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Gene therapy: can neural stem cells deliver?

Abstract

Neural stem cells are a self-renewing population that generates the neurons and glia of the developing brain. They can be isolated, proliferated, genetically manipulated and differentiated in vitro and reintroduced into a developing, adult or pathologically altered CNS. Neural stem cells have been considered for use in cell replacement therapies in various neurodegenerative diseases, and an unexpected and potentially valuable characteristic of these cells has recently been revealed — they are highly migratory and seem to be attracted to areas of brain pathology such as ischaemic and neoplastic lesions. Here, we speculate on the ways in which neural stem cells might be exploited as delivery vehicles for gene therapy in the CNS.

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Figure 1: Neural stem cell homing in brain tumours.
Figure 2: Determinants of neural stem cell homing to brain tumours for delivery of gene therapy.
Figure 3: Determinants of neural stem cell pathotropism.
Figure 4: Model of activated astrocyte mediation of neural stem cell homing to brain pathology.

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Zixuan Zhao, Xinyi Chen, … Hanry Yu

References

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

    CAS  PubMed  Google Scholar 

  2. Pevny, L. & Rao, M. S. The stem-cell menagerie. Trends Neurosci. 26, 351–359 (2003).

    CAS  PubMed  Google Scholar 

  3. Soares, S. & Sotelo, C. Adult neural stem cells from the mouse subventricular zone are limited in migratory ability compared to progenitor cells of similar origin. Neuroscience 128, 807–817 (2004).

    CAS  PubMed  Google Scholar 

  4. Doetsch, F., Petreanu, L., Caille, I., Garcia-Verdugo, J. M. & Alvarez-Buylla, A. EGF converts transit-amplifying neurogenic precursors in the adult brain into multipotent stem cells. Neuron 36, 1021–1034 (2002).

    CAS  PubMed  Google Scholar 

  5. Maslov, A. Y., Barone, T. A., Plunkett, R. J. & Pruitt, S. C. Neural stem cell detection, characterization, and age-related changes in the subventricular zone of mice. J. Neurosci. 24, 1726–1733 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Mi, R. et al. Immortalized neural stem cells differ from nonimmortalized cortical neurospheres and cerebellar granule cell progenitors. Exp. Neurol. 194, 301–319 (2005).

    CAS  PubMed  Google Scholar 

  7. Lie, D. C., Song, H., Colamarino, S. A., Ming, G. L. & Gage, F. H. Neurogenesis in the adult brain: new strategies for central nervous system diseases. Annu. Rev. Pharmacol. Toxicol. 44, 399–421 (2004).

    CAS  PubMed  Google Scholar 

  8. Emsley, J. G., Mitchell, B. D., Kempermann, G. & Macklis, J. D. Adult neurogenesis and repair of the adult CNS with neural progenitors, precursors, and stem cells. Prog. Neurobiol. 75, 321–341 (2005).

    CAS  PubMed  Google Scholar 

  9. Benedetti, S. et al. Gene therapy of experimental brain tumors using neural progenitor cells. Nature Med. 6, 447–450 (2000).

    CAS  PubMed  Google Scholar 

  10. Herrlinger, U. et al. Neural precursor cells for delivery of replication-conditional HSV-1 vectors to intracerebral gliomas. Mol. Ther. 1, 347–357 (2000).

    CAS  PubMed  Google Scholar 

  11. Aboody, K. S. et al. Neural stem cells display extensive tropism for pathology in adult brain: evidence from intracranial gliomas. Proc. Natl Acad. Sci. USA 97, 12846–12851 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Consiglio, A. et al. Robust in vivo gene transfer into adult mammalian neural stem cells by lentiviral vectors. Proc. Natl Acad. Sci. USA 101, 14835–14840 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Glass, R. et al. Glioblastoma-induced attraction of endogenous neural precursor cells is associated with improved survival. J. Neurosci. 25, 2637–2646 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Chi, L. et al. Motor neuron degeneration promotes neural progenitor cell proliferation, migration and neurogenesis in the spinal cords of ALS mice. Stem Cells Express 11 Aug 2005 (10.1634/stemcells.2005-0076).

