Skip to main content

Advertisement

SpringerLink
Log in

Current Challenges for the Advancement of Neural Stem Cell Biology and Transplantation Research

  • Published:
Stem Cell Reviews and Reports Aims and scope Submit manuscript

Abstract

Transplantation of neural stem cells (NSC) is hoped to become a promising primary or secondary therapy for the treatment of various neurodegenerative disorders of the central nervous system (CNS), as demonstrated by multiple pre-clinical animal studies in which functional recovery has already been demonstrated. However, for NSC therapy to be successful, the first challenge will be to define a transplantable cell population. In the first part of this review, we will briefly discuss the main features of ex vivo culture and characterisation of NSC. Next, NSC grafting itself may not only result in the regeneration of lost tissue, but more importantly has the potential to improve functional outcome through many bystander mechanisms. In the second part of this review, we will briefly discuss several pre-clinical studies that contributed to a better understanding of the therapeutic potential of NSC grafts in vivo. However, while many pre-clinical animal studies mainly report on the clinical benefit of NSC grafting, little is known about the actual in vivo fate of grafted NSC. Therefore, the third part of this review will focus on non-invasive imaging techniques for monitoring cellular grafts in the brain under in vivo conditions. Finally, as NSC transplantation research has evolved during the past decade, it has become clear that the host micro-environment itself, either in healthy or injured condition, is an important player in defining success of NSC grafting. The final part of this review will focus on the host environmental influence on survival, migration and differentiation of grafted NSC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Conti, L., & Cattaneo, E. (2010). Neural stem cell systems: physiological players or in vitro entities? Nature Reviews Neuroscience, 11(3), 176–187.

    PubMed  CAS  Google Scholar 

  2. Anthony, T. E., & Heintz, N. (2008). Genetic lineage tracing defines distinct neurogenic and gliogenic stages of ventral telencephalic radial glial development. Neural Development, 3, 30.

    PubMed  Google Scholar 

  3. Pinto, L., Mader, M. T., Irmler, M., Gentilini, M., Santoni, F., Drechsel, D., et al. (2008). Prospective isolation of functionally distinct radial glial subtypes–lineage and transcriptome analysis. Molecular and Cellular Neurosciences, 38(1), 15–42.

    PubMed  CAS  Google Scholar 

  4. Doetsch, F., Caille, I., Lim, D. A., Garcia-Verdugo, J. M., & Alvarez-Buylla, A. (1999). Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell, 97(6), 703–716.

    PubMed  CAS  Google Scholar 

  5. Seri, B., Garcia-Verdugo, J. M., McEwen, B. S., & Alvarez-Buylla, A. (2001). Astrocytes give rise to new neurons in the adult mammalian hippocampus. The Journal of Neuroscience, 21(18), 7153–7160.

    PubMed  CAS  Google Scholar 

  6. Morshead, C. M., Reynolds, B. A., Craig, C. G., McBurney, M. W., Staines, W. A., Morassutti, D., et al. (1994). Neural stem cells in the adult mammalian forebrain: a relatively quiescent subpopulation of subependymal cells. Neuron, 13(5), 1071–1082.

    PubMed  CAS  Google Scholar 

  7. Seri, B., Garcia-Verdugo, J. M., Collado-Morente, L., McEwen, B. S., & Alvarez-Buylla, A. (2004). Cell types, lineage, and architecture of the germinal zone in the adult dentate gyrus. The Journal of Comparative Neurology, 478(4), 359–378.

    PubMed  Google Scholar 

  8. Richards, L. J., Kilpatrick, T. J., & Bartlett, P. F. (1992). De novo generation of neuronal cells from the adult mouse brain. Proceedings of the National Academy of Sciences of the United States of America, 89(18), 8591–8595.

    PubMed  CAS  Google Scholar 

  9. Reynolds, B. A., Tetzlaff, W., & Weiss, S. (1992). A multipotent EGF-responsive striatal embryonic progenitor cell produces neurons and astrocytes. The Journal of Neuroscience, 12(11), 4565–4574.

    PubMed  CAS  Google Scholar 

  10. Reynolds, B. A., & Weiss, S. (1992). Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science, 255(5052), 1707–1710.

    PubMed  CAS  Google Scholar 

  11. Elkabetz, Y., Panagiotakos, G., Al Shamy, G., Socci, N. D., Tabar, V., & Studer, L. (2008). Human ES cell-derived neural rosettes reveal a functionally distinct early neural stem cell stage. Genes & Development, 22(2), 152–165.

    CAS  Google Scholar 

  12. Conti, L., Pollard, S. M., Gorba, T., Reitano, E., Toselli, M., Biella, G., et al. (2005). Niche-independent symmetrical self-renewal of a mammalian tissue stem cell. PLoS Biology, 3(9), e283.

    PubMed  Google Scholar 

  13. Reekmans, K.P., Praet, J., De Vocht, N., Tambuyzer, B.R., Bergwerf, I., Daans, J., et al. Clinical potential of intravenous neural stem cell delivery for treatment of neuro-inflammatory disease in mice? Cell Transplant, doi:10.3727/096368910X543411.

  14. Bez, A., Corsini, E., Curti, D., Biggiogera, M., Colombo, A., Nicosia, R. F., et al. (2003). Neurosphere and neurosphere-forming cells: morphological and ultrastructural characterization. Brain Research, 993(1–2), 18–29.

    PubMed  CAS  Google Scholar 

  15. Kriegstein, A., & Alvarez-Buylla, A. (2009). The glial nature of embryonic and adult neural stem cells. Annual Review of Neuroscience, 32, 149–184.

    PubMed  CAS  Google Scholar 

  16. Kazanis, I., Lathia, J. D., Vadakkan, T. J., Raborn, E., Wan, R., Mughal, M. R., et al. (2010). Quiescence and activation of stem and precursor cell populations in the subependymal zone of the mammalian brain are associated with distinct cellular and extracellular matrix signals. The Journal of Neuroscience, 30(29), 9771–9781.

    PubMed  CAS  Google Scholar 

  17. Ahmed, S. (2009). The culture of neural stem cells. Journal of Cellular Biochemistry, 106(1), 1–6.

    PubMed  CAS  Google Scholar 

  18. Morshead, C. M., Benveniste, P., Iscove, N. N., & van der Kooy, D. (2002). Hematopoietic competence is a rare property of neural stem cells that may depend on genetic and epigenetic alterations. Natural Medicines, 8(3), 268–273.

    CAS  Google Scholar 

  19. Stiles, C. D. (2003). Lost in space: misregulated positional cues create tripotent neural progenitors in cell culture. Neuron, 40(3), 447–449.

    PubMed  CAS  Google Scholar 

  20. Geoffroy, C. G., & Raineteau, O. (2007). A Cre-lox approach for transient transgene expression in neural precursor cells and long-term tracking of their progeny in vitro and in vivo. BMC Developmental Biology, 7, 45.

    PubMed  Google Scholar 

  21. Glaser, T., Pollard, S. M., Smith, A., & Brustle, O. (2007). Tripotential differentiation of adherently expandable neural stem (NS) cells. PLoS ONE, 2(3), e298.

    PubMed  Google Scholar 

  22. Sun, Y., Pollard, S., Conti, L., Toselli, M., Biella, G., Parkin, G., et al. (2008). Long-term tripotent differentiation capacity of human neural stem (NS) cells in adherent culture. Molecular and Cellular Neurosciences, 38(2), 245–258.

    PubMed  CAS  Google Scholar 

  23. Craig, C. G., Tropepe, V., Morshead, C. M., Reynolds, B. A., Weiss, S., & van der Kooy, D. (1996). In vivo growth factor expansion of endogenous subependymal neural precursor cell populations in the adult mouse brain. The Journal of Neuroscience, 16(8), 2649–2658.

