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Regeneration in the adult central nervous system: Experimental repair strategies

Nature Medicine volume 3, pages 1329–1335 (1997)Cite this article

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References

  1. Varga, Z.M., Bandtlow, C.E., Erulkar, S.D., Schwab, M.E. & Nicholls, J.G. The critical period for repair of CNS of neonatal opossum (Monodelphis domestica) in culture: correlation with development of glial cells, myelin and growth-inhibitory molecules. Eur J. Neurosci 7, 2119–2129 (1995).

    Article  CAS  PubMed  Google Scholar 

  2. Aubert, I., Ridet, J.L. & Gage, F.H. Regeneration in the adult mammalian CNS: guided by development. Curr Opin Neurobiol 5, 625–635 (1995).

    Article  CAS  PubMed  Google Scholar 

  3. Olson, L. Intact and regenerating sympathetic noradrenaline axons in the rat sciatic nerve. Histochemie 17, 349–367 (1969).

    Article  CAS  PubMed  Google Scholar 

  4. Becker, T., Wullimann, M.F., Becker, C.G., Bernhardt, R.R. & Schachner, M. Axonal regrowth after spinal cord transection in adult zebrafish. J Comp Neurol 377, 577–595 (1997).

    Article  CAS  PubMed  Google Scholar 

  5. Brustle, O. & McKay, R. Neuronal progenitors as tools for cell replacement in the nervous system. Curr Opin Neurobiol 6, 688–695 (1996).

    Article  CAS  PubMed  Google Scholar 

  6. Weiss, S., et al. Is there a neural stem cell in the mammalian forebrain? Trends Neurosci 19, 387–393 (1996).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  8. Bregman, B.S., Diener, P.S., McAtee, M., Dai, H.N. & James, C. Intervention strategies to enhance anatomical plasticity and recovery of function after spinal cord injury. Adv Neurol 72, 257–275 (1997).

    CAS  PubMed  Google Scholar 

  9. Aguayo, A.J., et al. Degenerative and regenerative responses of injured neurons in the central nervous system of adult mammals. Philos Trans R Soc Lond B Biol Sci 331, 337–343 (1991).

    Article  CAS  PubMed  Google Scholar 

  10. Weibel, D., Cadelli, D. & Schwab, M.E. Regeneration of lesioned rat optic nerve fibers is improved after neutralization of myelin-associated neurite growth inhibitors. Brain Res 642, 259–266 (1994).

    Article  CAS  PubMed  Google Scholar 

  11. Eitan, S., et al. Recovery of visual response of injured adult rat optic nerves treated with transglutaminase. Science 264, 1764–1768 (1994).

    Article  CAS  PubMed  Google Scholar 

  12. Aguayo, A., et al. Ensheathment and myelination of regenerating PNS fibres by transplanted optic nerve glia. Neurosci Lett 9, 97 (1978).

    Article  CAS  PubMed  Google Scholar 

  13. Nygren, L., Fuxe, K., Jonsson, G. & Olson, L. Functional regeneration of 5-hydroxytryptamine nerve terminals in the rat spinal cord following 5,6-dihydroxytryptamine induced degeneration. Brain Res. 78, 377–394 (1974).

    Article  CAS  PubMed  Google Scholar 

  14. Cheng, H. & Olson, L. A new surgical technique that allows proximodistal regeneration of 5-HT fibers after complete transection of the rat spinal cord. Exp Neurol 136, 149–161 (1995).

    Article  CAS  PubMed  Google Scholar 

  15. Davies, S.J., Field, P.M. & Raisman, G. Regeneration of cut adult axons fails even in the presence of continuous aligned glial pathways. Exp Neurol 142, 203–216 (1996).

    Article  CAS  PubMed  Google Scholar 

  16. Rubin, B.P., Dusart, I. & Schwab, M.E. A monoclonal antibody (IN-1) which neutralizes neurite growth inhibitory proteins in the rat CNS recognizes antigens localized in CNS myelin. J Neurocytol 23, 209–217 (1994).

    Article  CAS  PubMed  Google Scholar 

  17. Schwab, M.E. Molecules inhibiting neurite growth: a minireview. Neurochem Res 21, 755–761 (1996).

    Article  CAS  PubMed  Google Scholar 

  18. Schnell, L., Schneider, R., Kolbeck, R., Barde, Y.A. & Schwab, M. E. Neurotrophin-3 enhances sprouting of corticospinal tract during development and after adult spinal cord lesion. Nature 367, 170–173 (1994).

    Article  CAS  PubMed  Google Scholar 

  19. Bregman, B.S., et al. Recovery from spinal cord injury mediated by antibodies to neurite growth inhibitors. Nature 378, 498–501 (1995).