  15. Brown, A. B. et al. Intravascular delivery of neural stem cell lines to target intracranial and extracranial tumors of neural and non-neural origin. Hum. Gene Ther. 14, 1777–1785 (2003).

    CAS  PubMed  Google Scholar 

  16. Li, S. et al. Bystander effect-mediated gene therapy of gliomas using genetically engineered neural stem cells. Cancer Gene Ther. 12, 600–607 (2005).

    CAS  PubMed  Google Scholar 

  17. Kelly, S. et al. Transplanted human fetal neural stem cells survive, migrate, and differentiate in ischemic rat cerebral cortex. Proc. Natl Acad. Sci. USA 101, 11839–11844 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Song, H., Stevens, C. F. & Gage, F. H. Astroglia induce neurogenesis from adult neural stem cells. Nature 417, 39–44 (2002).

    CAS  PubMed  Google Scholar 

  19. Palmer, T. D., Willhoite, A. R. & Gage, F. H. Vascular niche for adult hippocampal neurogenesis. J. Comp. Neurol. 425, 479–494 (2000).

    CAS  PubMed  Google Scholar 

  20. Shen, Q. et al. Endothelial cells stimulate self-renewal and expand neurogenesis of neural stem cells. Science 304, 1338–1340 (2004).

    CAS  PubMed  Google Scholar 

  21. Mercier, F., Kitasako, J. T. & Hatton, G. I. Anatomy of the brain neurogenic zones revisited: fractones and the fibroblast/macrophage network. J. Comp. Neurol. 451, 170–188 (2002).

    PubMed  Google Scholar 

  22. Aarum, J., Sandberg, K., Haeberlein, S. L. & Persson, M. A. Migration and differentiation of neural precursor cells can be directed by microglia. Proc. Natl Acad. Sci. USA 100, 15983–15988 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Schmidt, N. O. et al. Brain tumor tropism of transplanted human neural stem cells is induced by vascular endothelial growth factor. Neoplasia 7, 623–629 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Imitola, J. et al. Directed migration of neural stem cells to sites of CNS injury by the stromal cell-derived factor 1α/CXC chemokine receptor 4 pathway. Proc. Natl Acad. Sci. USA 101, 18117–18122 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Ehtesham, M. et al. Glioma tropic neural stem cells consist of astrocytic precursors and their migratory capacity is mediated by CXCR4. Neoplasia 6, 287–293 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Widera, D. et al. MCP-1 induces migration of adult neural stem cells. Eur. J. Cell Biol. 83, 381–387 (2004).

    CAS  PubMed  Google Scholar 

  27. Ben-Hur, T. et al. Effects of proinflammatory cytokines on the growth, fate, and motility of multipotential neural precursor cells. Mol. Cell. Neurosci. 24, 623–631 (2003).

    CAS  PubMed  Google Scholar 

  28. Block, M. L. & Hong, J. S. Microglia and inflammation-mediated neurodegeneration: multiple triggers with a common mechanism. Prog. Neurobiol. 76, 77–98 (2005).

    CAS  PubMed  Google Scholar 

  29. Aharoni, R., Arnon, R. & Eilam, R. Neurogenesis and neuroprotection induced by peripheral immunomodulatory treatment of experimental autoimmune encephalomyelitis. J. Neurosci. 25, 8217–8228 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Ekdahl, C. T., Claasen, J. H., Bonde, S., Kokaia, Z. & Lindvall, O. Inflammation is detrimental for neurogenesis in adult brain. Proc. Natl Acad. Sci. USA 100, 13632–13637 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Monje, M. L., Toda, H. & Palmer, T. D. Inflammatory blockade restores adult hippocampal neurogenesis. Science 302, 1760–1765 (2003).