    PubMed  CAS  Google Scholar 

  24. Dayer, A. G., Jenny, B., Sauvain, M. O., Potter, G., Salmon, P., Zgraggen, E., et al. (2007). Expression of FGF-2 in neural progenitor cells enhances their potential for cellular brain repair in the rodent cortex. Brain, 130(Pt 11), 2962–2976.

    PubMed  Google Scholar 

  25. Kuhn, H. G., Winkler, J., Kempermann, G., Thal, L. J., & Gage, F. H. (1997). Epidermal growth factor and fibroblast growth factor-2 have different effects on neural progenitors in the adult rat brain. The Journal of Neuroscience, 17(15), 5820–5829.

    PubMed  CAS  Google Scholar 

  26. Gonzalez-Perez, O., Romero-Rodriguez, R., Soriano-Navarro, M., Garcia-Verdugo, J. M., & Alvarez-Buylla, A. (2009). Epidermal growth factor induces the progeny of subventricular zone type B cells to migrate and differentiate into oligodendrocytes. Stem Cells, 27(8), 2032–2043.

    PubMed  CAS  Google Scholar 

  27. Jin, K., LaFevre-Bernt, M., Sun, Y., Chen, S., Gafni, J., Crippen, D., et al. (2005). FGF-2 promotes neurogenesis and neuroprotection and prolongs survival in a transgenic mouse model of Huntington’s disease. Proceedings of the National Academy of Sciences of the United States of America, 102(50), 18189–18194.

    PubMed  CAS  Google Scholar 

  28. Tropepe, V., Sibilia, M., Ciruna, B. G., Rossant, J., Wagner, E. F., & van der Kooy, D. (1999). Distinct neural stem cells proliferate in response to EGF and FGF in the developing mouse telencephalon. Developmental Biology, 208(1), 166–188.

    PubMed  CAS  Google Scholar 

  29. Parmar, M., Skogh, C., Bjorklund, A., & Campbell, K. (2002). Regional specification of neurosphere cultures derived from subregions of the embryonic telencephalon. Molecular and Cellular Neurosciences, 21(4), 645–656.

    PubMed  CAS  Google Scholar 

  30. Nishikawa, S., Jakt, L. M., & Era, T. (2007). Embryonic stem-cell culture as a tool for developmental cell biology. Nature Reviews. Molecular Cell Biology, 8(6), 502–507.

    PubMed  CAS  Google Scholar 

  31. Koch, P., Opitz, T., Steinbeck, J. A., Ladewig, J., & Brustle, 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 

  32. Reubinoff, B. E., Itsykson, P., Turetsky, T., Pera, M. F., Reinhartz, E., Itzik, A., et al. (2001). Neural progenitors from human embryonic stem cells. Nature Biotechnology, 19(12), 1134–1140.

    PubMed  CAS  Google Scholar 

  33. Pruszak, J., Ludwig, W., Blak, A., Alavian, K., & Isacson, O. (2009). CD15, CD24, and CD29 define a surface biomarker code for neural lineage differentiation of stem cells. Stem Cells, 27(12), 2928–2940.

    PubMed  CAS  Google Scholar 

  34. Ohm, J. E., Mali, P., Van Neste, L., Berman, D. M., Liang, L., Pandiyan, K., et al. (2010). Cancer-related epigenome changes associated with reprogramming to induced pluripotent stem cells. Cancer Research, 70(19), 7662–7673.

    PubMed  CAS  Google Scholar 

  35. Clarke, S. R., Shetty, A. K., Bradley, J. L., & Turner, D. A. (1994). Reactive astrocytes express the embryonic intermediate neurofilament nestin. Neuroreport, 5(15), 1885–1888.

    PubMed  CAS  Google Scholar 

  36. Duggal, N., Schmidt-Kastner, R., & Hakim, A. M. (1997). Nestin expression in reactive astrocytes following focal cerebral ischemia in rats. Brain Research, 768(1–2), 1–9.

    PubMed  CAS  Google Scholar 

  37. Gilyarov, A. V. (2008). Nestin in central nervous system cells. Neuroscience and Behavioral Physiology, 38(2), 165–169.

    PubMed  CAS  Google Scholar 

  38. Ihrie, R. A., & Alvarez-Buylla, A. (2008). Cells in the astroglial lineage are neural stem cells. Cell and Tissue Research, 331(1), 179–191.

    PubMed  Google Scholar 

  39. Wang, D. D., & Bordey, A. (2008). The astrocyte odyssey. Progress in Neurobiology, 86(4), 342–367.

    PubMed  CAS  Google Scholar 

  40. Campbell, K., & Gotz, M. (2002). Radial glia: multi-purpose cells for vertebrate brain development. Trends in Neurosciences, 25(5), 235–238.

    PubMed  CAS  Google Scholar 

  41. Raponi, E., Agenes, F., Delphin, C., Assard, N., Baudier, J., Legraverend, C., et al. (2007). S100B expression defines a state in which GFAP-expressing cells lose their neural stem cell potential and acquire a more mature developmental stage. Glia, 55(2), 165–177.

    PubMed  Google Scholar 

  42. Deloulme, J. C., Raponi, E., Gentil, B. J., Bertacchi, N., Marks, A., Labourdette, G., et al. (2004). Nuclear expression of S100B in oligodendrocyte progenitor cells correlates with differentiation toward the oligodendroglial lineage and modulates oligodendrocytes maturation. Molecular and Cellular Neurosciences, 27(4), 453–465.

    PubMed  CAS  Google Scholar 

  43. Hachem, S., Aguirre, A., Vives, V., Marks, A., Gallo, V., & Legraverend, C. (2005). Spatial and temporal expression of S100B in cells of oligodendrocyte lineage. Glia, 51(2), 81–97.

    PubMed  CAS  Google Scholar 

  44. Maurer, M. H., & Kuschinsky, W. (2006). Screening the brain: molecular fingerprints of neural stem cells. Current Stem Cell Research & Therapy, 1(1), 65–77.

    CAS  Google Scholar 

  45. Sievertzon, M., Wirta, V., Mercer, A., Meletis, K., Erlandsson, R., Wikstrom, L., et al. (2005). Transcriptome analysis in primary neural stem cells using a tag cDNA amplification method. BMC Neuroscience, 6, 28.

    PubMed  Google Scholar 

  46. Silber, J., Lim, D. A., Petritsch, C., Persson, A. I., Maunakea, A. K., Yu, M., et al. (2008). miR-124 and miR-137 inhibit proliferation of glioblastoma multiforme cells and induce differentiation of brain tumor stem cells. BMC Medicine, 6, 14.

    PubMed  Google Scholar 

  47. Maiorano, N. A., & Mallamaci, A. (2009). Promotion of embryonic cortico-cerebral neuronogenesis by miR-124. Neural Development, 4, 40.

    PubMed  Google Scholar 

  48. Zhao, C., Sun, G., Li, S., & Shi, Y. (2009). A feedback regulatory loop involving microRNA-9 and nuclear receptor TLX in neural stem cell fate determination. Nature Structural & Molecular Biology, 16(4), 365–371.

    CAS  Google Scholar 

  49. Liu, C., Teng, Z. Q., Santistevan, N. J., Szulwach, K. E., Guo, W., Jin, P., et al. (2010). Epigenetic regulation of miR-184 by MBD1 governs neural stem cell proliferation and differentiation. Cell Stem Cell, 6(5), 433–444.

    PubMed  CAS  Google Scholar 

  50. Doetsch, F., Petreanu, L., Caille, I., Garcia-Verdugo, J. M., & Alvarez-Buylla, A. (2002). EGF converts transit-amplifying neurogenic precursors in the adult brain into multipotent stem cells. Neuron, 36(6), 1021–1034.

    PubMed  CAS  Google Scholar 

  51. Mi, R., Luo, Y., Cai, J., Limke, T. L., Rao, M. S., & Hoke, A. (2005). Immortalized neural stem cells differ from nonimmortalized cortical neurospheres and cerebellar granule cell progenitors. Experimental Neurology, 194(2), 301–319.

