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Neural stem cell therapy for neurological diseases: dreams and reality

Abstract

There is a pressing need for treatments for neurodegenerative diseases. Hopes have been raised by the prospect of neural stem cell therapy; however, despite intense research activities and media attention, stem cell therapy for neurological disorders is still a distant goal. Effective strategies must be developed to isolate, enrich and propagate homogeneous populations of neural stem cells, and to identify the molecules and mechanisms that are required for their proper integration into the injured brain. This article examines these requirements, discusses the results obtained so far, and considers the steps that need to be taken to provide instruction to donor cells and to elucidate the neurogenic potential of the adult central nervous system environment.

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Figure 1: Extent of anatomical repair required to achieve significant functional recovery in different pathological conditions.
Figure 2: Instructing stem cells for transplantation.
Figure 3: Host neurogenic cues direct neuronal differentiation of multipotent donor cells.
Figure 4: The interplay between neurogenic and gliogenic signals influences the fate of transplanted cells in the injured central nervous system.

References

  1. Björklund, A. & Lindvall, O. Cell replacement therapies for central nervous system disorders. Nature Neurosci. 3, 537–544 (2000).

    PubMed  Google Scholar 

  2. Bachoud-Levi, A. C. et al. Motor and cognitive improvements in patients with Huntington's disease after neural transplantation. Lancet 356, 1945–1946 (2000).

    Google Scholar 

  3. Freeman, T. B. et al. Transplanted fetal striatum in Huntington disease: phenotypic development and lack of pathology. Proc Natl Acad Sci U S A 97, 13877–13882 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Temple, S. Stem cell plasticity — building the brain of our dreams. Nature Rev. Neurosci. 2, 513–520 (2000).

    Google Scholar 

  5. Blakemore, W. F., Smith, P. M. & Franklin, R. J. Remyelinating the demyelinated CNS. Novartis Found. Symp. 231, 289–298 (2000).

    CAS  PubMed  Google Scholar 

  6. Brüstle, O. et al. Embryonic stem cell-derived glial precursors: a source of myelinating transplants. Science 285, 754–756 (1999).

    PubMed  Google Scholar 

  7. Liu, S. et al. Embryonic stem cells differentiate into oligodendrocytes and myelinate in culture and after spinal cord transplantation. Proc. Natl Acad. Sci. USA 97, 6126–6131 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Kohama, I. et al. Transplantation of cryopreserved adult human Schwann cells enhances axonal conduction in demyelinated spinal cord. J. Neurosci. 21, 944–950 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Jeffery, N. D., Crang, A. J., O' Leary, M. T., Hodge, S. J. & Blakemore, W. F. Behavioural consequences of oligodendrocyte progenitor cell transplantation into experimental demyelinating lesions in the rat spinal cord. Eur. J. Neurosci. 11, 1508–1514 (1999).

    CAS  PubMed  Google Scholar 

  11. Piccini, P. et al. Dopamine release from nigral transplants visualised in vivo in a Parkinson patient. Nature Neurosci. 2, 1137–1140 (1999).

    CAS  PubMed  Google Scholar 

  12. Sotelo, C. & Alvarado-Mallart, R. M. The reconstruction of cerebellar circuits. Trends Neurosci. 14, 350–355 (1991).

    CAS  PubMed  Google Scholar 

  13. Zhang, W., Lee, W. H. & Triarhou, L. C. Grafted cerebellar cells in a mouse model of hereditary ataxia express IGF-I system genes and partially restore behavioral function. Nature Med. 2, 65–71 (1996).

    CAS  PubMed  Google Scholar 

  14. Huntington's Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell 72, 971–983 (1993).

  15. Kendall, A. L. et al. Functional integration of striatal allografts in a primate model of Huntington's disease. Nature Med. 4, 727–729 (1998).

    CAS  PubMed  Google Scholar 

  16. Palfi, S. P. et al. Fetal striatal allografts reverse cognitive deficits in a primate model of Huntington disease. Nature Med. 4, 963–966 (1998).

