Regeneration in the spinal cord

Current Opinion in Neurobiology

Volumn 8, Issue 6, 1998, Pages 800-807

  Bregman, Barbara S ^a  

^a GEORGETOWN UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

NEUROTROPHIC FACTOR;

NERVE REGENERATION; PRIORITY JOURNAL; REVIEW; SPINAL CORD; SPINAL CORD INJURY;

EID: 0031648074     PISSN: 09594388     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0959-4388(98)80124-4     Document Type: Article

References (56)

1. Diener PS, Bregman BS. Neurotrophic factors prevent the death of CNS neurons after spinal cord lesions in newborn rats. Neuroreport. 5:1994;1913-1917.
2. Shibayama M, Hattori S, Himes BT, Murray M, Tessler A. Neurotrophin-3 prevents death of axotomized Clarke's nucleus neurons in adult rat. J Comp Neurol. 390:1998;102-111.
3. Kobayashi NR, Fan DP, Giehl KM, Bedard AM, Wiegand SJ, Tetzlaff W. BDNF and NT-4/5 prevent atrophy of rat rubrospinal neurons after cervical axotomy, stimulate GAP-43 and Ta1-tubulin mRNA expression, and promote axonal regeneration. of special interest J Neurosci. 17:1997;9583-9595 Along with [4], this paper demonstrates convincingly that one way in which neurotrophic factors increase axonal regeneration is by re-initiating cellular programs associated with regeneration-associated genes. In addition, it shows that the atrophy of axotomized nerve cells is prevented by application of neurotrophins.
4. Bregman BS, Broude E, McAtee M, Kelley MS. Transplants and neurotrophic factors prevent atrophy of mature CNS neurons after spinal cord injury. Exp Neurol. 149:1998;13-27 Transplants and neurotrophic factors, which have been shown to promote growth of axotomized CNS neurons (see [3]), are also capable of reversing axotomy-induced atrophy. These studies are of interest because they suggest that BDNF and NT-3 are both capable of influencing axotomized rubrospinal neurons, and that when applied in combination, transplants and neurotrophins have an additive influence in preserving cell morphology. Although the neurotrophins were applied acutely, there was long-term preservation of cell morphology. It is going to be critical to determine the extent to which specific axotomized neurons require specific neurotrophic support to increase axonal regrowth. At present, it appears that the requirements of particular neurons for trophic support for survival may, in general, be far more specific than the neurotrophic influences on axonal elongation and sprouting. It will also be essential to identify the temporal requirements for neurotrophins both in survival and axonal regrowth.
5. Broude E, McAtee M, Kelley MS, Bregman BS. c-Jun expression in adult rat dorsal root ganglion neurons: differential response after central or peripheral axotomy. of outstanding interest Exp Neurol. 148:1997;367-377 This study compares the effect of central and peripheral axotomy on c-Jun expression in DRG neurons. c-Jun was upregulated substantially in DRG neurons following peripheral axotomy; however, following central axotomy, few neurons expressed c-Jun. In contrast, c-Jun expression is upregulated dramatically under conditions that support regeneration of the central process of the DRG (e.g. dorsal rhizotomy and transplantation). These data indicate that c-Jun expression may be related to successful regenerative growth following both PNS and CNS lesions. Again, some neurons may have very particular trophic requirements. It was surprising that the upregulation of c-Jun was seen only in the small and medium diameter neurons, but not in the largest neurons. This parallels the capacity of these cells for axonal elongation. It will be important in the future to determine whether particular neurons differ in their intrinsic capacity for regrowth or in the stimuli that they require to initiate that growth.
6. Herdegen T, Skene JHP, Bahr M. The c-Jun transcription factor - bipotential mediator of neuronal death, survival and regeneration. of special interest Trends Neurosci. 20:1997;227-231 This is an excellent review article on c-Jun function in injury and regeneration. c-Jun's functional characteristics suggest a model whereby a single molecule serves as a pivotal regulator of death or survival. In vitro experiments have demonstrated that expression of c-Jun can kill neonatal neurons; however, in the adult nervous system, c-Jun may be involved in neuroprotection and regeneration. It is likely that alterations in signal transduction determine the fate of axotomized neurons. This paper reviews well the apparent disparity in the literature reporting c-Jun as a harbinger of death or regeneration. It will be important to identify the downstream pathways that determine whether (and which) cellular programs associated with regrowth are required for successful axonal regeneration.
