaemic stroke: an integrated view. Trends in Neurosciences, 22(9), 391–397.

    PubMed  CAS  Google Scholar 

  158. Darsalia, V., Allison, S. J., Cusulin, C., et al. (2011). Cell number and timing of transplantation determine survival of human neural stem cell grafts in stroke-damaged rat brain. Journal of Cerebral Blood Flow and Metabolism, 31(1), 235–242.

    PubMed  Google Scholar 

  159. Andres, R. H., Choi, R., Pendharkar, A. V., et al. (2011). The CCR2/CCL2 interaction mediates the transendothelial recruitment of intravascularly delivered neural stem cells to the ischemic brain. Stroke, 42(10), 2923–2931.

    PubMed  Google Scholar 

  160. Andres, R. H., Choi, R., Steinberg, G. K., & Guzman, R. (2008). Potential of adult neural stem cells in stroke therapy. Regenerative Medicine, 3(6), 893–905.

    PubMed  Google Scholar 

  161. Pluchino, S., Zanotti, L., Rossi, B., et al. (2005). Neurosphere-derived multipotent precursors promote neuroprotection by an immunomodulatory mechanism. Nature, 436(7048), 266–271.

    PubMed  CAS  Google Scholar 

  162. Bliss, T., Guzman, R., Daadi, M., & Steinberg, G. K. (2007). Cell transplantation therapy for stroke. Stroke, 38(2 Suppl), 817–826.

    PubMed  Google Scholar 

  163. Chen, J., Zhang, Z. G., Li, Y., et al. (2003). Intravenous administration of human bone marrow cells induces angiogenesis in the ischemic boundary zone after stroke in rats. Circulation Research, 92(6), 692–699.

    PubMed  CAS  Google Scholar 

  164. Guzman, R., De Los Angeles, A., Cheshier, S., et al. (2008). Intracarotid injection of fluorescence activated cell-sorted CD49d-positive neural stem cells improves targeted cell delivery and behavior after stroke in a mouse stroke model. Stroke, 39(4), 1300–1306.

    PubMed  Google Scholar 

  165. Shen, L. H., Li, Y., Chen, J., et al. (2007). One-year follow-up after bone marrow stromal cell treatment in middle-aged female rats with stroke. Stroke, 38(7), 2150–2156.

    PubMed  Google Scholar 

  166. Jin, K., Sun, Y., Xie, L., et al. (2005). Comparison of ischemia-directed migration of neural precursor cells after intrastriatal, intraventricular, or intravenous transplantation in the rat. Neurobiology of Disease, 18(2), 366–374.

    PubMed  CAS  Google Scholar 

  167. Shen, L. H., Li, Y., Chen, J., et al. (2006). Intracarotid transplantation of bone marrow stromal cells increases axon-myelin remodeling after stroke. Neuroscience, 137, 393–399.

    PubMed  CAS  Google Scholar 

  168. Li, L., Jian, Q., Ding, G., et al. (2010). Effects of administration route on migration and distribution of neural progenitor cells transplanted into rats with focal cerebral ischemia, an MRI study. Journal of Cerebral Blood Flow and Metabolism, 30(3), 653–662.

    PubMed  Google Scholar 

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Acknowledgments

The authors wish to thank members of their laboratory for their research work and fruitful discussions. Research at the authors’ laboratory was funded by the MICINN-ISCIII (PI-10/00291 and MPY1412/09) and Comunidad de Madrid (NEUROSTEMCM consortium; S2010/BMD-2336). PMM was supported by a Posdoctoral Fellowship from the Consejo Nacional de Ciencia y Tecnología (CONACYT), Mexico. DM is supported by the program INOV CONTACTO, AICEP, Portugal.

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The authors confirm that there are no conflicts of interest.

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  1. Unidad de Regeneración Neural, Unidad Funcional de Investigación de Enfermedades Crónicas, Instituto de Salud Carlos III (ISCIII), 28220, Majadahonda, Madrid, Spain

    P. L. Martínez-Morales, A. Revilla, I. Ocaña, C. González, P. Sainz, D. McGuire & I. Liste

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  1. P. L. Martínez-Morales
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  2. A. Revilla
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  7. I. Liste
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Correspondence to I. Liste.

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P. L. Martínez-Morales and A. Revilla contributed equally to this work

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Martínez-Morales, P.L., Revilla, A., Ocaña, I. et al. Progress in Stem Cell Therapy for Major Human Neurological Disorders. Stem Cell Rev and Rep 9, 685–699 (2013). https://doi.org/10.1007/s12015-013-9443-6

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