    PubMed  CAS  Google Scholar 

  52. Magnitsky, S., Walton, R. M., Wolfe, J. H., & Poptani, H. (2008). Magnetic resonance imaging detects differences in migration between primary and immortalized neural stem cells. Academic Radiology, 15(10), 1269–1281.

    PubMed  Google Scholar 

  53. Foroni, C., Galli, R., Cipelletti, B., Caumo, A., Alberti, S., Fiocco, R., et al. (2007). Resilience to transformation and inherent genetic and functional stability of adult neural stem cells ex vivo. Cancer Research, 67(8), 3725–3733.

    PubMed  CAS  Google Scholar 

  54. De Filippis, L., Lamorte, G., Snyder, E. Y., Malgaroli, A., & Vescovi, A. L. (2007). A novel, immortal, and multipotent human neural stem cell line generating functional neurons and oligodendrocytes. Stem Cells, 25(9), 2312–2321.

    PubMed  Google Scholar 

  55. Meissner, K. K., Kirkham, D. L., & Doering, L. C. (2005). Transplants of neurosphere cell suspensions from aged mice are functional in the mouse model of Parkinson’s. Brain Research, 1057(1–2), 105–112.

    PubMed  CAS  Google Scholar 

  56. Redmond, D. E., Jr., Bjugstad, K. B., Teng, Y. D., Ourednik, V., Ourednik, J., Wakeman, D. R., et al. (2007). Behavioral improvement in a primate Parkinson’s model is associated with multiple homeostatic effects of human neural stem cells. Proceedings of the National Academy of Sciences of the United States of America, 104(29), 12175–12180.

    PubMed  CAS  Google Scholar 

  57. Wei, P., Liu, J., Zhou, H. L., Han, Z. T., Wu, Q. Y., Pang, J. X., et al. (2007). Effects of engrafted neural stem cells derived from GFP transgenic mice in Parkinson’s diseases rats. Neuroscience Letters, 419(1), 49–54.

    PubMed  CAS  Google Scholar 

  58. Zhu, Q., Ma, J., Yu, L., & Yuan, C. (2009). Grafted neural stem cells migrate to substantia nigra and improve behavior in Parkinsonian rats. Neuroscience Letters, 462(3), 213–218.

    PubMed  CAS  Google Scholar 

  59. Lu, P., Jones, L. L., Snyder, E. Y., & Tuszynski, M. H. (2003). Neural stem cells constitutively secrete neurotrophic factors and promote extensive host axonal growth after spinal cord injury. Experimental Neurology, 181(2), 115–129.

    PubMed  CAS  Google Scholar 

  60. Barnabe-Heider, F., & Miller, F. D. (2003). Endogenously produced neurotrophins regulate survival and differentiation of cortical progenitors via distinct signaling pathways. The Journal of Neuroscience, 23(12), 5149–5160.

    PubMed  CAS  Google Scholar 

  61. Kang, H. C., Kim, D. S., Kim, J. Y., Kim, H. S., Lim, B. Y., Kim, H. D., et al. (2009). Behavioral improvement after transplantation of neural precursors derived from embryonic stem cells into the globally ischemic brain of adolescent rats. Brain & Development, 32(8), 658–668.

    Google Scholar 

  62. Madhavan, L., Daley, B. F., Paumier, K. L., & Collier, T. J. (2009). Transplantation of subventricular zone neural precursors induces an endogenous precursor cell response in a rat model of Parkinson’s disease. The Journal of Comparative Neurology, 515(1), 102–115.

    PubMed  Google Scholar 

  63. Aharonowiz, M., Einstein, O., Fainstein, N., Lassmann, H., Reubinoff, B., & Ben-Hur, T. (2008). Neuroprotective effect of transplanted human embryonic stem cell-derived neural precursors in an animal model of multiple sclerosis. PLoS ONE, 3(9), e3145.

    PubMed  Google Scholar 

  64. Einstein, O., Fainstein, N., Vaknin, I., Mizrachi-Kol, R., Reihartz, E., Grigoriadis, N., et al. (2007). Neural precursors attenuate autoimmune encephalomyelitis by peripheral immunosuppression. Annals of Neurology, 61(3), 209–218.

    PubMed  CAS  Google Scholar 

  65. Ben-Hur, T. (2008). Immunomodulation by neural stem cells. Journal of the Neurological Sciences, 265(1–2), 102–104.

    PubMed  CAS  Google Scholar 

  66. Bacigaluppi, M., Pluchino, S., Peruzzotti Jametti, L., Kilic, E., Kilic, U., Salani, G., et al. (2009). Delayed post-ischaemic neuroprotection following systemic neural stem cell transplantation involves multiple mechanisms. Brain, 132(Pt 8), 2239–2251.

    PubMed  Google Scholar 

  67. Einstein, O., Friedman-Levi, Y., Grigoriadis, N., & Ben-Hur, T. (2009). Transplanted neural precursors enhance host brain-derived myelin regeneration. The Journal of Neuroscience, 29(50), 15694–15702.

    PubMed  CAS  Google Scholar 

  68. Pluchino, S., Quattrini, A., Brambilla, E., Gritti, A., Salani, G., Dina, G., et al. (2003). Injection of adult neurospheres induces recovery in a chronic model of multiple sclerosis. Nature, 422(6933), 688–694.

    PubMed  CAS  Google Scholar 

  69. Blurton-Jones, M., Kitazawa, M., Martinez-Coria, H., Castello, N. A., Muller, F. J., Loring, J. F., 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 

  70. Shindo, T., Matsumoto, Y., Wang, Q., Kawai, N., Tamiya, T., & Nagao, S. (2006). Differences in the neuronal stem cells survival, neuronal differentiation and neurological improvement after transplantation of neural stem cells between mild and severe experimental traumatic brain injury. Journal of Medical Investigation, 53(1–2), 42–51.

    PubMed  Google Scholar 

  71. Hwang, D. H., Kim, B. G., Kim, E. J., Lee, S. I., Joo, I. S., Suh-Kim, H., et al. (2009). Transplantation of human neural stem cells transduced with Olig2 transcription factor improves locomotor recovery and enhances myelination in the white matter of rat spinal cord following contusive injury. BMC Neuroscience, 10, 117.

    PubMed  Google Scholar 

  72. Becerra, G. D., Tatko, L. M., Pak, E. S., Murashov, A. K., & Hoane, M. R. (2007). Transplantation of GABAergic neurons but not astrocytes induces recovery of sensorimotor function in the traumatically injured brain. Behavioural Brain Research, 179(1), 118–125.

    PubMed  CAS  Google Scholar 

  73. Fairless, R., & Barnett, S. C. (2005). Olfactory ensheathing cells: their role in central nervous system repair. The International Journal of Biochemistry & Cell Biology, 37(4), 693–699.

    CAS  Google Scholar 

  74. Lu, J., Feron, F., Mackay-Sim, A., & Waite, P. M. (2002). Olfactory ensheathing cells promote locomotor recovery after delayed transplantation into transected spinal cord. Brain, 125(Pt 1), 14–21.

    PubMed  Google Scholar 

  75. 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 

  76. Su, Z., Yuan, Y., Chen, J., Cao, L., Zhu, Y., Gao, L., et al. (2009). Reactive astrocytes in glial scar attract olfactory ensheathing cells migration by secreted TNF-alpha in spinal cord lesion of rat. PLoS ONE, 4(12), e8141.

    PubMed  Google Scholar 

  77. Barnett, S. C., & Chang, L. (2004). Olfactory ensheathing cells and CNS repair: going solo or in need of a friend? Trends in Neurosciences, 27(1), 54–60.