    CAS  PubMed  Google Scholar 

  32. Nimmerjahn, A., Kirchhoff, F. & Helmchen, F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308, 1314–1318 (2005).

    CAS  PubMed  Google Scholar 

  33. Barouch, R. & Schwartz, M. Autoreactive T cells induce neurotrophin production by immune and neural cells in injured rat optic nerve: implications for protective autoimmunity. FASEB J. 16, 1304–1306 (2002).

    CAS  PubMed  Google Scholar 

  34. Wong, G., Goldshmit, Y. & Turnley, A. M. Interferon-γ but not TNF α promotes neuronal differentiation and neurite outgrowth of murine adult neural stem cells. Exp. Neurol. 187, 171–177 (2004).

    CAS  PubMed  Google Scholar 

  35. Fernaud-Espinosa, I., Nieto-Sampedro, M. & Bovolenta, P. Differential activation of microglia and astrocytes in aniso- and isomorphic gliotic tissue. Glia 8, 277–291 (1993).

    CAS  PubMed  Google Scholar 

  36. Wang, K. & Walz, W. Unusual topographical pattern of proximal astrogliosis around a cortical devascularizing lesion. J. Neurosci. Res. 73, 497–506 (2003).

    CAS  PubMed  Google Scholar 

  37. da Cunha, A. et al. Control of astrocytosis by interleukin-1 and transforming growth factor-β 1 in human brain. Brain Res. 631, 39–45 (1993).

    CAS  PubMed  Google Scholar 

  38. Spranger, M. et al. Regulation of nerve growth factor (NGF) synthesis in the rat central nervous system: comparison between the effects of interleukin-1 and various growth factors in astrocyte cultures and in vivo. Eur. J. Neurosci. 2, 69–76 (1990).

    PubMed  Google Scholar 

  39. Friedman, W. J. et al. Regulation of β-nerve growth factor expression by inflammatory mediators in hippocampal cultures. J. Neurosci. Res. 27, 374–382 (1990).

    CAS  PubMed  Google Scholar 

  40. Liberto, C. M., Albrecht, P. J., Herx, L. M., Yong, V. W. & Levison, S. W. Pro-regenerative properties of cytokine-activated astrocytes. J. Neurochem. 89, 1092–1100 (2004).

    CAS  PubMed  Google Scholar 

  41. Babcock, A. A., Kuziel, W. A., Rivest, S. & Owens, T. Chemokine expression by glial cells directs leukocytes to sites of axonal injury in the CNS. J. Neurosci. 23, 7922–7930 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Wang, K., Bekar, L. K., Furber, K. & Walz, W. Vimentin-expressing proximal reactive astrocytes correlate with migration rather than proliferation following focal brain injury. Brain Res. 1024, 193–202 (2004).

    CAS  PubMed  Google Scholar 

  43. Leavitt, B. R., Hernit-Grant, C. S. & Macklis, J. D. Mature astrocytes transform into transitional radial glia within adult mouse neocortex that supports directed migration of transplanted immature neurons. Exp. Neurol. 157, 43–57 (1999).

    CAS  PubMed  Google Scholar 

  44. Hagino, S. et al. Slit and glypican-1 mRNAs are coexpressed in the reactive astrocytes of the injured adult brain. Glia 42, 130–138 (2003).

    PubMed  Google Scholar 

  45. Fawcett, J. W. & Asher, R. A. The glial scar and central nervous system repair. Brain Res. Bull. 49, 377–391 (1999).

    CAS  PubMed  Google Scholar 

  46. Back, S. A. et al. Hyaluronan accumulates in demyelinated lesions and inhibits oligodendrocyte progenitor maturation. Nature Med. 11, 966–972 (2005).

    CAS  PubMed  Google Scholar 

  47. Cleaver, O. & Melton, D. A. Endothelial signaling during development. Nature Med. 9, 661–668 (2003).

    CAS  PubMed  Google Scholar 

  48. Carmeliet, P. & Tessier-Lavigne, M. Common mechanisms of nerve and blood vessel wiring. Nature 436, 193–200 (2005).

    CAS  PubMed  Google Scholar 

  49. Alvarez-Buylla, A. & Lim, D. A. For the long run: maintaining germinal niches in the adult brain. Neuron 41, 683–686 (2004).