    CAS  PubMed  Google Scholar 

  17. Strata, P. & Rossi, F. Plasticity of the olivocerebellar pathway. Trends Neurosci. 21, 407–413 (1998).

    CAS  PubMed  Google Scholar 

  18. Rossi, F., Saggiorato, C. & Strata, P. Target-specific innervation of cerebellar transplants by regenerating olivocerebellar axons in the adult rat. Exp. Neurol. 173, 205–212 (2002).

    PubMed  Google Scholar 

  19. Grabowski, M., Brundin, P. & Johansson, B. B. Fetal neocortical grafts implanted in adult hypertensive rats with cortical infarcts following a middle cerebral artery occlusion: ingrowth of afferent fibers from the host brain. Exp. Neurol. 116, 106–121 (1992).

    Google Scholar 

  20. Grabowski, M., Johansson, B. B. & Brundin, P. Neocortical grafts placed in the infarcted brain of adult rats: few or no efferent fibers grow from transplant to host. Exp. Neurol. 134, 273–276 (1995).

    CAS  PubMed  Google Scholar 

  21. Mattson, B., Sorensen, J. C., Zimmer, J. & Johansson, B. B. Neural grafting to experimental neocortical infarcts improves behavioural outcome and reduces thalamic atrophy in rats housed in enriched but not in standard environments. Stroke 28, 1225–1231 (1997).

    Google Scholar 

  22. Piccini, P. et al. Delayed recovery of movement-related cortical function in Parkinson's disease after striatal dopaminergic grafts. Ann. Neurol. 48, 689–695 (2000).

    CAS  PubMed  Google Scholar 

  23. Döbrössy, M. D. & Dunnett, S. B. The influence of environment and experience on neural grafts. Nature Rev. Neurosci. 2, 871–879 (2001).

    Google Scholar 

  24. Brundin, P. et al. Improving the survival of grafted dopaminergic neurons: a review over current approaches. Cell Transplant. 9, 179–195 (2000).

    CAS  PubMed  Google Scholar 

  25. Schierle, G. S. et al. Caspase inhibition reduces apoptosis and increases survival of nigral transplants. Nature Med. 5, 97–100 (1999).

    CAS  PubMed  Google Scholar 

  26. Morrison, S. J., White, P. M., Zock, C. & Anderson, D. J. Prospective identification, isolation by flow cytometry, and in vivo self-renewal of multipotent mammalian neural crest stem cells. Cell 96, 737–749 (1999).

    CAS  PubMed  Google Scholar 

  27. Rietze, R. L. et al. Purification of a pluripotent neural stem cell from the adult mouse brain. Nature 412, 736–739 (2001).

    CAS  PubMed  Google Scholar 

  28. Keyoung, H. L. et al. High-yield selection and extraction of two promoter-defined phenotypes of neural stem cells from the fetal human brain. Nature Biotechnol. 19, 843–850 (2001).

    CAS  Google Scholar 

  29. Morrison, S. J. Neuronal potential and lineage determination by neural stem cells. Curr. Opin. Cell Biol. 13, 666–672 (2001).

    CAS  PubMed  Google Scholar 

  30. Temple, S. The development of neural stem cells. Nature 414, 112–117 (2002).

    Google Scholar 

  31. Zappone, M. V. et al. Sox2 regulatory sequences direct expression of a β-geo transgene to telencephalic neural stem cells and precursors of the mouse embryo, revealing regionalization of gene expression in CNS stem cells. Development 127, 2367–2382 (2000).

    CAS  PubMed  Google Scholar 

  32. Hitoshi, S., Tropepe, V., Ekker, M. & Van der Kooy, D. Neural stem cell lineages are regionally specified, but not committed, within distinct compartments of the developing brain. Development 129, 233–244 (2002).