    PubMed  CAS  Google Scholar 

  78. Wang, G., Ao, Q., Gong, K., Gong, Y., & Zhang, X. (2010). Synergistic effect of neural stem cells and olfactory ensheathing cells on repair of adult rat spinal cord injury. Cell Transplantation, 19(10), 1325–1337.

    PubMed  Google Scholar 

  79. Tang, Z. P., Xie, X. W., Shi, Y. H., Liu, N., Zhu, S. Q., Li, Z. W., et al. (2010). Combined transplantation of neural stem cells and olfactory ensheathing cells improves the motor function of rats with intracerebral hemorrhage. Biomedical and Environmental Sciences, 23(1), 62–67.

    PubMed  Google Scholar 

  80. Oppenheim, R. W., Houenou, L. J., Johnson, J. E., Lin, L. F., Li, L., Lo, A. C., et al. (1995). Developing motor neurons rescued from programmed and axotomy-induced cell death by GDNF. Nature, 373(6512), 344–346.

    PubMed  CAS  Google Scholar 

  81. Clarkson, E. D., Zawada, W. M., & Freed, C. R. (1997). GDNF improves survival and reduces apoptosis in human embryonic dopaminergic neurons in vitro. Cell and Tissue Research, 289(2), 207–210.

    PubMed  CAS  Google Scholar 

  82. Koeberle, P. D., & Ball, A. K. (1998). Effects of GDNF on retinal ganglion cell survival following axotomy. Vision Res, 38(10), 1505–1515.

    PubMed  CAS  Google Scholar 

  83. Ghribi, O., Herman, M. M., Forbes, M. S., DeWitt, D. A., & Savory, J. (2001). GDNF protects against aluminum-induced apoptosis in rabbits by upregulating Bcl-2 and Bcl-XL and inhibiting mitochondrial Bax translocation. Neurobiology of Disease, 8(5), 764–773.

    PubMed  CAS  Google Scholar 

  84. Smith, M. P., & Cass, W. A. (2007). GDNF reduces oxidative stress in a 6-hydroxydopamine model of Parkinson’s disease. Neuroscience Letters, 412(3), 259–263.

    PubMed  CAS  Google Scholar 

  85. Ebert, A. D., Beres, A. J., Barber, A. E., & Svendsen, C. N. (2008). Human neural progenitor cells over-expressing IGF-1 protect dopamine neurons and restore function in a rat model of Parkinson’s disease. Experimental Neurology, 209(1), 213–223.

    PubMed  CAS  Google Scholar 

  86. Ebert, A. D., Barber, A. E., Heins, B. M., & Svendsen, C. N. (2010). Ex vivo delivery of GDNF maintains motor function and prevents neuronal loss in a transgenic mouse model of Huntington’s disease. Experimental Neurology, 224(1), 155–162.

    PubMed  CAS  Google Scholar 

  87. Suzuki, M., McHugh, J., Tork, C., Shelley, B., Klein, S. M., Aebischer, P., et al. (2007). GDNF secreting human neural progenitor cells protect dying motor neurons, but not their projection to muscle, in a rat model of familial ALS. PLoS ONE, 2(1), e689.

    PubMed  Google Scholar 

  88. Kusano, K., Enomoto, M., Hirai, T., Tsoulfas, P., Sotome, S., Shinomiya, K., et al. (2010). Transplanted neural progenitor cells expressing mutant NT3 promote myelination and partial hindlimb recovery in the chronic phase after spinal cord injury. Biochemical and Biophysical Research Communications, 393(4), 812–817.

    PubMed  CAS  Google Scholar 

  89. Park, K. I., Himes, B. T., Stieg, P. E., Tessler, A., Fischer, I., & Snyder, E. Y. (2006). Neural stem cells may be uniquely suited for combined gene therapy and cell replacement: Evidence from engraftment of Neurotrophin-3-expressing stem cells in hypoxic-ischemic brain injury. Experimental Neurology, 199(1), 179–190.

    PubMed  CAS  Google Scholar 

  90. Yang, S. Y., Liu, H., & Zhang, J. N. (2004). Gene therapy of rat malignant gliomas using neural stem cells expressing IL-12. DNA and Cell Biology, 23(6), 381–389.

    PubMed  CAS  Google Scholar 

  91. Yang, J., Jiang, Z., Fitzgerald, D. C., Ma, C., Yu, S., Li, H., et al. (2009). Adult neural stem cells expressing IL-10 confer potent immunomodulation and remyelination in experimental autoimmune encephalitis. Journal of Clinical Investigation, 119(12), 3678–3691.

    PubMed  CAS  Google Scholar 

  92. Bergwerf, I., De Vocht, N., Tambuyzer, B., Verschueren, J., Reekmans, K., Daans, J., et al. (2009). Reporter gene-expressing bone marrow-derived stromal cells are immune-tolerated following implantation in the central nervous system of syngeneic immunocompetent mice. BMC Biotechnology, 9, 1.

    PubMed  Google Scholar 

  93. Bergwerf, I., Tambuyzer, B., De Vocht, N., Reekmans, K., Praet, J., Daans, J., et al. Recognition of cellular implants by the brain’s innate immune system. Immunol Cell Biol, doi:10.1038/icb.2010.141.

  94. Hoehn, M., Himmelreich, U., Kruttwig, K., & Wiedermann, D. (2008). Molecular and cellular MR imaging: potentials and challenges for neurological applications. Journal of Magnetic Resonance Imaging, 27(5), 941–954.

    PubMed  Google Scholar 

  95. Shapiro, E. M., Gonzalez-Perez, O., Manuel Garcia-Verdugo, J., Alvarez-Buylla, A., & Koretsky, A. P. (2006). Magnetic resonance imaging of the migration of neuronal precursors generated in the adult rodent brain. Neuroimage, 32(3), 1150–1157.

    PubMed  Google Scholar 

  96. Neri, M., Maderna, C., Cavazzin, C., Deidda-Vigoriti, V., Politi, L. S., Scotti, G., et al. (2008). Efficient in vitro labeling of human neural precursor cells with superparamagnetic iron oxide particles: relevance for in vivo cell tracking. Stem Cells, 26(2), 505–516.

    PubMed  CAS  Google Scholar 

  97. Panizzo, R. A., Kyrtatos, P. G., Price, A. N., Gadian, D. G., Ferretti, P., & Lythgoe, M. F. (2009). In vivo magnetic resonance imaging of endogenous neuroblasts labelled with a ferumoxide-polycation complex. Neuroimage, 44(4), 1239–1246.

    PubMed  Google Scholar 

  98. Sumner, J. P., Shapiro, E. M., Maric, D., Conroy, R., & Koretsky, A. P. (2009). In vivo labeling of adult neural progenitors for MRI with micron sized particles of iron oxide: quantification of labeled cell phenotype. Neuroimage, 44(3), 671–678.

    PubMed  Google Scholar 

  99. Vreys, R., Vande Velde, G., Krylychkina, O., Vellema, M., Verhoye, M., Timmermans, J. P., et al. (2010). MRI visualization of endogenous neural progenitor cell migration along the RMS in the adult mouse brain: validation of various MPIO labeling strategies. Neuroimage, 49(3), 2094–2103.

    PubMed  Google Scholar 

  100. Guzman, R., Uchida, N., Bliss, T. M., He, D., Christopherson, K. K., Stellwagen, D., et al. (2007). Long-term monitoring of transplanted human neural stem cells in developmental and pathological contexts with MRI. Proceedings of the National Academy of Sciences of the United States of America, 104(24), 10211–10216.

    PubMed  CAS  Google Scholar 

  101. Guzman, R., Bliss, T., De Los Angeles, A., Moseley, M., Palmer, T., & Steinberg, G. (2008). Neural progenitor cells transplanted into the uninjured brain undergo targeted migration after stroke onset. Journal of Neuroscience Research, 86(4), 873–882.

