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Repair of neural pathways by olfactory ensheathing cells

Abstract

Damage to nerve fibre pathways results in a devastating loss of function, due to the disconnection of nerve fibres from their targets. However, some recovery does occur and this has been correlated with the formation of new (albeit abnormal) connections. The view that an untapped growth potential resides in the adult CNS has led to various attempts to stimulate the repair of disconnectional injuries. A key factor in the failure of axonal regeneration in the CNS after injury is the loss of the aligned glial pathways that nerve fibres require for their elongation. Transplantation of cultured adult olfactory ensheathing cells into lesions is being investigated as a procedure to re-establish glial pathways permissive for the regeneration of severed axons.

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Figure 1: Sprouting at the cut ends of axons in the CNS.
Figure 2: Asymmetrical coating of astrocytic surfaces.
Figure 3: The pathway hypothesis of repair.
Figure 4: Olfactory ensheathing cell processes enclosing olfactory axons.
Figure 5: Closure of pathway by astrocytic scar and re-opening by OECs.

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References

  1. Amadio, J. P. & Walsh, C. A. Brain evolution and uniqueness in the human genome. Cell 126, 1033–1035 (2006).

    CAS  PubMed  Google Scholar 

  2. Pollard, K. S. et al. An RNA gene expressed during cortical development evolved rapidly in humans. Nature 443, 167–172 (2006).

    CAS  PubMed  Google Scholar 

  3. Briggman, K. L. & Denk, W. Towards neural circuit reconstruction with volume electron microscopy techniques. Curr. Opin. Neurobiol. 16, 562–570 (2006).

    CAS  PubMed  Google Scholar 

  4. Filbin, M. T. Myelin-associated inhibitors of axonal regeneration in the adult mammalian CNS. Nature Rev. Neurosci. 4, 703–713 (2003).

    CAS  Google Scholar 

  5. Yiu, G. & He, Z. Glial inhibition of CNS axon regeneration. Nature Rev. Neurosci. 7, 617–627 (2006).

    CAS  Google Scholar 

  6. Thuret, S., Moon, L. D. & Gage, F. H. Therapeutic interventions after spinal cord injury. Nature Rev. Neurosci. 7, 628–643 (2006).

    CAS  Google Scholar 

  7. Schwab, M. E. Nogo and axon regeneration. Curr. Opin. Neurobiol. 14, 118–124 (2004).

    CAS  PubMed  Google Scholar 

  8. Raisman, G. Neuronal plasticity in the septal nuclei of the adult rat. Brain Res. 14, 25–48 (1969).

    CAS  PubMed  Google Scholar 

  9. Bareyre, F. M. et al. The injured spinal cord spontaneously forms a new intraspinal circuit in adult rats. Nature Neurosci. 7, 269–277 (2004).

    CAS  PubMed  Google Scholar 

  10. Turner, J. P., Sauvé, Y., Varela-Rodriguez, C., Lund, R. D. & Salt, T. E. Recruitment of local excitatory circuits in the superior colliculus following deafferentation and the regeneration of retinocollicular inputs. Eur. J Neurosci. 22, 1643–1654 (2005).

    CAS  PubMed  Google Scholar 

  11. Tan, M. M. & Harvey, A. R. A comparison of postlesion growth of retinotectal and corticotectal axons after superior colliculus transections in neonatal rats. J. Comp. Neurol. 386, 681–699 (1997).

    CAS  PubMed  Google Scholar 

  12. Ramón y Cajal, S. Degeneration and Regeneration of the Nervous System (Hafner, New York, 1928).

    Google Scholar 

  13. Dinocourt, C., Gallagher, S. E. & Thompson, S. M. Injury-induced axonal sprouting in the hippocampus is initiated by activation of trkB receptors. Eur. J. Neurosci. 24, 1857–1866 (2006).

    PubMed  Google Scholar 

  14. Kerschensteiner, M., Schwab, M. E., Lichtman, J. W. & Misgeld, T. In vivo imaging of axonal degeneration and regeneration in the injured spinal cord. Nature Med. 11, 572–577 (2005).

    CAS  PubMed  Google Scholar 

  15. Bareyre, F. M., Kerschensteiner, M., Misgeld, T. & Sanes, J. R. Transgenic labeling of the corticospinal tract for monitoring axonal responses to spinal cord injury. Nature Med. 11, 1355–1360 (2005).

    CAS  PubMed  Google Scholar 

  16. Fernandes, K. J. L., Fan, D. P., Tsui, B. J., Cassar, S. L. & Tetzlaff, W. Influence of the axotomy to cell body distance in rat rubrospinal and spinal motoneurons: differential regulation of GAP-43, tubulins, and neurofilament-M. J. Comp. Neurol. 414, 495–510 (1999).

    CAS  PubMed  Google Scholar 

  17. Li, Y. & Raisman, G. Sprouts from cut corticospinal axons persist in the presence of astrocytic scarring in long-term lesions of the adult rat spinal cord. Exp. Neurol. 134, 102–111 (1995).

    CAS  PubMed  Google Scholar 

  18. Kwon, B. K. et al. Survival and regeneration of rubrospinal neurons 1 year after spinal cord injury. Proc. Natl Acad. Sci. USA 99, 3246–3251 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. O'Leary, D. D. M. & Wilkinson, D. G. Eph receptors and ephrins in neural development. Curr. Opin. Neurobiol. 9, 65–73 (1999).

    CAS  PubMed  Google Scholar 

  20. Charron, F. & Tessier-Lavigne, M. Novel brain wiring functions for classical morphogens: a role as graded positional cues in axon guidance. Development 132, 2251–2262 (2005).