    CAS  PubMed  Google Scholar 

  33. Winkler, C. et al. Incorporation and glial differentiation of mouse EGF-responsive neural progenitor cells after transplantation into the embryonic rat brain. Mol. Cell. Neurosci. 11, 99–116 (1998).

    CAS  PubMed  Google Scholar 

  34. Svendsen, C. N. et al. Long-term survival of human central nervous system progenitor cells transplanted into a rat model of Parkinson's disease. Exp. Neurol. 148, 135–146 (1997).

    CAS  PubMed  Google Scholar 

  35. Cao, Q. et al. Pluripotent stem cells engrafted in the normal or lesioned adult rat spinal cord are restricted to a glial cell lineage. Exp. Neurol. 167, 48–58 (2001).

    CAS  PubMed  Google Scholar 

  36. Chow, S. I. et al. Characterization and intraspinal grafting of EGF/bFGF-dependent neurospheres derived from embryonic rat spinal cord. Brain Res. 874, 87–106 (2000).

    CAS  PubMed  Google Scholar 

  37. Morshead, C. M., Benveniste, P., Iscove, N. N. & Van der Kooy, D. Hematopoietic competence is a rare property of neural stem cells and may depend on genetic and epigenetic alterations. Nature Med. 8, 268–273 (2002).

    CAS  PubMed  Google Scholar 

  38. Studer, L. et al. Enhanced proliferation, survival, and dopaminergic differentiation of CNS precursors in lowered oxygen. J. Neurosci. 20, 7377–7383 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Zetterström, R. H. et al. Dopamine neuron agenesis in Nurr-1-deficient mice. Science 276, 248–250 (1997).

    PubMed  Google Scholar 

  40. Wagner, J. et al. Induction of a midbrain dopaminergic phenotype in Nurr1-overexpressing neural stem cells by type 1 astrocytes. Nature Biotechnol. 17, 653–659 (1999).

    CAS  Google Scholar 

  41. Sakurada, K., Oshimo-Sakurada, M., Palmer, T. D. & Gage, F. H. Nurr1, an orphan nuclear receptor, is a transcriptional activator of endogenous tyrosine hydroxylase in neural progenitor cells derived from the adult brain. Development 126, 4017–4026 (1999).

    CAS  PubMed  Google Scholar 

  42. Bonni, A. et al. Regulation of gliogenesis in the central nervous system by the JAK-STAT signaling pathway. Science 278, 477–483 (1997).

    CAS  PubMed  Google Scholar 

  43. Conti, L. et al. Expression and activation of SH2/PTB-containing ShcA adapter protein reflects the pattern of neurogenesis in the mammalian brain. Proc. Natl Acad. Sci. USA 94, 8185–8190 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Cattaneo, E. & Pelicci, P. G. Emerging roles for SH2/PTB-containing Shc adapter proteins in the developing mammalian brain. Trends Neurosci. 21, 476–481 (1998).

    CAS  PubMed  Google Scholar 

  45. Conti, L. et al. Shc signaling in differentiating neural progenitor cells. Nature Neurosci. 4, 579–586 (2001).

    CAS  PubMed  Google Scholar 

  46. Sun, Y. et al. Neurogenin promotes neurogenesis and inhibits glial differentiation by independent mechanisms. Cell 104, 365–376 (2001).

    CAS  PubMed  Google Scholar 

  47. Bjornson, C. R. R., Rietze, R. L., Reynolds, B. A., Magli, L. C. & Vescovi, A. L. Turning brain into blood: a hematopoietic fate adopted by adult neural stem cells in vivo. Science 283, 534–537 (1999).

    CAS  PubMed  Google Scholar 

  48. Brazelton, T. R., Rossi, F. M. V., Keshet, G. I. & Blau, H. M. From marrow to brain: expression of neuronal phenotypes in adult mice. Science 290, 1775–1779 (2000).

    CAS  PubMed  Google Scholar 

  49. Mezey, E., Chandross, K. J., Harta, G., Maki, R. A. & McKercher, S. R. Turning blood into brain: cells bearing neuronal antigens generated in vivo from bone marrow. Science 290, 1779–1782 (2000).