    CAS  PubMed  Google Scholar 

  50. Bagnard, D. et al. Semaphorin 3A–vascular endothelial growth factor-165 balance mediates migration and apoptosis of neural progenitor cells by the recruitment of shared receptor. J. Neurosci. 21, 3332–3341 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Zhang, H., Vutskits, L., Pepper, M. S. & Kiss, J. Z. VEGF is a chemoattractant for FGF-2-stimulated neural progenitors. J. Cell Biol. 163, 1375–1384 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Allport, J. R., Shinde Patil, V. R. & Weissleder, R. Murine neuronal progenitor cells are preferentially recruited to tumor vasculature via α4-integrin and SDF-1α-dependent mechanisms. Cancer Biol. Ther. 3, 838–844 (2004).

    CAS  PubMed  Google Scholar 

  53. Pluchino, S. et al. Injection of adult neurospheres induces recovery in a chronic model of multiple sclerosis. Nature 422, 688–694 (2003).

    CAS  PubMed  Google Scholar 

  54. Pluchino, S. et al. Neurosphere-derived multipotent precursors promote neuroprotection by an immunomodulatory mechanism. Nature 436, 266–271 (2005).

    CAS  PubMed  Google Scholar 

  55. Ourednik, J., Ourednik, V., Lynch, W. P., Schachner, M. & Snyder, E. Y. Neural stem cells display an inherent mechanism for rescuing dysfunctional neurons. Nature Biotechnol. 20, 1103–1110 (2002).

    CAS  Google Scholar 

  56. Ruschenschmidt, C., Koch, P. G., Brustle, O. & Beck, H. Functional properties of ES cell-derived neurons engrafted into the hippocampus of adult normal and chronically epileptic rats. Epilepsia 46 (Suppl. 5), 174–183 (2005).

    PubMed  Google Scholar 

  57. 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 

  58. Imren, S. et al. High-level β-globin expression and preferred intragenic integration after lentiviral transduction of human cord blood stem cells. J. Clin. Invest. 114, 953–962 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Carpenter, M. K. et al. Enrichment of neurons and neural precursors from human embryonic stem cells. Exp. Neurol. 172, 383–397 (2001).

    CAS  PubMed  Google Scholar 

  60. Tang, Y. et al. In vivo tracking of neural progenitor cell migration to glioblastomas. Hum. Gene Ther. 14, 1247–1254 (2003).

    CAS  PubMed  Google Scholar 

  61. Hoehn, M. et al. Monitoring of implanted stem cell migration in vivo: a highly resolved in vivo magnetic resonance imaging investigation of experimental stroke in rat. Proc. Natl Acad. Sci. USA 99, 16267–16272 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Gene Therapy Wikipedia [online], <http://en.wikipedia.org/wiki/Gene_therapy> (2005).

  63. Pizzo, D. P., Coufal, N. G., Lortie, M. J., Gage, F. H. & Thal, L. J. Regulatable acetylcholine-producing fibroblasts enhance cognitive performance. Mol. Ther. 26 Sep 2005 (10.1016/j.mythe.2005.08.001).

  64. Bharali, D. J. et al. Organically modified silica nanoparticles: a nonviral vector for in vivo gene delivery and expression in the brain. Proc. Natl Acad. Sci. USA 102, 11539–11544 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Kustikova, O. et al. Clonal dominance of hematopoietic stem cells triggered by retroviral gene marking. Science 308, 1171–1174 (2005).

    CAS  PubMed  Google Scholar 

  66. Vroemen, M., Weidner, N. & Blesch, A. Loss of gene expression in lentivirus- and retrovirus-transduced neural progenitor cells is correlated to migration and differentiation in the adult spinal cord. Exp. Neurol. 195, 127–139 (2005).