    CAS  PubMed  Google Scholar 

  21. Harel, N. Y. & Strittmatter, S. M. Can regenerating axons recapitulate developmental guidance during recovery from spinal cord injury? Nature Rev. Neurosci. 7, 603–616 (2006).

    CAS  Google Scholar 

  22. Huber, A. B., Kolodkin, A. L., Ginty, D. D. & Cloutier, J. F. Signaling at the growth cone: ligand–receptor complexes and the control of axon growth and guidance. Annu. Rev. Neurosci. 26, 509–563 (2003).

    CAS  PubMed  Google Scholar 

  23. Rodger, J. et al. Expression of ephrin-A2 in the superior colliculus and EphA5 in the retina following optic nerve section in adult rat. Eur. J. Neurosci. 14, 1929–1936 (2001).

    CAS  PubMed  Google Scholar 

  24. O'Leary, D. D. M., Ruff, N. L. & Dyck, R. H. Development, critical period plasticity, and adult reorganizations of mammalian somatosensory systems. Curr. Opin. Neurobiol. 4, 535–544 (1994).

    CAS  PubMed  Google Scholar 

  25. Stanfield, B. B., Nahin, B. R. & O'Leary, D. D. M. A transient postmamillary component of the rat fornix during development: implications for interspecific differences in mature axonal projections. J. Neurosci. 7, 3350–3361 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Placzek, M., Tessier-Lavigne, M., Jessell, T. & Dodd, J. Orientation of commissural axons in vivo in response to a floor plate-derived chemoattractant. Development 110, 19–30 (1990).

    CAS  PubMed  Google Scholar 

  27. Del, R. T. & Feller, M. B. Early retinal activity and visual circuit development. Neuron 52, 221–222 (2006).

    Google Scholar 

  28. Hooks, B. M. & Chen, C. Distinct roles for spontaneous and visual activity in remodeling of the retinogeniculate synapse. Neuron 52, 281–291 (2006).

    CAS  PubMed  Google Scholar 

  29. Collingridge, G. L. & Bliss, T. V. Memories of NMDA receptors and LTP. Trends Neurosci. 18, 54–56 (1995).

    CAS  PubMed  Google Scholar 

  30. Wu, C. W. & Kaas, J. H. Reorganization in primary motor cortex of primates with long-standing therapeutic amputations. J. Neurosci. 19, 7679–7697 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Polley, D. B., Steinberg, E. E. & Merzenich, M. M. Perceptual learning directs auditory cortical map reorganization through top-down influences. J. Neurosci. 26, 4970–4982 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Callaway, E. M. Should I stay or should I go? Presynaptic boutons in the adult cortex still haven't made up their minds. Neuron 49, 780–783 (2006).

    CAS  PubMed  Google Scholar 

  33. Pasterkamp, R. J. & Verhaagen, J. Semaphorins in axon regeneration: developmental guidance molecules gone wrong? Philos. Trans. R. Soc. Lond. B Biol. Sci. 361, 1499–1511 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Li, D., Field, P. M. & Raisman, G. Failure of axon regeneration in postnatal rat entorhino-hippocampal slice co-culture is due to maturation of the axon, not that of the pathway or target. Eur. J. Neurosci. 7, 1164–1171 (1995).

    CAS  PubMed  Google Scholar 

  35. Blackmore, M. & Letourneau, P. C. Changes within maturing neurons limit axonal regeneration in the developing spinal cord. J. Neurobiol. 66, 348–360 (2006).

    CAS  PubMed  Google Scholar 

  36. Silver, J. & Miller, J. H. Regeneration beyond the glial scar. Nature Rev. Neurosci. 5, 146–156 (2004).

    CAS  Google Scholar 

  37. Fernandes, K. J., Fan, D. P., Tsui, B. J., Cassar, S. L. & Tetzlaff, W. Influence of the axotomy to cell body distance in rat rubrospinal and spinal motoneurons: differential regulation of GAP-43, tubulins, and neurofilament-M. J. Comp. Neurol. 414, 495–510 (1999).

    CAS  PubMed  Google Scholar 

  38. Shatz, C. J. Form from function in visual system development. Harvey Lect. 93, 17–34 (1997).

    PubMed  Google Scholar 

  39. Schwab, M. E. & Bartholdi, D. Degeneration and regeneration of axons in the lesioned spinal cord. Physiol. Rev. 76, 319–370 (1996).

    CAS  PubMed  Google Scholar 

  40. Niclou, S. P., Franssen, E. H., Ehlert, E. M., Taniguchi, M. & Verhaagen, J. Meningeal cell-derived semaphorin 3A inhibits neurite outgrowth. Mol. Cell. Neurosci. 24, 902–912 (2003).

    CAS  PubMed  Google Scholar 

  41. Rossi, F., Jankovski, A. & Sotelo, C. Differential regenerative response of Purkinje cell and inferior olivary axons confronted with embryonic grafts: environmental cues versus intrinsic neuronal determinants. J. Comp. Neurol. 359, 663–677 (1995).

    CAS  PubMed  Google Scholar 

  42. Easter, S. S. Jr, Ross, L. S. & Frankfurter, A. Initial tract formation in the mouse brain. J. Neurosci. 13, 285–299 (1993).

    PubMed  PubMed Central  Google Scholar 

  43. Sobkowicz, H. M., Waclawik, A. J. & August, B. K. The astroglial cell that guides nerve fibers from growth cone to synapse in organotypic cultures of the fetal mouse spinal cord. Synapse 59, 183–200 (2006).

