Opinion | Published:

Gene therapy: can neural stem cells deliver?

Nature Reviews Neuroscience volume 7, pages 7584 (2006) | Download Citation

Subjects

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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    Mammalian neural stem cells. Science 287, 1433–1438 (2000).

  2. 2.

    & The stem-cell menagerie. Trends Neurosci. 26, 351–359 (2003).

  3. 3.

    & 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).

  4. 4.

    , , , & EGF converts transit-amplifying neurogenic precursors in the adult brain into multipotent stem cells. Neuron 36, 1021–1034 (2002).

  5. 5.

    , , & Neural stem cell detection, characterization, and age-related changes in the subventricular zone of mice. J. Neurosci. 24, 1726–1733 (2004).

  6. 6.

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

  7. 7.

    , , , & Neurogenesis in the adult brain: new strategies for central nervous system diseases. Annu. Rev. Pharmacol. Toxicol. 44, 399–421 (2004).

  8. 8.

    , , & Adult neurogenesis and repair of the adult CNS with neural progenitors, precursors, and stem cells. Prog. Neurobiol. 75, 321–341 (2005).

  9. 9.

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

  10. 10.

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

  11. 11.

    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).

  12. 12.

    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).

  13. 13.

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

  14. 14.

    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. 15.

    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).

  16. 16.

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

  17. 17.

    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).

  18. 18.

    , & Astroglia induce neurogenesis from adult neural stem cells. Nature 417, 39–44 (2002).

  19. 19.

    , & Vascular niche for adult hippocampal neurogenesis. J. Comp. Neurol. 425, 479–494 (2000).

  20. 20.

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

  21. 21.

    , & Anatomy of the brain neurogenic zones revisited: fractones and the fibroblast/macrophage network. J. Comp. Neurol. 451, 170–188 (2002).

  22. 22.

    , , & Migration and differentiation of neural precursor cells can be directed by microglia. Proc. Natl Acad. Sci. USA 100, 15983–15988 (2003).

  23. 23.

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

  24. 24.

    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).

  25. 25.

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

  26. 26.

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

  27. 27.

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

  28. 28.

    & Microglia and inflammation-mediated neurodegeneration: multiple triggers with a common mechanism. Prog. Neurobiol. 76, 77–98 (2005).

  29. 29.

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

  30. 30.

    , , , & Inflammation is detrimental for neurogenesis in adult brain. Proc. Natl Acad. Sci. USA 100, 13632–13637 (2003).

  31. 31.

    , & Inflammatory blockade restores adult hippocampal neurogenesis. Science 302, 1760–1765 (2003).

  32. 32.

    , & Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308, 1314–1318 (2005).

  33. 33.

    & 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).

  34. 34.

    , & Interferon-γ but not TNF α promotes neuronal differentiation and neurite outgrowth of murine adult neural stem cells. Exp. Neurol. 187, 171–177 (2004).

  35. 35.

    , & Differential activation of microglia and astrocytes in aniso- and isomorphic gliotic tissue. Glia 8, 277–291 (1993).

  36. 36.

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

  37. 37.

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

  38. 38.

    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).

  39. 39.

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

  40. 40.

    , , , & Pro-regenerative properties of cytokine-activated astrocytes. J. Neurochem. 89, 1092–1100 (2004).

  41. 41.

    , , & Chemokine expression by glial cells directs leukocytes to sites of axonal injury in the CNS. J. Neurosci. 23, 7922–7930 (2003).

  42. 42.

    , , & Vimentin-expressing proximal reactive astrocytes correlate with migration rather than proliferation following focal brain injury. Brain Res. 1024, 193–202 (2004).

  43. 43.

    , & 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).

  44. 44.

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

  45. 45.

    & The glial scar and central nervous system repair. Brain Res. Bull. 49, 377–391 (1999).

  46. 46.

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

  47. 47.

    & Endothelial signaling during development. Nature Med. 9, 661–668 (2003).

  48. 48.

    & Common mechanisms of nerve and blood vessel wiring. Nature 436, 193–200 (2005).

  49. 49.

    & For the long run: maintaining germinal niches in the adult brain. Neuron 41, 683–686 (2004).

  50. 50.

    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).

  51. 51.

    , , & VEGF is a chemoattractant for FGF-2-stimulated neural progenitors. J. Cell Biol. 163, 1375–1384 (2003).

  52. 52.

    , & 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).

  53. 53.

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

  54. 54.

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

  55. 55.

    , , , & Neural stem cells display an inherent mechanism for rescuing dysfunctional neurons. Nature Biotechnol. 20, 1103–1110 (2002).