7. Bernstein-Goral H, Bregman BS. Axotomized rubrospinal neurons rescued by fetal spinal cord transplants maintain axon collaterals to rostral CNS targets. Exp Neurol. 148:1997;13-25.
8. Bernstein-Goral H, Diener PS, Bregman BS. Regenerating and sprouting axons differ in their requirements for axonal growth after injury. of outstanding interest Exp Neurol. 148:1997;51-72 This is the first in vivo demonstration that sprouting and regenerating axons may differ in their requirements for growth after injury. It will be important to understand the ways in which these two different forms of axonal growth are regulated. After spinal cord injury, it may be important to restrict the sprouting of some pathways (e.g. nociceptive) while enhancing the sprouting of others (e.g. cutaneous afferents). At present, we are far from understanding how each of these forms of axonal elongation be influenced.
9. Smith DS, Skeno JHP. A transcription-dependent switch controls competence of adult neurons for distinct modes of axon growth. of special interest J Neurosci. 17:1997;646-658 This paper is an important in vitro demonstration that axonal elongation and axonal branching may be regulated independently. Analysis of adult DRG neurons in culture shows that this competence for distinct types of axon growth depends on different patterns of gene expression. This represents one of the first demonstrations that the signals for the two different forms of axonal elongation differ. It will be essential to determine, at a cellular level, whether their regulation is distinct in vivo as well.
10. Fournier AE, Beer J, Arregui CO, Essagian C, Aguayo AJ, McKerracher L. Brain-derived neurotrophic factor modulates GAP-43 but not T alpha 1 expression in injured retinal ganglion cells of adult rats. J Neurosci Res. 47:1997;561-572.
11. of special interest Thallmair M, Metz GAS, Z'Graggen WJ, Raineteau O, Kartje GL, Schwab ME. Neurite growth inhibitors restrict plasticity and functional recovery following corticospinal tract lesions. of outstanding interest Nat Neurosci. 1:1998;124-131 Along with [13], this study demonstrates that blocking the myelin-associated inhibitors of axonal growth leads not only to regrowth of pathways damaged directly but also to axonal sprouting of undamaged pathways. The structural plasticity is accompanied by improvements in motor function. The study is important because is demonstrates that both sprouting and regeneration occur in response to blocking the myelin-associated inhibitors of growth. Both forms of CNS plasticity are in a position to influence the recovery of motor function.
12. Vanek P, Thallmair M, Schwab ME, Kapfhammer JP. Increased lesion-induced sprouting in the myelin-free rat spinal cord. Eur J Neurosci. 10:1998;45-56.
13. of outstanding interest Z'Graggen WJ, Metz GAS, Kartje GL, Thallmair M, Schwab ME. Functional recovery and enhanced corticofugal plasticity after unilateral pyramidal tract lesion and blockade of myelin-associated neurite growth inhibitors in adult rats. of special interest J Neurosci. 18:1998;4744-4757 A number of studies is beginning to define the wide-spread remodeling that takes place after CNS injury. This study is particularly important because it demonstrates that after spinal cord injury, supraspinal pathways are remodeled. Widespread remodeling after interruption of sensory systems has been well demonstrated, and parallel remodeling in descending motor systems would be predicted. Coupled with the remodeling of segmental pathways [52,54], this supraspinal remodeling expands the opportunities to influence recovery of both skilled and rhythmic alternating movement. See also annotation [11].
14. Bregman BS, Kunkel-Bagden E, Schnell L, Dai HN, Gao D, Schwab ME. Regrowth of injured adult corticospinal and brainstem-spinal fibers elicited by antibodies to neurite growth inhibitors leads to recovery of locomotor function after spinal cord injury. Nature. 378:1995;498-501.