    CAS  PubMed  Google Scholar 

  50. Clarke, D. L. et al. Generalized potential of adult neural stem cells. Science 288, 1660–1663 (2000).

    CAS  PubMed  Google Scholar 

  51. Ying, Q.-L., Nichols, J., Ewans, E. P. & Smith, A. G. Changing potency by spontaneous fusion. Nature 416, 545–548 (2002).

    CAS  PubMed  Google Scholar 

  52. Terada, N. et al. Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion. Nature 416, 542–545 (2002).

    CAS  PubMed  Google Scholar 

  53. McKinney-Freeman, S. L. et al. Muscle-derived hematopoietic stem cells are hematopoietic in origin. Proc. Natl Acad. Sci. USA 99, 1341–1346 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Toma, J. G. et al. Isolation of multipotent adult stem cells from the dermis of mammalian skin. Nature Cell Biol. 3, 778–784 (2001).

    CAS  PubMed  Google Scholar 

  55. Brüstle, O., Maskos, U. & McKay, R. D. G. Host-guided migration allows targeted introduction of neurons into the embryonic brain. Neuron 15, 1275–1285 (1995).

    PubMed  Google Scholar 

  56. Campbell, K., Olsson, M. & Björklund, A. Regional incorporation and site-specific differentiation of striatal precursors transplanted to the embryonic forebrain ventricle. Neuron 15, 1259–1273 (1995).

    CAS  PubMed  Google Scholar 

  57. Lim, D. A., Fishell, G. A. & Alvarez-Buylla, A. Postnatal mouse subventricular zone neuronal precursors can migrate and differentiate within multiple levels of the developing neuraxis. Proc. Natl Acad. Sci. USA 94, 14832–14836 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Magrassi, L. et al. Basal ganglia precursors found in aggregates following embryonic transplantation adopt a striatal phenotype in heterotopic locations. Development 125, 2847–2855 (1998).

    CAS  PubMed  Google Scholar 

  59. Gage, F. H. Mammalian neural stem cells. Science 287, 1433–1438 (2000).

    CAS  PubMed  Google Scholar 

  60. Gould, E., Reeves, A. J., Graziano, M. S. A. & Gross, C. G. Neurogenesis in the neocortex of adult primates. Science 286, 548–552 (1999).

    CAS  PubMed  Google Scholar 

  61. Kornack, D. R. & Rakic, P. Cell proliferation without neurogenesis in the adult primate neocortex. Science 294, 2127–2130 (2001).

    CAS  PubMed  Google Scholar 

  62. Suhonen, J. O., Peterson, D. A., Ray, J. & Gage, F. H. Differentiation of adult hippocampus-derived progenitors into olfactory neurons in vivo. Nature 383, 624–627 (1996).

    CAS  PubMed  Google Scholar 

  63. Shihabuddin, L. S., Horner, P. J., Ray, J. & Gage, F. H. Adult spinal cord stem cells generate neurons after transplantation in the adult dentate gyrus. J. Neurosci. 20, 8727–8735 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Herrera, D. G., Garcia-Verdugo, J. M. & Alvarez-Buylla, A. Adult-derived neural precursors transplanted into multiple regions in the adult brain. Ann. Neurol. 46, 867–877 (1999).

    CAS  PubMed  Google Scholar 

  65. Lim, D. A. et al. Noggin antagonizes BMP signaling to create a niche for adult neurogenesis. Neuron 28, 713–726 (2000).

    CAS  PubMed  Google Scholar 

  66. Renfranz, P. J., Cunningham, M. G. & McKay, R. D. G. Region-specific differentiation of the hippocampal cell line HiB5 upon implantation into the developing mammalian brain. Cell 66, 713–729 (1991).

    CAS  PubMed  Google Scholar 

  67. Snyder, E. Y. et al. Multipotent neural cell lines can engraft and participate in development of mouse cerebellum. Cell 68, 33–51 (1992).