    Article  CAS  PubMed  Google Scholar 

  20. Bahr, M. & Schwab, M. Antibody that neutralizes myelin-associated inhibitiors of axon growth does not interfere with recognition of target-specific guidance information by rat retinal axons. J Neurobiol 30, 281–292 (1996).

    Article  CAS  PubMed  Google Scholar 

  21. Savio, T. & Schwab, M. Lesioned corticospinal tract axons regenerate in myelin-free rat spinal cord. Proc Natl Acad Sci USA 87, 4130–4133 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Keirstead, H., et al. Axonal regeneration and physiological activity following transection and immunological disruption of myelin within the hatchling chick spinal cord. J Neurosci 15, 6963–6974 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kalderon, N. & Fuks, Z. Structural recovery in lesioned adult mammalian spinal cord by x-irradiation of the lesion site. Proc Natl Acad Sci USA 93, 11179–11184 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Richardson, P.M., Mcguinness, U.M. & Aguayo, A.J. Axons from CNS neurons regenerate into PNS grafts. Nature 284, 264–265 (1980).

    Article  CAS  PubMed  Google Scholar 

  25. David, S. & Aguayo, A. Axonal elongation into peripheral nervous system “bridges” after central nervous system injury in adult rats. Science 214, 931–933 (1981).

    Article  CAS  PubMed  Google Scholar 

  26. Meyer, M., Matsuoka, I., Wetmore, C., Olson, L. & Thoenen, H. Enhanced synthesis of brain-derived neurotrophic factor in the lesioned peripheral nerve: Different mechanisms are responsible for the regulation of BDNF and NGF mRNA. J Cell Biol 119, 45–54 (1992).

    Article  CAS  PubMed  Google Scholar 

  27. Carter, D.A., Bray, G.M. & Aguayo, A.J. Long-term growth and remodeling of regenerated retino-collicular connections in adult hamsters. J Neurosci 14, 590–598 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Gage, F., et al. Anatomical and functional consequences of grafting mesencephalic neurons into a peripheral nerve “bridge” connected to the denervated striatum. Exp Brain Res 60, 384–389 (1985).

    Article  Google Scholar 

  29. Cheng, H., Cao, Y. & Olson, L., Spinal cord repair in adult paraplegic rats: partial restoration of hind limb function. Science 273, 510–513 (1996).

    Article  CAS  PubMed  Google Scholar 

  30. Cheng, H., et al. Gait analysis of adult paraplegic rats after spinal cord repair. Exp Neurol (in press) (1997).

  31. Martini, R., Schachner, M. & Brushart, T. The L2/HNK-1 carbohydrate is preferentially expressed by previously motor axon-associated Schwann cells in reinnervated peripheral nerves. J Neurosci 41, 7180–7191 (1994).

    Article  Google Scholar 

  32. Carlstedt, T. Spinal nerve root injuries in brachial plexus lesions: basic science and clinical application of new surgical trategies. A review. Microsurgery 16, 13–16 (1995).

    Article  CAS  PubMed  Google Scholar 

  33. Cheng, H., Shoung, H., Chen, K., Wu, Z. & Lee, L. Functional connectivity of the transected brachial plexus after intercostal neurotization in monkeys. J Comp Neurol 380, 155–163 (1997).

    Article  CAS  PubMed  Google Scholar 

  34. Date, I., Asari, S. & Ohmoto, T. Two-year follow-up study of a patient with Parkinson's disease and severe motor fluctuations treated by co-grafts of adrenal medulla and peripheral nerve into bilateral caudate nuclei: case report. Neurosurgery 37, 515–519 (1995).

    Article  CAS  PubMed  Google Scholar 

  35. Bunge, R.P., Puckett, W.R., Becerra, J.L., Marcillo, A. & Quencer, R.M. Observations on the pathology of human spinal cord injury. A review and classification of 22 new cases with details from a case of chronic cord compression with extensive focal demyelination. Adv Neurol 59, 75–89 (1993).

    CAS  PubMed  Google Scholar 

  36. Bunge, R.P., Puckett, W.R. & Hiester, E.D. Observations on the pathology of several types of human spinal cord injury, with emphasis on the astrocyte response to penetrating injuries. Adv Neurol 72, 305–315 (1997).

    CAS  PubMed  Google Scholar 

  37. Tseng, G.F. & Prince, D. A. Structural and functional alterations in rat corticospinal neurons after axotomy. J Neurophysiol 75, 248–267 (1996).