15. of outstanding interest Ye JH, Houle JD. Treatment of the chronically injured spinal cord with neurotrophic factors can promote axonal regeneration from supraspinal neurons. of special interest Exp Neurol. 143:1997;70-81 Along with [17], this work is perhaps the clearest demonstration that chronically injured CNS neurons not only maintain the ability to regenerate, but also can increase their rate of growth in the presence of neurotrophic support. It will be very important to understand the manner in which particular neurons respond to particular neurotrophic factors. Owing to the design of these experiments, potential regrowth back into the spinal cord was not tested. There are some differences in the specificity of neurotrophic factors observed in this study compared to [29]. For example, CNTF increases axonal growth into peripheral nerve grafts but not into spinal cord transplants [29]. It is likely that there is an interaction between CNTF and Schwann cells that influences the growth of supraspinal axons into the peripheral nerve grafts. Thus, one must not only examine the intrinsic trophic requirements of particular populations of neurons, but also be aware that trophic dependency may be further regulated by the environment encountered by the growing axons.
16. Houle JD, Ye JH, Kane CJM. Axonal regeneration by chronically injured supraspinal neurons can be enhanced by exposure to insulin-like growth factor, basic fibroblast growth factor or transforming growth factor beta. Restorative Neurol Neurosci. 10:1997;205-215.
17. of special interest Houle JD, Ye JH. Changes occur in the ability to promote axonal regeneration as the post-injury period increases. of outstanding interest Neuroreport. 8:1997;751-755 This study is important because it begins to define some of the temporal parameters that affect axonal regeneration. The capacity of some brainstem spinal neurons to regenerate decreases by approximately 50% between 4 and 8 weeks after injury. See also annotation [15].
18. Feraboli-Lohnherr D, Orsal D, Yakovleff A, Gimenez y Ribotta M, Privat A. Recovery of locomotor activity in the adult chronic spinal rat after sublesional transplantation of embryonic nervous cells: specific role of serotonergic neurons. Exp Brain Res. 113:1997;443-453.
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21. Keirstead HS, Pataky DM, McGraw J, Steeves JD. In vivo immunological suppression of spinal cord myelin development. Brain Res Bull. 44:1997;727-734.
22. Nicholls JG, Saunders NR. Regeneration of immature mammalian spinal cord after injury. Trends Neurosci. 19:1996;229-234.
23. Hasan SJ, Kierstead HS, Muir GD, Steeves JD. Axonal regeneration contributes to repair of injured brainstem-spinal neurons in embryonic chick. J Neurosci. 13:1993;492-507.
24. Bregman BS. Spinal cord transplants permit the growth of serotonergic axons across the site of neonatal spinal cord transection. Dev Brain Res. 34:1987;265-279.
25. Miya D, Giszter S, Mori F, Adipudi V, Tessler A, Murray M. Fetal transplants after the development of function after spinal cord transection in newborn rats. of special interest J Neurosci. 17:1997;4856-4872 Earlier studies [24] showed that after thoracic spinal cord transection and transplants of fetal spinal cord tissue at the injury site, some of these transplanted rats recover locomotor function. The findings suggest that both axonal growth and nonspecific trophic influences of the transplants may contribute to the recovery observed.
26. Diener PS, Bregman BS. Fetal spinal cord transplants support growth of supraspinal and segmental projections after cervical spinal cord hemisection in the neonatal rat. of outstanding interest J Neurosci. 18:1998;779-793 See annotation [27].
27. Diener PS, Bregman BS. Fetal spinal cord transplants support the development of target reaching and coordinated postural adjustments after neonatal cervical spinal cord injury. of outstanding interest J Neurosci. 18:1998;763-778 Along with [26], this study was among the first to demonstrate that fetal spinal cord transplants into damaged neonatal spinal cord induce anatomical remodeling, which supports the recovery not only of rhythmic alternating movements, but also of more complex postural adjustments and skilled forelimb reaching. In this series of experiments, motor function was carefully examined both during development and at maturity.