    CAS  PubMed  Google Scholar 

  68. Gao, W.-Q. & Hatten, M. E. Immortalizing oncogenes subvert the establishment of granule cell identity in developing cerebellum. Development 120, 1059–1070 (1994).

    CAS  PubMed  Google Scholar 

  69. Shihabuddin, L. S., Hertz, J. A., Holets, V. R. & Whittemore, S. R. The adult CNS retains the potential to direct region-specific differentiation of a transplanted neuronal precursor cell line. J. Neurosci. 15, 6666–6678 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Lundberg, C., Englund, U., Trono, D., Björklund, A. & Wictorin, K. Differentiation of RN33B cell line into forebrain projection neurons after transplantation into the neonatal rat brain. Exp. Neurol. (in the press).

  71. Catapano, L. A., Sheen, V. L., Leavitt, B. R. & Macklis, J. D. Differentiation of transplanted neural precursors varies regionally in adults striatum. Neuroreport 10, 3971–3977 (1999).

    CAS  PubMed  Google Scholar 

  72. McEwen, B. S. Stress and hippocampal plasticity. Annu. Rev. Neurosci. 22, 105–122 (1999).

    CAS  PubMed  Google Scholar 

  73. Gould, E., Tanapat, P., Rydel, T. & Hastings, N. Regulation of hippocampal neurogenesis in adulthood. Biol. Psychiatry 48, 715–720 (2000).

    CAS  PubMed  Google Scholar 

  74. Doetsch, F., Caillé, I., Lim, D. A., Garcia-Verdugo, L. M. & Alvarez-Buylla, A. Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell 97, 703–716 (1999).

    CAS  PubMed  Google Scholar 

  75. Jin, K. et al. Neurogenesis in dentate subgranular zone and rostral subventricular zone after focal cerebral ischemia in the rat. Proc. Natl Acad. Sci. USA 98, 4710–4715 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Jankovski, A., Garcia, C., Soriano, E. & Sotelo, C. Proliferation, migration and differentiation of neuronal progenitor cells in the adult mouse subventricular zone surgically separated from its olfactory bulb. Eur. J. Neurosci. 10, 3853–3868 (1998).

    CAS  PubMed  Google Scholar 

  77. Gould, E. & Tanapat, P. Lesion-induced proliferation of neuronal progenitors in the dentate gyrus of the adult rat. Neuroscience 80, 427–436 (1997).

    CAS  PubMed  Google Scholar 

  78. Bengzon, J. et al. Apoptosis and proliferation of dentate gyrus neurons after single and intermittent limbic seizures. Proc. Natl Acad. Sci. USA 94, 10432–10437 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Parent, J. M. et al. Dentate granule cell neurogenesis is increased by seizures and contributes to aberrant network reorganization in the adult rat hippocampus. J. Neurosci. 17, 3727–3738 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Blumcke, I. et al. Increase of nestin-immunoreactive neural precursor cells in the dentate gyrus of pediatric patients with early-onset temporal lobe epilepsy. Hippocampus 11, 311–321 (2001).

    CAS  PubMed  Google Scholar 

  81. Yoshimura, S. et al. FGF-2 regulation of neurogenesis in adult hippocampus after brain injury. Proc. Natl Acad. Sci. USA 98, 5874–5879 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Palmer, T. D., Markakis, E. A., Willhoite, A. R., Safar, F. & Gage, F. H. Fibroblast growth factor-2 activates a latent neurogenic program in neural stem cells from diverse regions of the adult CNS. J. Neurosci. 19, 8487–8497 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Marti, H. H. et al. Erythropoietin gene expression in human, monkey and murine brain. Eur. J. Neurosci. 8, 666–676 (1996).