    Article  CAS  PubMed  Google Scholar 

  38. Barde, Y. Neurotrophins: a family of proteins supporting the survival of neurons. Prog Clin Biol Res 390, 45–56 (1994).

    CAS  PubMed  Google Scholar 

  39. Grill, R., Murai, K., Blesch, A., Gage, F. & Tuszynski, M. Cellular delivery of neurotrophin-3 promotes corticospinal axonal growth and partial functional recovery after spinal cord injury. J Neurosci 17, 5560–5572 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Fernandez-Valle, C., Bunge, R.P. & Bunge, M.B. Schwann cells degrade myelin and proliferate in the absence of macrophages: evidence from in vitro studies of Wallerian degeneration. J Neurocytol 24, 667–679 (1995).

    Article  CAS  PubMed  Google Scholar 

  41. Decherchi, P. & Gauthier, P. In vitro pre-degenerated nerve autografts support CNS axonal regeneration. Brain Res 726, 181–188 (1996).

    Article  CAS  PubMed  Google Scholar 

  42. Li, Y. & Raisman, G. Schwann cells induce sprouting in motor and sensory axons in the adult rat spinal cord. J Neurosci 14, 4050 & 4063 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Joosten, E.A., Bar, P.R. & Gispen, W.H. Collagen implants and cortico-spinal axonal growth after mid-thoracic spinal cord lesion in the adult rat. J Neurosci Res 41, 481–490 (1995).

    Article  CAS  PubMed  Google Scholar 

  44. Xu, X., Guenard, V., Kleitman, N. & Bunge, M. Axonal regeneration into Schwann cell-seeded guidance channels grafted into transected adult rat spinal cord. Glia 13, 309 & 318 (1995).

    Article  Google Scholar 

  45. Casella, G.T., Bunge, R.P. & Wood, P.M. Improved method for harvesting human Schwann cells from mature peripheral nerve and expansion in vitro. Glia 17, 327–338 (1996).

    Article  CAS  PubMed  Google Scholar 

  46. 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).

    Article  CAS  PubMed  Google Scholar 

  47. Xu, X.M., Chen, A., Guenard, V., Kleitman, N. & Bunge, M.B. Bridging Schwann cell transplants promote axonal regeneration from both the rostral and caudal stumps of transected adult rat spinal cord. J Neurocytol 26, 1–16 (1997).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  49. Lewin, G.R. & Barde, Y.A. Physiology of the neurotrophins. Annu Rev Neurosci 19, 289–317 (1996).

    Article  CAS  PubMed  Google Scholar 

  50. Dechant, G., Rodrigues-Tebar, A. & Barde, Y. Neurotrophin receptors. Prog Neurobiol 42, 347–352 (1994).

    Article  CAS  PubMed  Google Scholar 

  51. Eckenstein, F.P. Fibroblast growth factors in the nervous system. J Neurobiol 25, 1467–1480 (1994).

    Article  CAS  PubMed  Google Scholar 

  52. Krieglstein, K., Rufer, M., Suter, C.C. & Unsicker, K. Neural functions of the transforming growth factors beta. Int J Dev Neurosci 13, 301–315 (1995).

    Article  CAS  PubMed  Google Scholar 

  53. Unsicker, K. GDNF: a cytokine at the interface of TGF-betas and neurotrophins. Cell Tissue Res 286, 175–178 (1996).

    Article  CAS  PubMed  Google Scholar 

  54. Campenot, R.B. NGF and the local control of nerve terminal growth. J Neurobiol 25, 599–611 (1994).

    Article  CAS  PubMed  Google Scholar 

  55. Gallo, G., Lefcort, F.B. & Letoumeau, P.C. The trkA receptor mediates growth cone turning toward a localized source of nerve growth factor. J Neurosci 17, 5445–5454 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Riccio, A., Pierchala, B., Ciarallo, C. & Ginty, D., NGF-TrkA-mediated retrograde signal to transcription factor CREB in sympathetic neurons. Science 277, 1097–1100 (1997).

    Article  CAS  PubMed  Google Scholar 

  57. Tomac, A., et al. Protection and repair of the nigrostriatal dopaminergic system by GDNF in vivo. Nature 373, 335–339 (1995).

    Article  CAS  PubMed  Google Scholar 

  58. Berry, M., Carlile, J. & Hunter, A. Peripheral nerve explants grafted into the vitreous body of the eye promote the regeneration of retinal ganglion cell axons severed in the optic nerve. J Neurocytol 25, 147–170 (1996).

    Article  CAS  PubMed  Google Scholar 

  59. Kaneko, M., et al. Neurotrophic 3,9-bis (alkylthio)methyl-and-bis (alkoxymethyl)-K-252a derivatives. J Med Chem 40, 1863–1869 (1997).