    CAS  PubMed  Google Scholar 

  67. Zurn, A. D., Tseng, J. & Aebischer, P. Treatment of Parkinson's disease. Symptomatic cell therapies: cells as biological minipumps. Eur. Neurol. 36, 405–408 (1996).

    CAS  PubMed  Google Scholar 

  68. Freed, C. R., Breeze, R. E., Fahn, S. & Eidelberg, D. Preoperative response to levodopa is the best predictor of transplant outcome. Ann. Neurol. 55, 896; author reply 896–897 (2004).

    PubMed  Google Scholar 

  69. Akerud, P., Canals, J. M., Snyder, E. Y. & Arenas, E. Neuroprotection through delivery of glial cell line-derived neurotrophic factor by neural stem cells in a mouse model of Parkinson's disease. J. Neurosci. 21, 8108–8118 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Casper, D. et al. Enhanced vascularization and survival of neural transplants with ex vivo angiogenic gene transfer. Cell Transplant. 11, 331–349 (2002).

    PubMed  Google Scholar 

  71. Yasuhara, T. et al. Neurorescue effects of VEGF on a rat model of Parkinson's disease. Brain Res. 1053, 10–18 (2005).

    CAS  PubMed  Google Scholar 

  72. Tuszynski, M. H. et al. A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease. Nature Med. 11, 551–555 (2005).

    CAS  PubMed  Google Scholar 

  73. Kaspar, B. K., Llado, J., Sherkat, N., Rothstein, J. D. & Gage, F. H. Retrograde viral delivery of IGF-1 prolongs survival in a mouse ALS model. Science 301, 839–842 (2003).

    CAS  PubMed  Google Scholar 

  74. Azzouz, M. et al. VEGF delivery with retrogradely transported lentivector prolongs survival in a mouse ALS model. Nature 429, 413–417 (2004).

    CAS  PubMed  Google Scholar 

  75. Klein, S. M. et al. GDNF delivery using human neural progenitor cells in a rat model of ALS. Hum. Gene Ther. 16, 509–521 (2005).

    CAS  PubMed  Google Scholar 

  76. Ehtesham, M. et al. Induction of glioblastoma apoptosis using neural stem cell-mediated delivery of tumor necrosis factor-related apoptosis-inducing ligand. Cancer Res. 62, 7170–7174 (2002).

    CAS  PubMed  Google Scholar 

  77. Kim, S. K. et al. PEX-producing human neural stem cells inhibit tumor growth in a mouse glioma model. Clin. Cancer Res. 11, 5965–5970 (2005).

    CAS  PubMed  Google Scholar 

  78. Snyder, E. Y., Taylor, R. M. & Wolfe, J. H. Neural progenitor cell engraftment corrects lysosomal storage throughout the MPS VII mouse brain. Nature 374, 367–370 (1995).

    CAS  PubMed  Google Scholar 

  79. Monje, M. L. & Palmer, T. Prevention of deficits in neurogenesis with anti-inflammatory agents. US Patent application 20040254152 (2004).

  80. Hains, B. C., Johnson, K. M., Eaton, M. J., Willis, W. D. & Hulsebosch, C. E. Serotonergic neural precursor cell grafts attenuate bilateral hyperexcitability of dorsal horn neurons after spinal hemisection in rat. Neuroscience 116, 1097–1110 (2003).

    CAS  PubMed  Google Scholar 

  81. Hofstetter, C. P. et al. Allodynia limits the usefulness of intraspinal neural stem cell grafts; directed differentiation improves outcome. Nature Neurosci. 8, 346–353 (2005).

    CAS  PubMed  Google Scholar 

  82. Weissleder, R. & Ntziachristos, V. Shedding light onto live molecular targets. Nature Med. 9, 123–128 (2003).

    CAS  PubMed  Google Scholar 

  83. Allport, J. R., Shinde Patil, V. R. & Weissleder, R. Murine neuronal progenitor cells are preferentially recruited to tumor vasculature via α4-integrin and SDF-1α-dependent mechanisms. Cancer Biol. Ther. 3, 838–844 (2004).