    CAS  PubMed  Google Scholar 

  84. Shingo, T., Sorokan, S. T., Shimazaki, T. & Weiss, S. Erythropoietin regulates the in vitro and in vivo production of neuronal progenitors by mammalian forebrain neural stem cells. J. Neurosci. 21, 9733–9743 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Magavi, S. S., Leavitt, B. R. & Macklis, J. D. Induction of neurogenesis in the neocortex of adult mice. Nature 405, 951–955 (2000).

    CAS  PubMed  Google Scholar 

  86. Macklis, J. D. Transplanted neocortical neurons migrate selectively in regions of neuronal degeneration produced by chromophore-targeted laser photolysis. J. Neurosci. 13, 3848–3863 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Snyder, E. Y., Yoon, C., Flax, J. D. & Macklis, J. D. Mulitpotent neural precursors can differentiate toward replacement of neurons undergoing targeted apoptotic degeneration in adult mouse neocortex. Proc. Natl Acad. Sci. USA 94, 11663–11668 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Priller, J. et al. Neogenesis of cerebellar Purkinje neurons from gene-marked bone marrow cells in vivo. J. Cell Biol. 155, 733–738 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Zigova, T. et al. Neuronal progenitor cells of the neonatal subventricular zone differentiate and disperse following transplantation into the adult rat striatum. Cell Transplant. 7, 137–156 (1998).

    CAS  PubMed  Google Scholar 

  90. Gage, F. H. et al. Survival and differentiation of adult neuronal progenitor cells transplanted to the adult brain. Proc. Natl Acad. Sci. USA 92, 11879–11883 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Shihabuddin, L. S., Holets, V. R. & Whittemore, S. R. Selective hippocampal lesions differentially affect the phenotypic fate of transplanted neuronal precursors. Exp. Neurol. 139, 61–72 (1996).

    CAS  PubMed  Google Scholar 

  92. Lundberg, C., Winkler, C., Whittemore, S. R. & Björklund, A. Conditionally immortalised neural progenitor cells grafted to the striatum exhibit site-specific neuronal differentiation and establish connections with the host globus pallidus. Neurobiol. Dis. 3, 33–50 (1996).

    CAS  PubMed  Google Scholar 

  93. Lundberg, C., Martinez-Serrano, A., Cattaneo, E., McKay, R. D. G. & Björklund, A. Survival, integration, and differentiation of neural stem cell lines after transplantation to the adult rat striatum. Exp. Neurol. 145, 342–360 (1997).

    CAS  PubMed  Google Scholar 

  94. Björklund, L. M. et al. Embryonic stem cells develop into functional dopaminergic neurons after transplantation in a Parkinson rat model. Proc. Natl Acad. Sci. USA 99, 2344–2349 (2002).

    PubMed  PubMed Central  Google Scholar 

  95. Vallières, L., Campbell, I. L., Gage, F. H. & Sawchenko, P. E. Reduced hippocampal neurogenesis in adult transgenic mice with chronic astrocytic production of interleukin-6. J. Neurosci. 22, 486–492 (2002).

    PubMed  PubMed Central  Google Scholar 

  96. Craig, C. G. et al. In vivo growth factor expansion of endogenous subependymal neural precursor cell populations in the adult mouse brain. J. Neurosci. 16, 2649–2658 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Kuhn, G. H., Winkler, J., Kempermann, G., Thal, L. J. & Gage, F. H. Epidermal growth factor and fibroblast growth factor-2 have different effects on neural progenitors in the adult rat brain. J. Neurosci. 17, 5820–5829 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Benraiss, A., Chmielnicki, E., Lerner, K., Roh, D. & Goldman, S. A. Adenoviral brain-derived neurotrophic factor induces both neostriatal and olfactory neuronal recruitment from endogenous progenitor cells in the adult forebrain. J. Neurosci. 21, 6718–6731 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Zigova, T., Pencea, V., Wiegand, S. J. & Luskin, M. B. Intraventricular administration of BDNF increases the number of newly generated neurons in the adult olfactory bulb. Mol. Cell. Neurosci. 11, 234–245 (1998).