  56. 56.

    , , & 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).

  57. 57.

    & Immortalizing oncogenes subvert the establishment of granule cell identity in developing cerebellum. Development 120, 1059–1070 (1994).

  58. 58.

    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).

  59. 59.

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

  60. 60.

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

  61. 61.

    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).

  62. 62.

    Gene Therapy Wikipedia [online], <> (2005).

  63. 63.

    , , , & Regulatable acetylcholine-producing fibroblasts enhance cognitive performance. Mol. Ther. 26 Sep 2005 (10.1016/j.mythe.2005.08.001).

  64. 64.

    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).

  65. 65.

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

  66. 66.

    , & 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).

  67. 67.

    , & Treatment of Parkinson's disease. Symptomatic cell therapies: cells as biological minipumps. Eur. Neurol. 36, 405–408 (1996).

  68. 68.

    , , & Preoperative response to levodopa is the best predictor of transplant outcome. Ann. Neurol. 55, 896; author reply 896–897 (2004).

  69. 69.

    , , & 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).

  70. 70.

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

  71. 71.

    et al. Neurorescue effects of VEGF on a rat model of Parkinson's disease. Brain Res. 1053, 10–18 (2005).

  72. 72.

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

  73. 73.

    , , , & Retrograde viral delivery of IGF-1 prolongs survival in a mouse ALS model. Science 301, 839–842 (2003).

  74. 74.

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

  75. 75.

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

  76. 76.

    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).

  77. 77.

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

  78. 78.

    , & Neural progenitor cell engraftment corrects lysosomal storage throughout the MPS VII mouse brain. Nature 374, 367–370 (1995).

  79. 79.

    & Prevention of deficits in neurogenesis with anti-inflammatory agents. US Patent application 20040254152 (2004).

  80. 80.

    , , , & Serotonergic neural precursor cell grafts attenuate bilateral hyperexcitability of dorsal horn neurons after spinal hemisection in rat. Neuroscience 116, 1097–1110 (2003).

  81. 81.

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

  82. 82.

    & Shedding light onto live molecular targets. Nature Med. 9, 123–128 (2003).

  83. 83.

    , & 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).

  84. 84.

    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).

  85. 85.

    , , , & Survival and migration of transplanted neural stem cell-derived dopamine cells in the brain of parkinsonian rat. Int. J. Neurosci. 114, 575–585 (2004).

  86. 86.

    , & Neurogenesis of corticospinal motor neurons extending spinal projections in adult mice. Proc. Natl Acad. Sci. USA 101, 16357–16362 (2004).

  87. 87.

    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).

  88. 88.

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

  89. 89.

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

  90. 90.

    , , , & 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).

  91. 91.

    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).

  92. 92.

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

  93. 93.

    , , & 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).

  94. 94.

    , , & 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).

  95. 95.

    & Chemokines promote quiescence and survival of human neural progenitor cells. Stem Cells 22, 109–118 (2004).

  96. 96.

    & 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).

  97. 97.

    , & Neuronally expressed stem cell factor induces neural stem cell migration to areas of brain injury. J. Clin. Invest. 113, 1364–1374 (2004).

  98. 98.

    , , , & Stem cell factor stimulates neurogenesis in vitro and in vivo. J. Clin. Invest. 110, 311–319 (2002).

  99. 99.

    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).

  100. 100.

    , & 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).

  101. 101.

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

  102. 102.

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

  103. 103.

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

  104. 104.

    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).

  105. 105.

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

  106. 106.

    , , & Lumbar transplants of immortalized serotonergic neurons alleviate chronic neuropathic pain. Pain 72, 59–69 (1997).

  107. 107.

    , , , & 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).

  108. 108.

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

  109. 109.

    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).

  110. 110.

    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).

  111. 111.

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

Download references

Acknowledgements

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

Author information

Affiliations

  1. Franz-Josef Müller, Evan Y. Snyder and Jeanne F. Loring are at the Burnham Institute for Medical Research, La Jolla, California, USA.

    • Franz-Josef Müller
    • , Evan Y. Snyder
    •  & Jeanne F. Loring
  2. Franz-Josef Müller is also at the Zentrum für Integrative Psychiatrie, Kiel, Germany.

    • Franz-Josef Müller

Authors

  1. Search for Franz-Josef Müller in:

  2. Search for Evan Y. Snyder in:

  3. Search for Jeanne F. Loring in:

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Franz-Josef Müller.

About this article

Publication history

Published

DOI

https://doi.org/10.1038/nrn1829

Further reading