28. Bregman BS, Diener PS, McAtee M, Dai HN, James CV. Intervention strategies to enhance anatomical plasticity and recovery of function after spinal cord injury. Adv Neurol. 72:1997;257-275.
29. of outstanding interest Bregman BS, McAtee M, Dai HN, Kuhn PL. Neurotrophic factors increase axonal growth after spinal cord injury and transplantation in the adult rat. of special interest Exp Neurol. 148:1997;475-494 These results indicate that in addition to influencing the survival of developing CNS and PNS neurons, neurotrophic factors influence injured mature CNS neurons by increasing their axonal growth into transplants. The study suggests that there may be some synergistic interaction between the neurotrophic influence on the cell body [4] and the environment encountered by the growing axons. The work also suggests that axonal elongation and branching are regulated independently. These results, together with others [15], suggest that in the damaged CNS and PNS, neuron-specific trophic requirements interact with the environment encountered by the growing axons.
30. Oudega M, Hagg T. Nerve growth factor promotes regeneration of sensory axons into adult rat spinal cord. Exp Neurol. 140:1996;218-229.
31. Oudega M, Varon S, Hagg T. Regeneration of adult rat sensory axons into intraspinal nerve grafts: promoting effects of conditioning lesion and graft predegeneration. Exp Neurol. 129:1994;194-206.
32. Xu XM, Guenard V, Kleitman N, Bunge MB. Axonal regeneration into Schwann cell-seeded guidance channels grafted into transected adult rat spinal cord. J Comp Neurol. 351:1995;145-160.
33. Xu XM, Guenard V, Kleitman N, Aebischer P, Bunge MB. A combination of BDNF and NT-3 promotes supraspinal axonal regeneration into Schwann cell grafts in adult rat thoracic spinal cord. Exp Neurol. 134:1995;261-272.
34. Oudega M, Xu XM, Guenard V, Kleitman N, Bunge MB. A combination of insulin-like growth factor-I and platelet-derived growth factor enhances myelination but diminishes axonal regeneration into Schwann cell grafts in the adult rat spinal cord. Glia. 19:1997;247-258.
35. Tuszynski MH, Gabriel K, Gage FH, Suhr S, Meyer S, Rosetti A. Nerve growth factor delivery by gene transfer induces differential outgrowth of sensory, motor, and noradrenergic neurites after adult spinal cord injury. Exp Neurol. 137:1996;157-173.
36. Tuszynski MH, Murai K, Blesch A, Grill R, Miller I. Functional characterization of NGF secreting cell grafts to the acutely injured spinal cord. Cell Transpl. 6:1997;361-368.
37. Grill R, Murai K, Blesch A, Gage FH, Tuszynski MH. Cellular delivery of neurotrophin-3 promotes corticospinal axonal growth and partial functional recovery after spinal cord injury. of outstanding interest J Neurosci. 17:1997;5560-5572 This important work reports the beneficial effects of neurotrophin-3 (NT-3) - secreted by transgenically modified cells - on morphological and functional disturbances after corticospinal axotomy. The local delivery of NT-3 supports anatomical regrowth of corticospinal axons and some recovery of motor function.
38. Shihabuddin LS, Ray J, Gage FH. FGF-2 is sufficient to isolate progenitors found in the adult mammalian spinal cord. of special interest Exp Neurol. 148:1997;577-586 This work suggests that in addition to other strategies aimed at replacing cells to repair injured spinal cord, it is possible to influence progenitors within the adult mammalian spinal cord. When isolated, these progenitors give rise to both neuronal and glial phenotypes.
39. McTigue DM, Horner PJ, Stokes BT, Gage FH. Neurotrophin-3 and brain-derived neurotrophic factor induce oligodendrocyte proliferation and myelination of regenerating axons in the contused adult rat spinal cord. J Neurosci. 18:1998;5354-5365.