    CAS  PubMed  Google Scholar 

  44. Hatten, M. E. New directions in neuronal migration. Science 297, 1660–1663 (2002).

    CAS  PubMed  Google Scholar 

  45. Suzuki, M. & Raisman, G. Multifocal pattern of postnatal development of the macroglial framework of the rat fimbria. Glia 12, 294–308 (1994).

    CAS  PubMed  Google Scholar 

  46. Suzuki, M. & Raisman, G. The glial framework of central white matter tracts: segmented rows of contiguous interfascicular oligodendrocytes and solitary astrocytes give rise to a continuous meshwork of transverse and longitudinal processes in the adult rat fimbria. Glia 6, 222–235 (1992).

    CAS  PubMed  Google Scholar 

  47. Barry, D. & McDermott, K. Differentiation of radial glia from radial precursor cells and transformation into astrocytes in the developing rat spinal cord. Glia 50, 187–197 (2005).

    PubMed  Google Scholar 

  48. Wanner, I. B. et al. Invariant mantling of growth cones by Schwann cell precursors characterize growing peripheral nerve fronts. Glia 54, 424–438 (2006).

    PubMed  Google Scholar 

  49. Walsh, F. S. & Doherty, P. Neural cell adhesion molecules of the immunoglobulin superfamily: role in axon growth and guidance. Annu. Rev. Cell Dev. Biol. 13, 425–456 (1997).

    CAS  PubMed  Google Scholar 

  50. Lemons, M. L. & Condic, M. L. Combined integrin activation and intracellular cAMP cause Rho GTPase dependent growth cone collapse on laminin-1. Exp. Neurol. 202, 324–335 (2006).

    CAS  PubMed  Google Scholar 

  51. Janzer, R. C. & Raff, M. C. Astrocytes induce blood–brain barrier properties in endothelial cells. Nature 325, 253–257 (1987).

    CAS  PubMed  Google Scholar 

  52. Reier, P. J., Stensaas, L. J. & Guth, L. in Spinal Cord Reconstruction (eds Kao, C. C., Bunge, R. P. & Reier, P. J.) 163–195 (Raven, New York, 1983).

    Google Scholar 

  53. Faulkner, J. R. et al. Reactive astrocytes protect tissue and preserve function after spinal cord injury. J. Neurosci. 24, 2143–2155 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Li, Y. & Raisman, G. Long axon growth from embryonic neurons transplanted into myelinated tracts of the adult rat spinal cord. Brain Res. 629, 115–127 (1993).

    CAS  PubMed  Google Scholar 

  55. Davies, S. J. A., Field, P. M. & Raisman, G. Long interfascicular axon growth from embryonic neurons transplanted into adult myelinated tracts. J. Neurosci. 14, 1596–1612 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Cowan, W. M. Viktor Hamburger and Rita Levi-Montalcini: the path to the discovery of nerve growth factor. Annu. Rev. Neurosci. 24, 551–600 (2001).

    CAS  PubMed  Google Scholar 

  57. Vidal-Sanz, M., Bray, G. M., Villegas-Pérez, M. P., Thanos, S. & Aguayo, A. J. Axonal regeneration and synapse formation in the superior colliculus by retinal ganglion cells in the adult rat. J. Neurosci. 7, 2894–2909 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Paíno, C. L. & Bunge, M. B. Induction of axon growth into Schwann cell implants into lesioned adult rat spinal cord. Exp. Neurol. 114, 254–257 (1991).

    PubMed  Google Scholar 

  59. Carter, D. A., Bray, G. M. & Aguayo, A. J. Regenerated retinal ganglion cell axons can form well-differentiated synapses in the superior colliculus of adult hamsters. J. Neurosci. 9, 4042–4050 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Li, Y., Carlstedt, T., Berthold, C. -H. & Raisman, G. Interaction of transplanted olfactory-ensheathing cells and host astrocytic processes provides a bridge for axons to regenerate across the dorsal root entry zone. Exp. Neurol. 188, 300–308 (2004).

    PubMed  Google Scholar 

  61. Berry, M., Rees, L., Hall, S., Yiu, P. & Sievers, J. Optic axons regenerate into sciatic nerve isografts only in the presence of Schwann cells. Brain Res. Bull. 20, 223–231 (1988).

    CAS  PubMed  Google Scholar 

  62. Fouad, K. et al. Combining Schwann cell bridges and olfactory-ensheathing glia grafts with chondroitinase promotes locomotor recovery after complete transection of the spinal cord. J. Neurosci. 25, 1169–1178 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Pasterkamp, R. J., Ruitenberg, M. J. & Verhaagen, J. Semaphorins and their receptors in olfactory axon guidance. Cell. Mol. Biol. (Noisy-le-grand) 45, 763–779 (1999).

    CAS  Google Scholar 

  64. Baker, C. V. H. & Bronner-Fraser, M. Vertebrate cranial placodes I. Embryonic induction. Dev. Biol. 232, 1–61 (2001).

    CAS  PubMed  Google Scholar 

  65. Doucette, J. R. The glial cells in the nerve fiber layer of the rat olfactory bulb. Anat. Rec. 210, 385–391 (1984).

    CAS  PubMed  Google Scholar 

  66. Raisman, G. Specialized neuroglial arrangement may explain the capacity of vomeronasal axons to reinnervate central neurons. Neuroscience 14, 237–254 (1985).

    CAS  PubMed  Google Scholar 

  67. Valverde, F. & Lopez-Mascaraque, L. Neuroglial arrangements in the olfactory glomeruli of the hedgehog. J. Comp. Neurol. 307, 658–674 (1991).