    PubMed  CAS  Google Scholar 

  102. Cohen, M. E., Muja, N., Fainstein, N., Bulte, J. W., & Ben-Hur, T. (2010). Conserved fate and function of ferumoxides-labeled neural precursor cells in vitro and in vivo. Journal of Neuroscience Research, 88(5), 936–944.

    PubMed  CAS  Google Scholar 

  103. Daadi, M. M., Li, Z., Arac, A., Grueter, B. A., Sofilos, M., Malenka, R. C., et al. (2009). Molecular and magnetic resonance imaging of human embryonic stem cell-derived neural stem cell grafts in ischemic rat brain. Molecular Therapy, 17(7), 1282–1291.

    PubMed  CAS  Google Scholar 

  104. Bulte, J. W., Ben-Hur, T., Miller, B. R., Mizrachi-Kol, R., Einstein, O., Reinhartz, E., et al. (2003). MR microscopy of magnetically labeled neurospheres transplanted into the Lewis EAE rat brain. Magnetic Resonance in Medicine, 50(1), 201–205.

    PubMed  Google Scholar 

  105. Zhang, Z., Jiang, Q., Jiang, F., Ding, G., Zhang, R., Wang, L., et al. (2004). In vivo magnetic resonance imaging tracks adult neural progenitor cell targeting of brain tumor. Neuroimage, 23(1), 281–287.

    PubMed  CAS  Google Scholar 

  106. Watson, D. J., Walton, R. M., Magnitsky, S. G., Bulte, J. W., Poptani, H., & Wolfe, J. H. (2006). Structure-specific patterns of neural stem cell engraftment after transplantation in the adult mouse brain. Human Gene Therapy, 17(7), 693–704.

    PubMed  CAS  Google Scholar 

  107. Politi, L. S., Bacigaluppi, M., Brambilla, E., Cadioli, M., Falini, A., Comi, G., et al. (2007). Magnetic-resonance-based tracking and quantification of intravenously injected neural stem cell accumulation in the brains of mice with experimental multiple sclerosis. Stem Cells, 25(10), 2583–2592.

    PubMed  Google Scholar 

  108. Ben-Hur, T., van Heeswijk, R. B., Einstein, O., Aharonowiz, M., Xue, R., Frost, E. E., et al. (2007). Serial in vivo MR tracking of magnetically labeled neural spheres transplanted in chronic EAE mice. Magnetic Resonance in Medicine, 57(1), 164–171.

    PubMed  Google Scholar 

  109. Delcroix, G. J., Jacquart, M., Lemaire, L., Sindji, L., Franconi, F., Le Jeune, J. J., et al. (2009). Mesenchymal and neural stem cells labeled with HEDP-coated SPIO nanoparticles: in vitro characterization and migration potential in rat brain. Brain Research, 1255, 18–31.

    PubMed  CAS  Google Scholar 

  110. Flexman, J. A., Cross, D. J., Kim, Y., & Minoshima, S. (2007). Morphological and parametric estimation of fetal neural stem cell migratory capacity in the rat brain. Conf Proc IEEE Eng Med Biol Soc, 2007, 4464–4467.

    PubMed  CAS  Google Scholar 

  111. Lepore, A. C., Walczak, P., Rao, M. S., Fischer, I., & Bulte, J. W. (2006). MR imaging of lineage-restricted neural precursors following transplantation into the adult spinal cord. Experimental Neurology, 201(1), 49–59.

    PubMed  CAS  Google Scholar 

  112. Miyoshi, S., Flexman, J. A., Cross, D. J., Maravilla, K. R., Kim, Y., Anzai, Y., et al. (2005). Transfection of neuroprogenitor cells with iron nanoparticles for magnetic resonance imaging tracking: cell viability, differentiation, and intracellular localization. Molecular Imaging and Biology, 7(4), 286–295.

    PubMed  Google Scholar 

  113. Massoud, T. F., & Gambhir, S. S. (2003). Molecular imaging in living subjects: seeing fundamental biological processes in a new light. Genes & Development, 17(5), 545–580.

    CAS  Google Scholar 

  114. Sadikot, R. T., & Blackwell, T. S. (2005). Bioluminescence imaging. Proceedings of the American Thoracic Society, 2(6), 537–540.

    PubMed  CAS  Google Scholar 

  115. Bradbury, M. S., Panagiotakos, G., Chan, B. K., Tomishima, M., Zanzonico, P., Vider, J., et al. (2007). Optical bioluminescence imaging of human ES cell progeny in the rodent CNS. Journal of Neurochemistry, 102(6), 2029–2039.

    PubMed  CAS  Google Scholar 

  116. Okada, S., Ishii, K., Yamane, J., Iwanami, A., Ikegami, T., Katoh, H., et al. (2005). In vivo imaging of engrafted neural stem cells: its application in evaluating the optimal timing of transplantation for spinal cord injury. The FASEB Journal, 19(13), 1839–1841.

    CAS  Google Scholar 

  117. Sher, F., van Dam, G., Boddeke, E., & Copray, S. (2009). Bioluminescence imaging of Olig2-neural stem cells reveals improved engraftment in a demyelination mouse model. Stem Cells, 27(7), 1582–1591.

    PubMed  CAS  Google Scholar 

  118. Ogawa, D., Okada, Y., Nakamura, M., Kanemura, Y., Okano, H. J., Matsuzaki, Y., et al. (2009). Evaluation of human fetal neural stem/progenitor cells as a source for cell replacement therapy for neurological disorders: properties and tumorigenicity after long-term in vitro maintenance. Journal of Neuroscience Research, 87(2), 307–317.

    PubMed  CAS  Google Scholar 

  119. Pendharkar, A. V., Chua, J. Y., Andres, R. H., Wang, N., Gaeta, X., Wang, H., et al. (2010). Biodistribution of Neural Stem Cells After Intravascular Therapy for Hypoxic-Ischemia. Stroke, 41(9), 2064–2070.

    PubMed  Google Scholar 

  120. Wang, L., Martin, D. R., Baker, H. J., Zinn, K. R., Kappes, J. C., Ding, H., et al. (2007). Neural progenitor cell transplantation and imaging in a large animal model. Neuroscience Research, 59(3), 327–340.

    PubMed  CAS  Google Scholar 

  121. Chan, A., Magnus, T., & Gold, R. (2001). Phagocytosis of apoptotic inflammatory cells by microglia and modulation by different cytokines: mechanism for removal of apoptotic cells in the inflamed nervous system. Glia, 33(1), 87–95.

    PubMed  CAS  Google Scholar 

  122. Hausler, K. G., Prinz, M., Nolte, C., Weber, J. R., Schumann, R. R., Kettenmann, H., et al. (2002). Interferon-gamma differentially modulates the release of cytokines and chemokines in lipopolysaccharide- and pneumococcal cell wall-stimulated mouse microglia and macrophages. The European Journal of Neuroscience, 16(11), 2113–2122.

    PubMed  Google Scholar 

  123. Rock, R. B., Gekker, G., Hu, S., Sheng, W. S., Cheeran, M., Lokensgard, J. R., et al. (2004). Role of microglia in central nervous system infections. Clinical Microbiology Reviews, 17(4), 942–964. table of contents.

    PubMed  CAS  Google Scholar 

  124. Liu, Y. P., Lin, H. I., & Tzeng, S. F. (2005). Tumor necrosis factor-alpha and interleukin-18 modulate neuronal cell fate in embryonic neural progenitor culture. Brain Research, 1054(2), 152–158.

    PubMed  CAS  Google Scholar 

  125. Butovsky, O., Landa, G., Kunis, G., Ziv, Y., Avidan, H., Greenberg, N., et al. (2006). Induction and blockage of oligodendrogenesis by differently activated microglia in an animal model of multiple sclerosis. Journal of Clinical Investigation, 116(4), 905–915.