    Article  CAS  PubMed  Google Scholar 

  60. Strömberg, I., et al. Rescue of basal forebrain cholinergic neurons after implantation of genetically modified cells producing recombinant NGF. J Neurosci Res 25, 405–411 (1990).

    Article  PubMed  Google Scholar 

  61. Nakahara, Y., Gage, F.H. & Tuszynski, M.H. Grafts of fibroblasts genetically modified to secrete NGF, BDNF, NT-3, or basic FGF elicit differential responses in the adult spinal cord. Cell Transplant 5, 191–204 (1996).

    Article  CAS  PubMed  Google Scholar 

  62. Tuszynski, M.H. & Gage, F.H. Somatic gene therapy for nervous system disease. Ciba Found Symp 196, 85–97 (1996).

    CAS  PubMed  Google Scholar 

  63. Tuszynski, M., et al. Nerve growth factor delivery by gene transfer induces differential outgrowth of sensory motor and noradrenergic neurites after adult spinal cord injury. Exp Neurol 137, 157–173 (1996).

    Article  CAS  PubMed  Google Scholar 

  64. Choi-Lundberg, D., et al. Dopaminergic neurons protected from degeneration by GDNF gene therapy. Science 275, 838–841 (1997).

    Article  CAS  PubMed  Google Scholar 

  65. Zhou, F. & Chiang, Y. Excitochemical-induced trophic bridging directs axonal growth of transplanted neurons to distal target. Cell Transplant 4, 103–112 (1995).

    Article  CAS  PubMed  Google Scholar 

  66. Humpel, C., et al. Neurons of the hippocampal formation express glial cell line-derived neurotrophic factor messenger RNA in the response to kainate-induced excitation. Neuroscience 59, 791–795 (1994).

    Article  CAS  PubMed  Google Scholar 

  67. Wang, Y., Tien, L.T., Lapchak, P.A. & Hoffer, B.J. GDNF triggers fiber outgrowth of fetal ventral mesencephalic grafts from nigra to striatum in 6-OHDA-lesioned rats. Cell Tissue Res 286, 225–233 (1996).

    Article  CAS  PubMed  Google Scholar 

  68. Sydow, O., et al. Nerve growth factor infusion to support adrenal medullary autografts in Parkinson's disease; Further clinical trials. Eur. J. Neurol. 2, 1–10 (1995).

    Article  Google Scholar 

  69. Olson, L., et al. Nerve growth factor affects 11C-nicotine binding, blood flow, EEG, and verbal episodic memory in an Alzheimer patient (case report). J Neural Transm (Park. Dis. Dement. Sect.) 4, 79–95 (1992).

    Article  CAS  Google Scholar 

  70. Olson, L. NGF and the treatment of Alzheimer's disease. Exp. Neurol. 124, 5–15 (1993).

    Article  CAS  PubMed  Google Scholar 

  71. Dyck, P.J., et al. Intradermal recombinant human nerve growth factor induces pressure allodynia and lowered heat-pain threshold in humans. Neurology 48, 501–505 (1997).

    Article  CAS  PubMed  Google Scholar 

  72. Aebischer, P., et al. Gene therapy for amyotrophic lateral sclerosis (ALS) using a polymer encapsulated xenogenic cell line engineered to secrete hCNTF. Hum Gene Ther 7, 851–860 (1996).

    Article  CAS  PubMed  Google Scholar 

  73. Lindsay, R.M. Therapeutic potential of the neurotrophins and neurotrophin-CNTF combinations in peripheral neuropathies and motor neuron diseases. Ciba Found Symp 196, 39–53 (1996).

    CAS  PubMed  Google Scholar 

  74. The ALS CNTF Treatment Study Group. A double-blind placebo-controlled clinical trial of subcutaneous recombinant human ciliary neurotrophic factor (rHCNTF) in amyotrophic lateral sclerosis. ALS CNTF Treatment Study Group. Neurology 46, 1244–1249 (1996).

  75. Apfel, S.C. & Kessler, J.A. Neurotrophic factors in the treatment of peripheral neuropathy. Ciba Found Symp 196, 98–112 (1996).

    CAS  PubMed  Google Scholar 

  76. Levi-Montalcini, R., Skaper, S.D., Dal, T.R., Petrelli, L. & Leon, A. Nerve growth factor: from neurotrophin to neurokine. Trends Neurosci 19, 514–520 (1996).