    CAS  PubMed  Google Scholar 

  68. Barnett, S. C., Hutchins, A. -M. & Noble, M. Purification of olfactory nerve ensheathing cells from the olfactory bulb. Dev. Biol. 155, 337–350 (1993).

    CAS  PubMed  Google Scholar 

  69. Ramón-Cueto, A. & Nieto-Sampedro, M. Glial cells from adult rat olfactory bulb: immunocytochemical properties of pure cultures of ensheathing cells. Neuroscience 47, 213–220 (1992).

    PubMed  Google Scholar 

  70. Ramón-Cueto, A. & Valverde, F. Olfactory bulb ensheathing glia: a unique cell type with axonal growth-promoting properties. Glia 14, 163–173 (1995).

    PubMed  Google Scholar 

  71. Murrell, W. et al. Multipotent stem cells from adult olfactory mucosa. Dev. Dyn. 233, 496–515 (2005).

    PubMed  Google Scholar 

  72. Huard, J. M. T., Youngentob, S. L., Goldstein, B. J., Luskin, M. B. & Schwob, J. E. Adult olfactory epithelium contains multipotent progenitors that give rise to neurons and non-neural cells. J. Comp. Neurol. 400, 469–486 (1998).

    CAS  PubMed  Google Scholar 

  73. Moulton, D. G. Dynamics of cell populations in the olfactory epithelium. Ann. NY Acad. Sci. 237, 52–61 (1974).

    CAS  PubMed  Google Scholar 

  74. Graziadei, P. P. C. & Montigraziadei, G. A. Neurogenesis and neuron regeneration in the olfactory system of mammals. I. Morphological aspects of differentiation and structural organization of the olfactory sensory neurons. J. Neurocytol. 8, 1–18 (1979).

    CAS  PubMed  Google Scholar 

  75. Mackay-Sim, A. & Kittel, P. W. On the life span of olfactory receptor neurons. Eur. J. Neurosci. 3, 209–215 (1991).

    PubMed  Google Scholar 

  76. Carr, V. M. & Farbman, A. I. Ablation of the olfactory bulb up-regulates the rate of neurogenesis and induces precocious cell death in olfactory epithelium. Exp. Neurol. 115, 55–59 (1992).

    CAS  PubMed  Google Scholar 

  77. Schwob, J. E., Youngentob, S. L., Ring, G., Iwema, C. L. & Mezza, R. C. Reinnervation of the rat olfactory bulb after methyl bromide-induced lesion: timing and extent of reinnervation. J. Comp Neurol. 412, 439–457 (1999).

    CAS  PubMed  Google Scholar 

  78. Graziadei, P. P. C. & Montigraziadei, G. A. Neurogenesis and neuron regeneration in the olfactory system of mammals. 3. Deafferentation and reinnervation of the olfactory bulb following section of the fila-olfactoria in rat. J. Neurocytol. 9, 145–162 (1980).

    CAS  PubMed  Google Scholar 

  79. Barber, P. C. & Raisman, G. Replacement of receptor neurones after section of the vomeronasal nerves in the adult mouse. Brain Res. 147, 297–313 (1978).

    CAS  PubMed  Google Scholar 

  80. Williams, S. K., Franklin, R. J. & Barnett, S. C. Response of olfactory ensheathing cells to the degeneration and regeneration of the peripheral olfactory system and the involvement of the neuregulins. J. Comp. Neurol. 470, 50–62 (2004).

    CAS  PubMed  Google Scholar 

  81. Li, Y., Field, P. M. & Raisman, G. Olfactory ensheathing cells and olfactory nerve fibroblasts maintain continuous open channels for regrowth of olfactory nerve fibres. Glia 52, 245–251 (2005).

    PubMed  Google Scholar 

  82. Field, P. M., Li, Y. & Raisman, G. Ensheathment of the olfactory nerves in the adult rat. J. Neurocytol. 32, 317–324 (2003).

    PubMed  Google Scholar 

  83. Valverde, F., Santacana, M. & Heredia, M. Formation of an olfactory glomerulus: morphological aspects of development and organization. Neuroscience 49, 255–276 (1992).

    CAS  PubMed  Google Scholar 

  84. Li, Y., Li, D. & Raisman, G. Interaction of olfactory ensheathing cells with astrocytes may be the key to repair of tract injuries in the spinal ord: the 'pathway hypothesis'. J. Neurocytol. 34, 343–351 (2005).

    PubMed  Google Scholar 

  85. Beites, C. L., Kawauchi, S., Crocker, C. E. & Calof, A. L. Identification and molecular regulation of neural stem cells in the olfactory epithelium. Exp. Cell Res. 306, 309–316 (2005).

    CAS  PubMed  Google Scholar 

  86. Carter, L. A., MacDonald, J. L. & Roskams, A. J. Olfactory horizontal basal cells demonstrate a conserved multipotent progenitor phenotype. J. Neurosci. 24, 5670–5683 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Devon, R. & Doucette, R. Olfactory ensheathing cells do not require L-ascorbic acid in vitro to assemble a basal lamina or to myelinate dorsal root ganglion neurites. Brain Res. 688, 223–229 (1995).

    CAS  PubMed  Google Scholar 

  88. Boyd, J. G., Skihar, V., Kawaja, M. & Doucette, R. Olfactory ensheathing cells: historical perspective and therapeutic potential. Anat. Rec. B New Anat. 271, 49–60 (2003).

    CAS  PubMed  Google Scholar 

  89. Jani, H. R. & Raisman, G. Ensheathing cell cultures from the olfactory bulb and mucosa. Glia 47, 130–137 (2004).

    PubMed  Google Scholar 

  90. Au, E. & Roskams, A. J. Olfactory ensheathing cells of the lamina propria in vivo and in vitro. Glia 41, 224–236 (2003).