    PubMed  CAS  Google Scholar 

  126. Butovsky, O., Ziv, Y., Schwartz, A., Landa, G., Talpalar, A. E., Pluchino, S., et al. (2006). Microglia activated by IL-4 or IFN-gamma differentially induce neurogenesis and oligodendrogenesis from adult stem/progenitor cells. Molecular and Cellular Neurosciences, 31(1), 149–160.

    PubMed  CAS  Google Scholar 

  127. Walton, N. M., Sutter, B. M., Laywell, E. D., Levkoff, L. H., Kearns, S. M., Marshall, G. P., 2nd, et al. (2006). Microglia instruct subventricular zone neurogenesis. Glia, 54(8), 815–825.

    PubMed  Google Scholar 

  128. Mathieu, P., Piantanida, A. P., & Pitossi, F. (2010). Chronic expression of transforming growth factor-beta enhances adult neurogenesis. Neuroimmunomodulation, 17(3), 200–201.

    PubMed  CAS  Google Scholar 

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

    CAS  Google Scholar 

  130. Hoehn, B. D., Palmer, T. D., & Steinberg, G. K. (2005). Neurogenesis in rats after focal cerebral ischemia is enhanced by indomethacin. Stroke, 36(12), 2718–2724.

    PubMed  CAS  Google Scholar 

  131. Whitney, N. P., Eidem, T. M., Peng, H., Huang, Y., & Zheng, J. C. (2009). Inflammation mediates varying effects in neurogenesis: relevance to the pathogenesis of brain injury and neurodegenerative disorders. Journal of Neurochemistry, 108(6), 1343–1359.

    PubMed  CAS  Google Scholar 

  132. Pluchino, S., Muzio, L., Imitola, J., Deleidi, M., Alfaro-Cervello, C., Salani, G., et al. (2008). Persistent inflammation alters the function of the endogenous brain stem cell compartment. Brain, 131(Pt 10), 2564–2578.

    PubMed  Google Scholar 

  133. Thored, P., Heldmann, U., Gomes-Leal, W., Gisler, R., Darsalia, V., Taneera, J., et al. (2009). Long-term accumulation of microglia with proneurogenic phenotype concomitant with persistent neurogenesis in adult subventricular zone after stroke. Glia, 57(8), 835–849.

    PubMed  Google Scholar 

  134. Napoli, I., & Neumann, H. (2010). Protective effects of microglia in multiple sclerosis. Experimental Neurology, 255(1), 24–28.

    Google Scholar 

  135. Song, H., Stevens, C. F., & Gage, F. H. (2002). Astroglia induce neurogenesis from adult neural stem cells. Nature, 417(6884), 39–44.

    PubMed  CAS  Google Scholar 

  136. Gaughwin, P. M., Caldwell, M. A., Anderson, J. M., Schwiening, C. J., Fawcett, J. W., Compston, D. A., et al. (2006). Astrocytes promote neurogenesis from oligodendrocyte precursor cells. The European Journal of Neuroscience, 23(4), 945–956.

    PubMed  CAS  Google Scholar 

  137. Kernie, S. G., Erwin, T. M., & Parada, L. F. (2001). Brain remodeling due to neuronal and astrocytic proliferation after controlled cortical injury in mice. Journal of Neuroscience Research, 66(3), 317–326.

    PubMed  CAS  Google Scholar 

  138. Polikov, V. S., Hong, J. S., & Reichert, W. M. (2010). Soluble factor effects on glial cell reactivity at the surface of gel-coated microwires. Journal of Neuroscience Methods, 190(2), 180–187.

    PubMed  CAS  Google Scholar 

  139. Itoh, T., Satou, T., Nishida, S., Hashimoto, S., & Ito, H. (2007). Immature and mature neurons coexist among glial scars after rat traumatic brain injury. Neurological Research, 29(7), 734–742.

    PubMed  CAS  Google Scholar 

  140. Popovich, P. G., Wei, P., & Stokes, B. T. (1997). Cellular inflammatory response after spinal cord injury in Sprague-Dawley and Lewis rats. The Journal of Comparative Neurology, 377(3), 443–464.

    PubMed  CAS  Google Scholar 

  141. Fleming, J. C., Norenberg, M. D., Ramsay, D. A., Dekaban, G. A., Marcillo, A. E., Saenz, A. D., et al. (2006). The cellular inflammatory response in human spinal cords after injury. Brain, 129(Pt 12), 3249–3269.

    PubMed  Google Scholar 

  142. White, R. E., McTigue, D. M., & Jakeman, L. B. (2010). Regional heterogeneity in astrocyte responses following contusive spinal cord injury in mice. The Journal of Comparative Neurology, 518(8), 1370–1390.

    PubMed  Google Scholar 

  143. Fitch, M. T., & Silver, J. (2008). CNS injury, glial scars, and inflammation: Inhibitory extracellular matrices and regeneration failure. Experimental Neurology, 209(2), 294–301.

    PubMed  CAS  Google Scholar 

  144. Ronsyn, M. W., Berneman, Z. N., Van Tendeloo, V. F., Jorens, P. G., & Ponsaerts, P. (2008). Can cell therapy heal a spinal cord injury? Spinal Cord, 46(8), 532–539.

    PubMed  CAS  Google Scholar 

  145. Cao, Q. L., Zhang, Y. P., Howard, R. M., Walters, W. M., Tsoulfas, P., & Whittemore, S. R. (2001). Pluripotent stem cells engrafted into the normal or lesioned adult rat spinal cord are restricted to a glial lineage. Experimental Neurology, 167(1), 48–58.

    PubMed  CAS  Google Scholar 

  146. Pallini, R., Vitiani, L. R., Bez, A., Casalbore, P., Facchiano, F., Di Giorgi Gerevini, V., et al. (2005). Homologous transplantation of neural stem cells to the injured spinal cord of mice. Neurosurgery, 57(5), 1014–1025. discussion 1014–25.

    PubMed  Google Scholar 

  147. Karimi-Abdolrezaee, S., Eftekharpour, E., Wang, J., Schut, D., & Fehlings, M. G. (2010). Synergistic effects of transplanted adult neural stem/progenitor cells, chondroitinase, and growth factors promote functional repair and plasticity of the chronically injured spinal cord. The Journal of Neuroscience, 30(5), 1657–1676.

    PubMed  CAS  Google Scholar 

  148. Zhang, S. C., Goetz, B. D., & Duncan, I. D. (2003). Suppression of activated microglia promotes survival and function of transplanted oligodendroglial progenitors. Glia, 41(2), 191–198.

    PubMed  Google Scholar 

  149. Pineau, I., & Lacroix, S. (2007). Proinflammatory cytokine synthesis in the injured mouse spinal cord: multiphasic expression pattern and identification of the cell types involved. The Journal of Comparative Neurology, 500(2), 267–285.

    PubMed  CAS  Google Scholar 

  150. Okano, H., Ogawa, Y., Nakamura, M., Kaneko, S., Iwanami, A., & Toyama, Y. (2003). Transplantation of neural stem cells into the spinal cord after injury. Seminars in Cell & Developmental Biology, 14(3), 191–198.

    CAS  Google Scholar 

  151. Ishii, K., Nakamura, M., Dai, H., Finn, T. P., Okano, H., Toyama, Y., et al. (2006). Neutralization of ciliary neurotrophic factor reduces astrocyte production from transplanted neural stem cells and promotes regeneration of corticospinal tract fibers in spinal cord injury. Journal of Neuroscience Research, 84(8), 1669–1681.

    PubMed  CAS  Google Scholar 

  152. Bonner, J. F., Blesch, A., Neuhuber, B., & Fischer, I. (2010). Promoting directional axon growth from neural progenitors grafted into the injured spinal cord. Journal of Neuroscience Research, 88(6), 1182–1192.

    PubMed  CAS  Google Scholar 

  153. Ziv, Y., Avidan, H., Pluchino, S., Martino, G., & Schwartz, M. (2006). Synergy between immune cells and adult neural stem/progenitor cells promotes functional recovery from spinal cord injury. Proceedings of the National Academy of Sciences of the United States of America, 103(35), 13174–13179.