    Article  CAS  PubMed  Google Scholar 

  77. Lazarov-Spiegler, O., et al. Transplantation of activated macrophages overcomes central nervous system regrowth failure. FASEB J 10, 1296–1302 (1996).

    Article  CAS  PubMed  Google Scholar 

  78. Lotan, M., Solomon, A., Ben, B.S. & Schwartz, M. Cytokines modulate the inflammatory response and change permissiveness to neuronal adhesion in injured mammalian central nervous system. Exp Neurol 126, 284–290 (1994).

    Article  CAS  PubMed  Google Scholar 

  79. Monsonego, A., et al. Expression of GTP-dependent and GTP-independent tissue-type transglutaminase in cytokine-treated rat brain astrocytes. J Biol Chem 272, 3724–3732 (1997).

    Article  CAS  PubMed  Google Scholar 

  80. Snyder, S. & Sabatini, D. Immunophilins and the nervous system. Nature 1, 32–37 (1995).

    CAS  Google Scholar 

  81. Steiner, J., et al. Neurotrophic actions of nonimmunosuppressive analalogues of cyclosporin A. Nature 3, 421–428 (1997).

    CAS  Google Scholar 

  82. Steiner, J., et al. Neurotrophic immunophilin ligands stimulate structural and functional recovery in neurodegenerative animal models. Proc Natl Acad Sci USA 94, 2019–2024 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Björklund, A. & Stenevi, U. Reconstruction of the nigrostriatal dopamine pathway by intracerebral nigral transplants. Brain Res 177, 555–560 (1979).

    Article  PubMed  Google Scholar 

  84. Perlow, M.J., et al. Brain grafts reduce motor abnormalities produced by destruction of nigrostriatal dopamine system. Science 204, 643–647 (1979).

    Article  CAS  PubMed  Google Scholar 

  85. Strömberg, I., Bygdeman, M. & Almqvist, P. Target specific outgrowth from human mesencephalic tissue grafted to cortex or ventricle of immunosuppressed rats. J Comp Neurol 315, 445–456 (1992).

    Article  PubMed  Google Scholar 

  86. Wictorin, K., Brundin, P., Gustavii, B., Lindvall, O. & Bjorklund, A. Reformation of long axon pathways in adult rat central nervous system by human forebrain neuroblasts. Nature 347, 556–558 (1990).

    Article  CAS  PubMed  Google Scholar 

  87. Lindvall, O. Clinical application of neuronal grafts in Parkinson's disease. J Neurol 242 (1 Suppl 1), S54–S56 (1994).

    Article  CAS  PubMed  Google Scholar 

  88. Howland, D., Bregman, B.S., Tessler, A., Goldberger, ME. Transplants enhance locomotion in neonatal kittens whose spinal cords are transected: a behavioral and anatomical study. Exp Neurol 135, 123–145 (1995).

    Article  CAS  PubMed  Google Scholar 

  89. Goodman, C.S. Mechanisms and molecules that control growth cone guidance. Annu Rev Neurosci 19, 341–377 (1996).

    Article  CAS  PubMed  Google Scholar 

  90. Tessier-Lavigne, M. & Goodman, C.S. The molecular biology of axon guidance. Science 274, 1123–1133 (1996).

    Article  CAS  PubMed  Google Scholar 

  91. Seilheimer, B. & Schachner, M. Studies of adhesion molecules mediating interactions between cells of peripheral nervous system indicate a major role for L1 in mediating sensory neuron growth on Schwann cells in culture. J Cell Biol 107, 341–351 (1988).

    Article  CAS  PubMed  Google Scholar 

  92. Schachner, M. Neural recognition molecules in disease and regeneration. Curr Opin Neurobiol 4, 726–734 (1994).

    Article  CAS  PubMed  Google Scholar 

  93. Stittmatter, S., Fankhauser, C., Huang, P., Mashimo, H. & Fishman, M. Neuronal pathfinding is abnormal in mice lacking the neuronal growth cone protein GAP-43. Cell 80, 445–452 (1995).

    Article  Google Scholar 

  94. Schachner, M. Lessons from genetic knockout mice deficient in neural recognition molecules. Prog Brain Res 100, 25–30 (1994).

    Article  CAS  PubMed  Google Scholar 

  95. Doster, S., Lozano, A., Aguayo, A. & Willard, M. Expression of the growth-associated protein GAP-43 in adult rat retinal ganglion cells following axon injury. Neuron 6, 635–647 (1991).

    Article  CAS  PubMed  Google Scholar 

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    Lars Olson

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Olson, L. Regeneration in the adult central nervous system: Experimental repair strategies. Nat Med 3, 1329–1335 (1997). https://doi.org/10.1038/nm1297-1329

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