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  92. Ramón-Cueto, A., Plant, G. W., Avila, J. & Bunge, M. B. Long-distance axonal regeneration in the transected adult rat spinal cord is promoted by olfactory ensheathing glia transplants. J. Neurosci. 18, 3803–3815 (1998).

    PubMed  PubMed Central  Google Scholar 

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

    PubMed  Google Scholar 

  94. Li, Y., Field, P. M. & Raisman, G. Repair of adult rat corticospinal tract by transplants of olfactory ensheathing cells. Science 277, 2000–2002 (1997).

    CAS  PubMed  Google Scholar 

  95. Ramer, L. M. et al. Peripheral olfactory ensheathing cells reduce scar and cavity formation and promote regeneration after spinal cord injury. J. Comp. Neurol. 473, 1–15 (2004).

    PubMed  Google Scholar 

  96. Plant, G. W., Christensen, C. L., Oudega, M. & Bunge, M. B. Delayed transplantation of olfactory ensheathing glia promotes sparing/regeneration of supraspinal axons in the contused adult rat spinal cord. J. Neurotrauma 20, 1–16 (2003).

    PubMed  Google Scholar 

  97. Lopez-Vales, R., Fores, J., Navarro, X. & Verdu, E. Chronic transplantation of olfactory ensheathing cells promotes partial recovery after complete spinal cord transection in the rat. Glia 55, 303–311 (2007).

    PubMed  Google Scholar 

  98. Andrews, M. R. & Stelzner, D. J. Modification of the regenerative response of dorsal column axons by olfactory ensheathing cells or peripheral axotomy in adult rat. Exp. Neurol. 190, 311–327 (2004).

    PubMed  Google Scholar 

  99. Lu, J. & Ashwell, K. Olfactory ensheathing cells: their potential use for repairing the injured spinal cord. Spine 27, 887–892 (2002).

    PubMed  Google Scholar 

  100. Smale, K. A., Doucette, R. & Kawaja, M. D. Implantation of olfactory ensheathing cells in the adult rat brain following fimbria-fornix transection. Exp. Neurol. 137, 225–233 (1996).

    CAS  PubMed  Google Scholar 

  101. Bartolomei, J. C. & Greer, C. A. Olfactory ensheathing cells: bridging the gap in spinal cord injury. Neurosurgery 47, 1057–1069 (2000).

    CAS  PubMed  Google Scholar 

  102. Perry, C., Mackay-Sim, A., Féron, F. & McGrath, J. Olfactory neural cells: an untapped diagnostic and therapeutic resource. The 2000 Ogura Lecture. Laryngoscope 112, 603–607 (2002).

    PubMed  Google Scholar 

  103. Ramón-Cueto, A. & Nieto-Sampedro, M. Regeneration into the spinal cord of transected dorsal root axons is promoted by ensheathing glia transplants. Exp. Neurol. 127, 232–244 (1994).

    PubMed  Google Scholar 

  104. Lakatos, A., Franklin, R. J. M. & Barnett, S. C. Olfactory ensheathing cells and Schwann cells differ in their in vitro interactions with astrocytes. Glia 32, 214–225 (2000).

    CAS  PubMed  Google Scholar 

  105. Lakatos, A., Barnett, S. C. & Franklin, R. J. Olfactory ensheathing cells induce less host astrocyte response and chondroitin sulphate proteoglycan expression than Schwann cells following transplantation into adult CNS white matter. Exp. Neurol. 184, 237–246 (2003).

    CAS  PubMed  Google Scholar 

  106. Plant, G. W., Bates, M. L. & Bunge, M. B. Inhibitory proteoglycan immunoreactivity is higher at the caudal than the rostral Schwann cell graft-transected spinal cord interface. Mol. Cell. Neurosci. 17, 471–487 (2001).

    CAS  PubMed  Google Scholar 

  107. Verdu, E. et al. Effects of ensheathing cells transplanted into photochemically damaged spinal cord. NeuroReport 12, 2303–2309 (2001).

    CAS  PubMed  Google Scholar 

  108. Keyvan-Fouladi, N., Raisman, G. & Li, Y. Functional repair of the corticospinal tract by delayed transplantation of olfactory ensheathing cells in adult rats. J. Neurosci. 23, 9428–9434 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Pearse, D. D. et al. Transplantation of Schwann cells and olfactory ensheathing glia after spinal cord injury: does pretreatment with methylprednisolone and interleukin-10 enhance recovery? J. Neurotrauma 21, 1223–1239 (2004).

    PubMed  Google Scholar 

  110. Imaizumi, T., Lankford, K. L., Burton, W. V., Fodor, W. L. & Kocsis, J. D. Xenotransplantation of transgenic pig olfactory ensheathing cells promotes axonal regeneration in rat spinal cord. Nature Biotechnol. 18, 949–953 (2000).

    CAS  Google Scholar 

  111. Doucette, J. R. PNS–CNS transition zone of the first cranial nerve. J. Comp. Neurol. 312, 451–466 (1991).

    CAS  PubMed  Google Scholar 

  112. Nash, H. H., Borke, R. C. & Anders, J. J. Ensheathing cells and methylprednisolone promote axonal regeneration and functional recovery in the lesioned adult rat spinal cord. J. Neurosci. 22, 7111–7120 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Polentes, J., Stamegna, J. C., Nieto-Sampedro, M. & Gauthier, P. Phrenic rehabilitation and diaphragm recovery after cervical injury and transplantation of olfactory ensheathing cells. Neurobiol. Dis. 16, 638–653 (2004).