    PubMed  CAS  Google Scholar 

  154. Pennell, N. A., & Streit, W. J. (1997). Colonization of neural allografts by host microglial cells: relationship to graft neovascularization. Cell Transplantation, 6(3), 221–230.

    PubMed  CAS  Google Scholar 

  155. Muraoka, K., Shingo, T., Yasuhara, T., Kameda, M., Yuan, W., Hayase, H., et al. (2006). The high integration and differentiation potential of autologous neural stem cell transplantation compared with allogeneic transplantation in adult rat hippocampus. Experimental Neurology, 199(2), 311–327.

    PubMed  CAS  Google Scholar 

  156. Ideguchi, M., Shinoyama, M., Gomi, M., Hayashi, H., Hashimoto, N., & Takahashi, J. (2008). Immune or inflammatory response by the host brain suppresses neuronal differentiation of transplanted ES cell-derived neural precursor cells. Journal of Neuroscience Research, 86(9), 1936–1943.

    PubMed  CAS  Google Scholar 

  157. Nakanishi, M., Niidome, T., Matsuda, S., Akaike, A., Kihara, T., & Sugimoto, H. (2007). Microglia-derived interleukin-6 and leukaemia inhibitory factor promote astrocytic differentiation of neural stem/progenitor cells. The European Journal of Neuroscience, 25(3), 649–658.

    PubMed  Google Scholar 

  158. Aarum, J., Sandberg, K., Haeberlein, S. L., & Persson, M. A. (2003). Migration and differentiation of neural precursor cells can be directed by microglia. Proceedings of the National Academy of Sciences of the United States of America, 100(26), 15983–15988.

    PubMed  CAS  Google Scholar 

  159. Faijerson, J., Tinsley, R. B., Aprico, K., Thorsell, A., Nodin, C., Nilsson, M., et al. (2006). Reactive astrogliosis induces astrocytic differentiation of adult neural stem/progenitor cells in vitro. Journal of Neuroscience Research, 84(7), 1415–1424.

    PubMed  CAS  Google Scholar 

  160. Johann, V., Schiefer, J., Sass, C., Mey, J., Brook, G., Kruttgen, A., et al. (2007). Time of transplantation and cell preparation determine neural stem cell survival in a mouse model of Huntington’s disease. Experimental Brain Research, 177(4), 458–470.

    Google Scholar 

  161. Makri, G., Lavdas, A. A., Katsimpardi, L., Charneau, P., Thomaidou, D., & Matsas, R. (2010). Transplantation of embryonic neural stem/precursor cells overexpressing BM88/Cend1 enhances the generation of neuronal cells in the injured mouse cortex. Stem Cells, 28(1), 127–139.

    PubMed  CAS  Google Scholar 

  162. Bernreuther, C., Dihne, M., Johann, V., Schiefer, J., Cui, Y., Hargus, G., et al. (2006). Neural cell adhesion molecule L1-transfected embryonic stem cells promote functional recovery after excitotoxic lesion of the mouse striatum. The Journal of Neuroscience, 26(45), 11532–11539.

    PubMed  CAS  Google Scholar 

  163. Cui, Y. F., Hargus, G., Xu, J. C., Schmid, J. S., Shen, Y. Q., Glatzel, M., et al. (2010). Embryonic stem cell-derived L1 overexpressing neural aggregates enhance recovery in Parkinsonian mice. Brain, 133(Pt 1), 189–204.

    PubMed  Google Scholar 

  164. Tate, M. C., Shear, D. A., Hoffman, S. W., Stein, D. G., Archer, D. R., & LaPlaca, M. C. (2002). Fibronectin promotes survival and migration of primary neural stem cells transplanted into the traumatically injured mouse brain. Cell Transplantation, 11(3), 283–295.

    PubMed  Google Scholar 

  165. Zhong, J., Chan, A., Morad, L., Kornblum, H. I., Fan, G., & Carmichael, S. T. (2010). Hydrogel Matrix to Support Stem Cell Survival After Brain Transplantation in Stroke. Neurorehabilitation and Neural Repair, 24(7), 636–644.

    PubMed  Google Scholar 

  166. Uemura, M., Refaat, M. M., Shinoyama, M., Hayashi, H., Hashimoto, N., & Takahashi, J. (2010). Matrigel supports survival and neuronal differentiation of grafted embryonic stem cell-derived neural precursor cells. Journal of Neuroscience Research, 88(3), 542–551.

    PubMed  CAS  Google Scholar 

  167. Mahoney, M. J., & Anseth, K. S. (2007). Contrasting effects of collagen and bFGF-2 on neural cell function in degradable synthetic PEG hydrogels. Journal of Biomedical Materials Research. Part A, 81(2), 269–278.

    PubMed  Google Scholar 

  168. Rubio, F. J., Kokaia, Z., del Arco, A., Garcia-Simon, M. I., Snyder, E. Y., Lindvall, O., et al. (1999). BDNF gene transfer to the mammalian brain using CNS-derived neural precursors. Gene Therapy, 6(11), 1851–1866.

    PubMed  CAS  Google Scholar 

  169. Widera, D., Holtkamp, W., Entschladen, F., Niggemann, B., Zanker, K., Kaltschmidt, B., et al. (2004). MCP-1 induces migration of adult neural stem cells. European Journal of Cell Biology, 83(8), 381–387.

    PubMed  CAS  Google Scholar 

  170. Belmadani, A., Tran, P. B., Ren, D., & Miller, R. J. (2006). Chemokines regulate the migration of neural progenitors to sites of neuroinflammation. The Journal of Neuroscience, 26(12), 3182–3191.

    PubMed  CAS  Google Scholar 

  171. Dziembowska, M., Tham, T. N., Lau, P., Vitry, S., Lazarini, F., & Dubois-Dalcq, M. (2005). A role for CXCR4 signaling in survival and migration of neural and oligodendrocyte precursors. Glia, 50(3), 258–269.

    PubMed  CAS  Google Scholar 

  172. Imitola, J., Raddassi, K., Park, K. I., Mueller, F. J., Nieto, M., Teng, Y. D., et al. (2004). Directed migration of neural stem cells to sites of CNS injury by the stromal cell-derived factor 1alpha/CXC chemokine receptor 4 pathway. Proceedings of the National Academy of Sciences of the United States of America, 101(52), 18117–18122.

    PubMed  CAS  Google Scholar 

  173. van der Meulen, A. A., Biber, K., Lukovac, S., Balasubramaniyan, V., den Dunnen, W. F., Boddeke, H. W., et al. (2009). The role of CXC chemokine ligand (CXCL)12-CXC chemokine receptor (CXCR)4 signalling in the migration of neural stem cells towards a brain tumour. Neuropathology and Applied Neurobiology, 35(6), 579–591.

    PubMed  Google Scholar 

  174. Carbajal, K. S., Schaumburg, C., Strieter, R., Kane, J., & Lane, T. E. (2010). Migration of engrafted neural stem cells is mediated by CXCL12 signaling through CXCR4 in a viral model of multiple sclerosis. Proceedings of the National Academy of Sciences of the United States of America, 107(24), 11068–11073.

    PubMed  CAS  Google Scholar 

  175. Zhang, R., Zhang, Z., Wang, L., Wang, Y., Gousev, A., Zhang, L., et al. (2004). Activated neural stem cells contribute to stroke-induced neurogenesis and neuroblast migration toward the infarct boundary in adult rats. Journal of Cerebral Blood Flow and Metabolism, 24(4), 441–448.

    PubMed  Google Scholar 

  176. Zhang, R. L., LeTourneau, Y., Gregg, S. R., Wang, Y., Toh, Y., Robin, A. M., et al. (2007). Neuroblast division during migration toward the ischemic striatum: a study of dynamic migratory and proliferative characteristics of neuroblasts from the subventricular zone. The Journal of Neuroscience, 27(12), 3157–3162.