    CAS  PubMed  Google Scholar 

  100. Pencea, V., Bingaman, K. D., Wiegand, S. J. & Luskin, M. B. Infusion of brain-derived neurotrophic factor into the lateral ventricle of the adult rat leads to new neurons in the parenchyma of the striatum, septum, thalamus, and hypothalamus. J. Neurosci. 21, 6706–6717 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Fallon, J. et al. In vivo induction of massive proliferation, directed migration, and differentiation of neural cells in the adult mammalian brain. Proc. Natl Acad. Sci. USA 97, 14686–14691 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. McLaren, A. Ethical and social considerations of stem cell research. Nature 414, 129–131 (2001).

    CAS  PubMed  Google Scholar 

  103. Adam, D. Britain banks on embryonic stem cells to gain competitive edge. Nature 416, 3–4 (2002).

    CAS  PubMed  Google Scholar 

  104. Terskikh, A. V. et al. From hematopoiesis to neuropoiesis: evidence of overlapping genetic programs. Proc. Natl Acad. Sci. USA 98, 7934–7939 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Kornblum, H. I. & Geschwind, D. H. Molecular targets in CNS stem cell research: hitting a moving target. Nature Rev. Neurosci. 2, 843–846 (2001).

    CAS  Google Scholar 

  106. Thomson, J. A. et al. Embryonic stem cell lines derived from human blastocysts. Science 282, 1145–1147 (1998).

    CAS  PubMed  Google Scholar 

  107. Smith, A. G. Embryo-derived stem cells: of mice and men. Annu. Rev. Cell Dev. Biol. 17, 435–462 (2001).

    CAS  PubMed  Google Scholar 

  108. Eiges, R. et al. Establishment of human embryonic stem cell-transfected clones carrying a marker for undifferentiated cells. Curr. Biol. 11, 514–518 (2001).

    CAS  PubMed  Google Scholar 

  109. Reubinoff, B. E. et al. Neural progenitors from human embryonic stem cells. Nature Biotechnol. 19, 1134–1140 (2001).

    CAS  Google Scholar 

  110. Zhang, S. C., Wernig, M., Duncan, I. D., Brustle, O. & Thomson, J. A. In vitro differentiation of transplantable neural precursors from human embryonic stem cells. Nature Biotechnol. 19, 1129–1133 (2001).

    CAS  Google Scholar 

  111. Vogel, G. Stem cells. In the Mideast, pushing back the stem cell frontier. Science 295, 1818–1820 (2002).

    CAS  PubMed  Google Scholar 

  112. Zuccato, C. et al. Loss of Huntingtin–mediated BDNF gene transcription in Huntington's disease. Science 293, 493–498 (2001).

    CAS  PubMed  Google Scholar 

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Acknowledgements

Our work is supported by grants from the Ministero dell'Istruzione, dell'Università e della Ricerca, the Ministero della Sanità-Progetto Alzheimer, Telethon, the Associazione Italiana Ricerca sul Cancro, the Huntington's Disease Society of America and the Hereditary Disease Foundation. We thank L. Conti, R. McKay, M. Peschanski and P. Strata for helpful comments. We apologize for the omission of several beautiful papers that could not be cited owing to space limitations.

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DATABASES

LocusLink

BMP

EGF

erythropoietin

Fgf2

Fgf8

GFAP

huntingtin

interleukin 6

musashi 1

nestin

neurogenin

noggin

Nurr1

ShcA

ShcC

sonic hedgehog

STAT3

TGF-α

OMIM

amyotrophic lateral sclerosis

Huntington's disease

Parkinson's disease

FURTHER INFORMATION

Encyclopedia of Life Sciences

amyotrophic lateral sclerosis

Huntington disease

Parkinson disease

trophic support

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Rossi, F., Cattaneo, E. Neural stem cell therapy for neurological diseases: dreams and reality. Nat Rev Neurosci 3, 401–409 (2002). https://doi.org/10.1038/nrn809

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