    CAS  PubMed  Google Scholar 

  114. Sasaki, M. et al. Molecular reconstruction of nodes of Ranvier after remyelination by transplanted olfactory ensheathing cells in the demyelinated spinal cord. J. Neurosci. 26, 1803–1812 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Radtke, C. et al. Remyelination of the nonhuman primate spinal cord by transplantation of H-transferase transgenic adult pig olfactory ensheathing cells. FASEB J. 18, 335–337 (2004).

    CAS  PubMed  Google Scholar 

  116. Smith, P. M., Lakatos, A., Barnett, S. C., Jeffery, N. D. & Franklin, R. J. M. Cryopreserved cells isolated from the adult canine olfactory bulb are capable of extensive remyelination following transplantation into the adult rat CNS. Exp. Neurol. 176, 402–406 (2002).

    CAS  PubMed  Google Scholar 

  117. Lipson, A. C., Widenfalk, J., Lindqvist, E., Ebendal, T. & Olson, L. Neurotrophic properties of olfactory ensheathing glia. Exp. Neurol. 180, 167–171 (2003).

    PubMed  Google Scholar 

  118. Ruitenberg, M. J. et al. NT-3 expression from engineered olfactory ensheathing glia promotes spinal sparing and regeneration. Brain 128, 839–853 (2005).

    PubMed  Google Scholar 

  119. Chuah, M. I. et al. Olfactory ensheathing cells promote collateral axonal branching in the injured adult rat spinal cord. Exp. Neurol. 185, 15–25 (2004).

    CAS  PubMed  Google Scholar 

  120. Laporte, Y. Charles-Edouard Brown-Sequard: an eventful life and a significant contribution to the study of the nervous system. C. R. Biol. 329, 363–368 (2006).

    PubMed  Google Scholar 

  121. Li, Y., Sauvé, Y., Li, D., Lund, R. D. & Raisman, G. Transplanted olfactory ensheathing cells promote regeneration of cut adult rat optic nerve axons. J. Neurosci. 23, 7922–7930 (2003).

    Google Scholar 

  122. Guntinas-Lichius, O. et al. Transplantation of olfactory mucosa minimizes axonal branching and promotes the recovery of vibrissae motor performance after facial nerve repair in rats. J. Neurosci. 22, 7121–7131 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Choi, D. & Raisman, G. Disorganization of the facial nucleus after nerve lesioning and regeneration in the rat: effects of transplanting candidate reparative cells to the site of injury. Neurosurgery 56, 1093–1100 (2005).

    PubMed  Google Scholar 

  124. Li, Y., Yamamoto, M., Raisman, G., Choi, D. & Carlstedt, T. An experimental model of ventral root repair showing the beneficial effect of transplanting olfactory ensheathing cells. Neurosurgery (in the press).

  125. Riddell, J. S., Enriquez-Denton, M., Toft, A., Fairless, R. & Barnett, S. C. Olfactory ensheathing cell grafts have minimal influence on regeneration at the dorsal root entry zone following rhizotomy. Glia 47, 150–167 (2004).

    PubMed  Google Scholar 

  126. Gomez, V. M. et al. Transplantation of olfactory ensheathing cells fails to promote significant axonal regeneration from dorsal roots into the rat cervical cord. J. Neurocytol. 32, 53–70 (2003).

    PubMed  Google Scholar 

  127. Ramer, L. M., Richter, M. W., Roskams, A. J., Tetzlaff, W. & Ramer, M. S. Peripherally-derived olfactory ensheathing cells do not promote primary afferent regeneration following dorsal root injury. Glia 47, 189–206 (2004).

    PubMed  Google Scholar 

  128. Deumens, R. et al. Olfactory ensheathing cells, olfactory nerve fibroblasts and biomatrices to promote long-distance axon regrowth and functional recovery in the dorsally hemisected adult rat spinal cord. Exp. Neurol. 200, 89–103 (2006).

    CAS  PubMed  Google Scholar 

  129. Verdú, E. et al. Effects of ensheathing cells transplanted into photochemically damaged spinal cord. NeuroReport 12, 2303–2309 (2001).

    PubMed  Google Scholar 

  130. Ruitenberg, M. J. et al. Ex vivo adenoviral vector-mediated neurotrophin gene transfer to olfactory ensheathing glia: effects on rubrospinal tract regeneration, lesion size, and functional recovery after implantation in the injured rat spinal cord. J. Neurosci. 23, 7045–7058 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Takami, T. et al. Schwann cell but not olfactory ensheathing glia transplants improve hindlimb locomotor performance in the moderately contused adult rat thoracic spinal cord. J. Neurosci. 22, 6670–6681 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Deumens, R. et al. Chronically injured corticospinal axons do not cross large spinal lesion gaps after a multifactorial transplantation strategy using olfactory ensheathing cell/olfactory nerve fibroblast–biomatrix bridges. J. Neurosci. Res. 83, 811–820 (2006).

    CAS  PubMed  Google Scholar 

  133. Lu, P. et al. Olfactory ensheathing cells do not exhibit unique migratory or axonal growth-promoting properties after spinal cord injury. J. Neurosci. 26, 11120–11130 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Steward, O. et al. A re-assessment of the consequences of delayed transplantation of olfactory lamina propria following complete spinal cord transection in rats. Exp. Neurol. 198, 483–499 (2006).