    CAS  PubMed  Google Scholar 

  84. Burnstein, R. M. et al. Differentiation and migration of long term expanded human neural progenitors in a partial lesion model of Parkinson's disease. Int. J. Biochem. Cell Biol. 36, 702–713 (2004).

    CAS  PubMed  Google Scholar 

  85. Ahn, T. B., Kim, J. M., Kwon, K. M., Lee, S. H. & Jeon, B. S. Survival and migration of transplanted neural stem cell-derived dopamine cells in the brain of parkinsonian rat. Int. J. Neurosci. 114, 575–585 (2004).

    PubMed  Google Scholar 

  86. Chen, J., Magavi, S. S. & Macklis, J. D. Neurogenesis of corticospinal motor neurons extending spinal projections in adult mice. Proc. Natl Acad. Sci. USA 101, 16357–16362 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Shihabuddin, L. S. et al. Intracerebral transplantation of adult mouse neural progenitor cells into the Niemann–Pick-A mouse leads to a marked decrease in lysosomal storage pathology. J. Neurosci. 24, 10642–10651 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Hayashi, T. et al. Neural precursor cells division and migration in neonatal rat brain after ischemic/hypoxic injury. Brain Res. 1038, 41–49 (2005).

    CAS  PubMed  Google Scholar 

  89. Shear, D. A. et al. Neural progenitor cell transplants promote long-term functional recovery after traumatic brain injury. Brain Res. 1026, 11–22 (2004).

    CAS  PubMed  Google Scholar 

  90. Wennersten, A., Meier, X., Holmin, S., Wahlberg, L. & Mathiesen, T. Proliferation, migration, and differentiation of human neural stem/progenitor cells after transplantation into a rat model of traumatic brain injury. J. Neurosurg. 100, 88–96 (2004).

    PubMed  Google Scholar 

  91. Picard-Riera, N. et al. Experimental autoimmune encephalomyelitis mobilizes neural progenitors from the subventricular zone to undergo oligodendrogenesis in adult mice. Proc. Natl Acad. Sci. USA 99, 13211–13216 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Ben-Hur, T. et al. Transplanted multipotential neural precursor cells migrate into the inflamed white matter in response to experimental autoimmune encephalomyelitis. Glia 41, 73–80 (2003).

    PubMed  Google Scholar 

  93. Totoiu, M. O., Nistor, G. I., Lane, T. E. & Keirstead, H. S. Remyelination, axonal sparing, and locomotor recovery following transplantation of glial-committed progenitor cells into the MHV model of multiple sclerosis. Exp. Neurol. 187, 254–265 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Ji, J. F., He, B. P., Dheen, S. T. & Tay, S. S. Expression of chemokine receptors CXCR4, CCR2, CCR5 and CX3CR1 in neural progenitor cells isolated from the subventricular zone of the adult rat brain. Neurosci. Lett. 355, 236–240 (2004).

    CAS  PubMed  Google Scholar 

  95. Krathwohl, M. D. & Kaiser, J. L. Chemokines promote quiescence and survival of human neural progenitor cells. Stem Cells 22, 109–118 (2004).

    CAS  PubMed  Google Scholar 

  96. Martinez-Serrano, A. & Bjorklund, A. Ex vivo nerve growth factor gene transfer to the basal forebrain in presymptomatic middle-aged rats prevents the development of cholinergic neuron atrophy and cognitive impairment during aging. Proc. Natl Acad. Sci. USA 95, 1858–1863 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Sun, L., Lee, J. & Fine, H. A. Neuronally expressed stem cell factor induces neural stem cell migration to areas of brain injury. J. Clin. Invest. 113, 1364–1374 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Jin, K., Mao, X. O., Sun, Y., Xie, L. & Greenberg, D. A. Stem cell factor stimulates neurogenesis in vitro and in vivo. J. Clin. Invest. 110, 311–319 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Schanzer, A. et al. Direct stimulation of adult neural stem cells in vitro and neurogenesis in vivo by vascular endothelial growth factor. Brain Pathol. 14, 237–248 (2004).