    PubMed  CAS  Google Scholar 

  177. Zhu, W. Z., Li, X., Qi, J. P., Tang, Z. P., Wang, W., Wei, L., et al. (2008). Experimental study of cell migration and functional differentiation of transplanted neural stem cells co-labeled with superparamagnetic iron oxide and BrdU in an ischemic rat model. Biomedical and Environmental Sciences, 21(5), 420–424.

    PubMed  Google Scholar 

  178. Ben-Hur, T., Einstein, O., Mizrachi-Kol, R., Ben-Menachem, O., Reinhartz, E., Karussis, D., et al. (2003). Transplanted multipotential neural precursor cells migrate into the inflamed white matter in response to experimental autoimmune encephalomyelitis. Glia, 41(1), 73–80.

    PubMed  Google Scholar 

  179. Jenny, B., Kanemitsu, M., Tsupykov, O., Potter, G., Salmon, P., Zgraggen, E., et al. (2009). Fibroblast growth factor-2 overexpression in transplanted neural progenitors promotes perivascular cluster formation with a neurogenic potential. Stem Cells, 27(6), 1309–1317.

    PubMed  CAS  Google Scholar 

  180. Freed, C. R., Greene, P. E., Breeze, R. E., Tsai, W. Y., DuMouchel, W., Kao, R., et al. (2001). Transplantation of embryonic dopamine neurons for severe Parkinson’s disease. The New England Journal of Medicine, 344(10), 710–719.

    PubMed  CAS  Google Scholar 

  181. Piccini, P., Brooks, D. J., Bjorklund, A., Gunn, R. N., Grasby, P. M., Rimoldi, O., et al. (1999). Dopamine release from nigral transplants visualized in vivo in a Parkinson’s patient. Nature Neuroscience, 2(12), 1137–1140.

    PubMed  CAS  Google Scholar 

  182. Olanow, C. W., Goetz, C. G., Kordower, J. H., Stoessl, A. J., Sossi, V., Brin, M. F., et al. (2003). A double-blind controlled trial of bilateral fetal nigral transplantation in Parkinson’s disease. Annals of Neurology, 54(3), 403–414.

    PubMed  Google Scholar 

  183. Sanchez-Pernaute, R., Studer, L., Bankiewicz, K. S., Major, E. O., & McKay, R. D. (2001). In vitro generation and transplantation of precursor-derived human dopamine neurons. Journal of Neuroscience Research, 65(4), 284–288.

    PubMed  CAS  Google Scholar 

  184. Mukhida, K., Hong, M., Miles, G. B., Phillips, T., Baghbaderani, B. A., McLeod, M., et al. (2008). A multitarget basal ganglia dopaminergic and GABAergic transplantation strategy enhances behavioural recovery in parkinsonian rats. Brain, 131(Pt 8), 2106–2126.

    PubMed  CAS  Google Scholar 

  185. Klein, S. M., Behrstock, S., McHugh, J., Hoffmann, K., Wallace, K., Suzuki, M., et al. (2005). GDNF delivery using human neural progenitor cells in a rat model of ALS. Human Gene Therapy, 16(4), 509–521.

    PubMed  CAS  Google Scholar 

  186. Hwang, D. H., Lee, H. J., Park, I. H., Seok, J. I., Kim, B. G., Joo, I. S., et al. (2009). Intrathecal transplantation of human neural stem cells overexpressing VEGF provide behavioral improvement, disease onset delay and survival extension in transgenic ALS mice. Gene Therapy, 16(10), 1234–1244.

    PubMed  CAS  Google Scholar 

  187. Park, S., Kim, H. T., Yun, S., Kim, I. S., Lee, J., Lee, I. S., et al. (2009). Growth factor-expressing human neural progenitor cell grafts protect motor neurons but do not ameliorate motor performance and survival in ALS mice. Experimental & Molecular Medicine, 41(7), 487–500.

    CAS  Google Scholar 

  188. Ryu, J. K., Cho, T., Wang, Y. T., & McLarnon, J. G. (2009). Neural progenitor cells attenuate inflammatory reactivity and neuronal loss in an animal model of inflamed AD brain. Journal of Neuroinflammation, 6, 39.

    PubMed  Google Scholar 

  189. Aubry, L., Bugi, A., Lefort, N., Rousseau, F., Peschanski, M., & Perrier, A. L. (2008). Striatal progenitors derived from human ES cells mature into DARPP32 neurons in vitro and in quinolinic acid-lesioned rats. Proceedings of the National Academy of Sciences of the United States of America, 105(43), 16707–16712.

    PubMed  CAS  Google Scholar 

  190. Amariglio, N., Hirshberg, A., Scheithauer, B. W., Cohen, Y., Loewenthal, R., Trakhtenbrot, L., et al. (2009). Donor-derived brain tumor following neural stem cell transplantation in an ataxia telangiectasia patient. PLoS Medicine, 6(2), e1000029.

    PubMed  Google Scholar 

  191. White, P. M., Morrison, S. J., Orimoto, K., Kubu, C. J., Verdi, J. M., & Anderson, D. J. (2001). Neural crest stem cells undergo cell-intrinsic developmental changes in sensitivity to instructive differentiation signals. Neuron, 29(1), 57–71.

    PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We acknowledge helpful assistance from Frank Rylant and Ingrid Bernaert (Laboratory of Pathology) with histological techniques. This work was supported by research grant G.0132.07 (granted to ZB) and 1.5.021.09.N.00 (granted to PP) of the Fund for Scientific Research-Flanders (FWO-Vlaanderen, Belgium), by SBO research grant IWT-60838: BRAINSTIM of the Flemish Institute for Science and Technology (granted to ZB and AVDL), in part by a Methusalem research grant from the Flemish government (granted to ZB), in part by EC-FP6-NoE DiMI (LSHB-CT-2005-512146), EC-FP6-NoE EMIL (LSHC-CT-2004-503569), and by the Inter University Attraction Poles IUAP-NIMI-P6/38 (granted to AVDL). Peter Ponsaerts is a post-doctoral fellow of the FWO-Vlaanderen.

Disclosures

The authors indicate no potential conflicts of interest.

Author information

Authors and Affiliations

  1. Laboratory of Experimental Hematology, Vaccine and Infectious Disease Institute (Vaxinfectio), University of Antwerp, Antwerp, Belgium

    Kristien Reekmans, Jelle Praet, Jasmijn Daans, Zwi N. Berneman & Peter Ponsaerts

  2. Laboratory for Neurobiology & Gene Therapy, Katholieke Universiteit Leuven, Leuven, Belgium

    Veerle Reumers

  3. Laboratory of Pathology, University of Antwerp, Antwerp, Belgium

    Patrick Pauwels

  4. BioImaging Laboratory, University of Antwerp, Antwerp, Belgium

    Jelle Praet & Annemie Van der Linden

  5. Laboratory of Experimental Hematology, Vaccine and Infectious Disease Institute (Vaxinfectio), University of Antwerp, Campus Drie Eiken (CDE-T1.17), Universiteitsplein 1, 2610, Antwerp, Wilrijk, Belgium

    Peter Ponsaerts

Authors
  1. Kristien Reekmans
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jelle Praet
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jasmijn Daans
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Veerle Reumers
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Patrick Pauwels
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Annemie Van der Linden
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Zwi N. Berneman
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Peter Ponsaerts
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Peter Ponsaerts.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Reekmans, K., Praet, J., Daans, J. et al. Current Challenges for the Advancement of Neural Stem Cell Biology and Transplantation Research. Stem Cell Rev and Rep 8, 262–278 (2012). https://doi.org/10.1007/s12015-011-9266-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12015-011-9266-2

Keywords

Search

Navigation