    PubMed  Google Scholar 

  135. Richter, M. W., Fletcher, P. A., Liu, J., Tetzlaff, W. & Roskams, A. J. Lamina propria and olfactory bulb ensheathing cells exhibit differential integration and migration and promote differential axon sprouting in the lesioned spinal cord. J. Neurosci. 25, 10700–10711 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Kumar, R., Hayat, S., Felts, P., Bunting, S. & Wigley, C. Functional differences and interactions between phenotypic subpopulations of olfactory ensheathing cells in promoting CNS axonal regeneration. Glia 50, 12–20 (2005).

    PubMed  Google Scholar 

  137. Li, Y., Decherchi, P. & Raisman, G. Transplantation of olfactory ensheathing cells into spinal cord lesions restores breathing and climbing. J. Neurosci. 23, 727–731 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Keyvan-Fouladi, N., Raisman, G. & Li, Y. Delayed repair of corticospinal tract lesions as an assay for the effectiveness of transplantation of Schwann cells. Glia 51, 306–311 (2005).

    PubMed  Google Scholar 

  139. Lakatos, A., Smith, P. M., Barnett, S. C. & Franklin, R. J. Meningeal cells enhance limited CNS remyelination by transplanted olfactory ensheathing cells. Brain 126, 598–609 (2003).

    PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  141. Li, Y., Field, P. M. & Raisman, G. Regeneration of adult rat corticospinal axons induced by transplanted olfactory ensheathing cells. J. Neurosci. 18, 10514–10524 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Boyd, J. G., Doucette, R. & Kawaja, M. D. Defining the role of olfactory ensheathing cells in facilitating axon remyelination following damage to the spinal cord. FASEB J. 19, 694–703 (2005).

    CAS  PubMed  Google Scholar 

  143. Plant, G. W. et al. Purified adult ensheathing glia fail to myelinate axons under culture conditions that enable Schwann cells to form myelin. J. Neurosci. 22, 6083–6091 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Fairless, R., Frame, M. C. & Barnett, S. C. N-cadherin differentially determines Schwann cell and olfactory ensheathing cell adhesion and migration responses upon contact with astrocytes. Mol. Cell. Neurosci. 28, 253–263 (2005).

    CAS  PubMed  Google Scholar 

  145. Ibanez, C., Ito, D., Zawadzka, M., Jeffery, N. D. & Franklin, R. J. Calponin is expressed by fibroblasts and meningeal cells but not olfactory ensheathing cells in the adult peripheral olfactory system. Glia 55, 144–151 (2007).

    PubMed  Google Scholar 

  146. Vincent, A. J., Taylor, J. M., Choi-Lundberg, D. L., West, A. K. & Chuah, M. I. Genetic expression profile of olfactory ensheathing cells is distinct from that of Schwann cells and astrocytes. Glia 51, 132–147 (2005).

    PubMed  Google Scholar 

  147. Devon, R. & Doucette, R. Olfactory ensheathing cells myelinate dorsal root ganglion neurites. Brain Res. 589, 175–179 (1992).

    CAS  PubMed  Google Scholar 

  148. Boyd, J. G., Lee, J., Skihar, V., Doucette, R. & Kawaja, M. D. LacZ-expressing olfactory ensheathing cells do not associate with myelinated axons after implantation into the compressed spinal cord. Proc. Natl Acad. Sci. USA 101, 2162–2166 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Li, Y., Li, D. & Raisman, G. Transplanted Schwann cells but not olfactory ensheathing cells myelinate optic nerve fibres. Glia 55, 312–316 (2007).

    PubMed  Google Scholar 

  150. Dunning, M. D. et al. Superparamagnetic iron oxide-labeled Schwann cells and olfactory ensheathing cells can be traced in vivo by magnetic resonance imaging and retain functional properties after transplantation into the CNS. J. Neurosci. 24, 9799–9810 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Ruitenberg, M. J. et al. Viral vector-mediated gene expression in olfactory ensheathing glia implants in the lesioned rat spinal cord. Gene Ther. 9, 135–146 (2002).

    CAS  PubMed  Google Scholar 

  152. Dusart, I. & Schwab, M. E. Secondary cell death and the inflammatory reaction after dorsal hemisection of the rat spinal cord. Eur. J. Neurosci. 6, 712–724 (1994).

    CAS  PubMed  Google Scholar 

  153. Tuszynski, M. H. et al. NT-3 gene delivery elicits growth of chronically injured corticospinal axons and modestly improves functional deficits after chronic scar resection. Exp. Neurol. 181, 47–56 (2003).

    CAS  PubMed  Google Scholar 

  154. Shearer, M. C. & Fawcett, J. W. The astrocyte/meningeal cell interface — a barrier to successful nerve regeneration? Cell Tissue Res. 305, 267–273 (2001).

    CAS  PubMed  Google Scholar 

  155. Geller, H. M. & Fawcett, J. W. Building a bridge: Engineering spinal cord repair. Exp. Neurol. 174, 125–136 (2002).

    PubMed  Google Scholar 

  156. Boruch, A. V. et al. Neurotrophic and migratory properties of an olfactory ensheathing cell line. Glia 33, 225–229 (2001).

    CAS  PubMed  Google Scholar 

  157. Woodhall, E., West, A. K. & Chuah, M. I. Cultured olfactory ensheathing cells express nerve growth factor, brain-derived neurotrophic factor, glia cell line-derived neurotrophic factor and their receptors. Brain Res. Mol. Brain Res. 88, 203–213 (2001).

    CAS  PubMed  Google Scholar 

  158. Chung, R. S. et al. Olfactory ensheathing cells promote neurite sprouting of injured axons in vitro by direct cellular contact and secretion of soluble factors. Cell. Mol. Life Sci. 61, 1238–1245 (2004).