    PubMed  Google Scholar 

  100. Martinez-Serrano, A., Hantzopoulos, P. A. & Bjorklund, A. Ex vivo gene transfer of brain-derived neurotrophic factor to the intact rat forebrain: neurotrophic effects on cholinergic neurons. Eur. J. Neurosci. 8, 727–735 (1996).

    CAS  PubMed  Google Scholar 

  101. Low, W. C. et al. Function recovery following neural transplantation of embryonic septal nuclei in adult rats with septohippocampal lesions. Nature 300, 260–262 (1982).

    CAS  PubMed  Google Scholar 

  102. Ehtesham, M. et al. The use of interleukin 12-secreting neural stem cells for the treatment of intracranial glioma. Cancer Res. 62, 5657–5663 (2002).

    CAS  PubMed  Google Scholar 

  103. Barresi, V. et al. Transplantation of prodrug-converting neural progenitor cells for brain tumor therapy. Cancer Gene Ther. 10, 396–402 (2003).

    CAS  PubMed  Google Scholar 

  104. Lee, J. et al. Cellular and genetic characterization of human adult bone marrow-derived neural stem-like cells: a potential antiglioma cellular vector. Cancer Res. 63, 8877–8889 (2003).

    CAS  PubMed  Google Scholar 

  105. Shah, K. et al. Glioma therapy and real-time imaging of neural precursor cell migration and tumor regression. Ann. Neurol. 57, 34–41 (2005).

    CAS  PubMed  Google Scholar 

  106. Eaton, M. J., Santiago, D. I., Dancausse, H. A. & Whittemore, S. R. Lumbar transplants of immortalized serotonergic neurons alleviate chronic neuropathic pain. Pain 72, 59–69 (1997).

    CAS  PubMed  Google Scholar 

  107. Eaton, M. J., Plunkett, J. A., Karmally, S., Martinez, M. A. & Montanez, K. Changes in GAD- and GABA-immunoreactivity in the spinal dorsal horn after peripheral nerve injury and promotion of recovery by lumbar transplant of immortalized serotonergic precursors. J. Chem. Neuroanat. 16, 57–72 (1998).

    CAS  PubMed  Google Scholar 

  108. Eaton, M. J. et al. Transplants of neuronal cells bioengineered to synthesize GABA alleviate chronic neuropathic pain. Cell Transplant. 8, 87–101 (1999).

    CAS  PubMed  Google Scholar 

  109. Eaton, M. J. et al. Lumbar transplant of neurons genetically modified to secrete galanin reverse pain-like behaviors after partial sciatic nerve injury. J. Peripher. Nerv. Syst. 4, 245–257 (1999).

    CAS  PubMed  Google Scholar 

  110. Cejas, P. J. et al. Lumbar transplant of neurons genetically modified to secrete brain-derived neurotrophic factor attenuates allodynia and hyperalgesia after sciatic nerve constriction. Pain 86, 195–210 (2000).

    CAS  PubMed  Google Scholar 

  111. Lin, C. R. et al. Intrathecal spinal progenitor cell transplantation for the treatment of neuropathic pain. Cell Transplant. 11, 17–24 (2002).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We would like to thank N. O. Schmidt for his helpful comments on the manuscript.

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Correspondence to Franz-Josef Müller.

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Alzheimer's disease

Amyotrophic lateral sclerosis

Krabbe disease

Parkinson's disease

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Clinical trial results, Alzheimer's Disease Education & Referral Center

The official National Institutes of Health resource for stem cell research

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Müller, FJ., Snyder, E. & Loring, J. Gene therapy: can neural stem cells deliver?. Nat Rev Neurosci 7, 75–84 (2006). https://doi.org/10.1038/nrn1829

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