    CAS  PubMed  Google Scholar 

  159. Cao, L. et al. Olfactory ensheathing cells genetically modified to secrete GDNF to promote spinal cord repair. Brain 127, 535–549 (2004).

    PubMed  Google Scholar 

  160. Davies, J. E. et al. Astrocytes derived from glial-restricted precursors promote spinal cord repair. J. Biol. 5, 7 (2006).

    PubMed  PubMed Central  Google Scholar 

  161. Liu, Y. et al. Transplants of fibroblasts genetically modified to express BDNF promote regeneration of adult rat rubrospinal axons and recovery of forelimb function. J. Neurosci. 19, 4370–4387 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  163. Xu, X. M., Guénard, V., Kleitman, N. & Bunge, M. B. Axonal regeneration into Schwann cell-seeded guidance channels grafted into transected adult rat spinal cord. J. Comp. Neurol. 351, 145–160 (1995).

    CAS  PubMed  Google Scholar 

  164. King, V. R., Henseler, M., Brown, R. A. & Priestley, J. V. Mats made from fibronectin support oriented growth of axons in the damaged spinal cord of the adult rat. Exp. Neurol. 182, 383–398 (2003).

    CAS  PubMed  Google Scholar 

  165. Sterne, G. D., Brown, R. A., Green, C. J. & Terenghi, G. Neurotrophin-3 delivered locally via fibronectin mats enhances peripheral nerve regeneration. Eur. J. Neurosci. 9, 1388–1396 (1997).

    CAS  PubMed  Google Scholar 

  166. Ibrahim, A., Li, Y., Raisman, G. & el Masry, W. S. Olfactory ensheathing cells: ripples of an incoming tide? Lancet Neurol. 5, 453–457 (2006).

    PubMed  Google Scholar 

  167. Frankel, H. L. et al. The value of postural reduction in the initial management of closed injuries of the spine with paraplegia and tetraplegia. I. Paraplegia 7, 179–192 (1969).

    CAS  PubMed  Google Scholar 

  168. Fawcett, J. W. et al. Guidelines for the conduct of clinical trials for spinal cord injury as developed by the ICCP panel: spontaneous recovery after spinal cord injury and statistical power needed for therapeutic clinical trials. Spinal Cord 19 Dec 2006 (doi:10.1038/sj.sc.3102007).

    PubMed  Google Scholar 

  169. Féron, F., Perry, C., McGrath, J. J. & Mackay-Sim, A. New techniques for biopsy and culture of human olfactory epithelial neurons. Arch. Otolaryngol. Head. Neck Surg. 124, 861–866 (1998).

    PubMed  Google Scholar 

  170. Féron, F. et al. Autologous olfactory ensheathing cell transplantation in human spinal cord injury. Brain 128, 2951–2960 (2005).

    PubMed  Google Scholar 

  171. Huang, H. et al. Influence of patients' age on functional recovery after transplantation of olfactory ensheathing cells into injured spinal cord injury. Chin. Med. J. (Engl.) 1488–1491 (2003).

  172. Lima, C. et al. Olfactory mucosa autografts in human spinal cord injury: a pilot clinical study. J. Spinal Cord Med. 29, 191–203 (2006).

    PubMed  PubMed Central  Google Scholar 

  173. Anderson, D. K. et al. Recommended guidelines for studies of human subjects with spinal cord injury. Spinal Cord 43, 453–458 (2005).

    CAS  PubMed  Google Scholar 

  174. Steeves, J. D. et al. Guidelines for the conduct of clinical trials for spinal cord injury (SCI) as developed by the ICCP panel: clinical trial outcome measures. Spinal Cord 19 Dec 2006 (doi:10.1038/sj.sc.3102008).

    PubMed  Google Scholar 

  175. Tuszynski, M. H. et al. Guidelines for the conduct of clinical trials for spinal cord injury as developed by the ICCP Panel: clinical trial inclusion/exclusion criteria and ethics. Spinal Cord 19 Dec 2006 (doi:10.1038/sj.sc.3102009).

    PubMed  Google Scholar 

  176. Lammertse, D. et al. Guidelines for the conduct of clinical trials for spinal cord injury as developed by the ICCP panel: clinical trial design. Spinal Cord 19 Dec 2006 (doi:10.1038/sj.sc.3102010).

    PubMed  PubMed Central  Google Scholar 

  177. Dobkin, B. H., Curt, A. & Guest, J. Cellular transplants in China: observational study from the largest human experiment in chronic spinal cord injury. Neurorehabil. Neural Repair 20, 5–13 (2006).

    PubMed  PubMed Central  Google Scholar 

  178. Htut, M., Misra, P., Anand, P., Birch, R. & Carlstedt, T. Pain phenomena and sensory recovery following brachial plexus avulsion injury and surgical repairs. J. Hand Surg. [Br.] 31, 596–605 (2006).

    CAS  Google Scholar 

  179. Kato, N., Htut, M., Taggart, M., Carlstedt, T. & Birch, R. The effects of operative delay on the relief of neuropathic pain after injury to the brachial plexus: a review of 148 cases. J. Bone Joint Surg. Br. 88, 756–759 (2006).

    CAS  PubMed  Google Scholar 

  180. Raisman, G. Repair of spinal cord injury: ripples of an incoming tide, or how I spent my first forty years in research. Spinal Cord 44, 406–413 (2006).

    CAS  PubMed  Google Scholar 

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The British Neurological Research Trust, Spinal Research, and Henry Smith Charity.

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Raisman, G., Li, Y. Repair of neural pathways by olfactory ensheathing cells. Nat Rev Neurosci 8, 312–319 (2007). https://doi.org/10.1038/nrn2099

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