40. Fournier AE, McKerracher L. Expression of specific tubulin isotypes increases during regeneration of injured CNS neurons, but not after the application of brain-derived neurotrophic factor (BDNF). of outstanding interest J Neurosci. 17:1997;4623-4632 This important study highlights the important distinctions between the response of particular neurons to neurotrophic factors in vitro and in vivo. Despite the ability of BDNF to support the survival of injured retinal ganglion cells and enhance neurite outgrowth in vitro, it is unable to induce changes in regeneration-associated genes in vivo. It is likely that complex interactions between neurotrophins and the substrate encountered by the regrowing axons regulate the capacity for regeneration.
41. Ramon-Cueto A, Plant GW, Avila J, Bunge MB. Long-distance axonal regeneration in the transected adult rat spinal cord is promoted by olfactory ensheathing glia transplants. of outstanding interest J Neurosci. 18:1998;3803-3815 Along with [42], this paper demonstrates that olfactory ensheathing glial transplanted to the lesion site, are able to migrate and appear to overcome any inhibitory influence of CNS myelin. The olfactory ensheathing cells support the regrowth of axons over long distances within the spinal cord. This study is important in that it demonstrates convincingly that this cell type is able to support axonal regeneration after extensive disruption of the CNS environment.
42. Li Y, Field PM, Raisman G. Repair of adult rat corticospinal tract by transplants of olfactory ensheating cells. of outstanding interest Science. 277:1997;2000-2002 Along with [41], this study demonstrates the contribution of olfactory ensheating cells to axonal regeneration after spinal cord injury. In this study, axonal regrowth was associated with improvements in forelimb motor function.
43. Schwab ME, Bartholdi D. Degeneration and regeneration of axons in the lesioned spinal cord. Physiol Rev. 76:1996;319-370.
44. Silver J. Inhibitory molecules in development and regeneration. J Neurol. 242:1994;22-44.
45. Fitch MT, Silver J. Glial cell extracellular matrix: boundaries for axon growth in development and regeneration. Cell Tissue Res. 290:1997;379-384.
46. Fawcett JW. Astrocytic and neuronal factors affecting axon regeneration in the damaged central nervous system. Cell Tissue Res. 290:1997;371-377.
47. McKerracher L, David S, Jackson DL, Kottis V, Dunn RJ, Braun PE. Identification of myelin-associated glycoprotein as a major myelin-derived inhibitor of neurite growth. Neuron. 13:1994;805-811.
48. Tang S, Woodhall RW, Shen YJ, Debellard ME, Saffell JL, Doherty P, Filbin MT. Soluble myelin-associated glycoprotein (MAG) found in vivo inhibits axonal regeneration. Mol Cell Neurosci. 9:1997;333-346.
49. Davies SJA, Fitch MT, Member GSP, Hall AK, Raisman G, Silver J. Regeneration of adult axons in white matter tracts of the central nervous system. of outstanding interest Nature. 390:1997;680-683 Using microtransplantation of DRG neurons to CNS white matter, the authors demonstrate the critical role for astrocytes in inhibiting axonal regeneration. Astrocytes express proteoglycans within the extracellular matrix. Thus, the contribution of astrocytes in limiting regeneration is not simply a physical impediment, but also a chemical one as they change the environment of the growing axons. A surprising finding in these studies is that beyond the lesion site itself, the adult DRG neurons are able to grow within CNS white matter. It is not yet clear whether these neurons have particular characteristics that enable them to overcome myelin-inhibitory influences or whether most neurons are capable of such growth.
50. Fitch MT, Silver J. Activated macrophages and the blood-brain barrier: inflammation after CNS injury leads to increases in putative inhibitory molecules. of special interest Exp Neurol. 148:1997;587-603 This important study describes some of the signals that lead to increased expression of chondroitin sulfate proteoglycans (CSPGs) at the injury site. Increases in CSPGs after CNS injury are associated with the breakdown of the blood - brain barrier and the infiltration of macrophages at the lesion site. The inhibitory influences on axonal elongation after injury are complex. Along with [49], this study indicates that the conditions that restrict growth at the injury site itself and the environment more distal to the injury combine to limit plasticity in the mature CNS after injury.
51. Roy RR, Talmadge RJ, Hodgson JA, Zhong H, Baldwin KM, Edgerton VR. Training effects on soleus of cats spinal cord transected (T12-13) as adults. Muscle Nerve. 21:1998;63-71.
52. Edgerton VR, DeLeon RD, Tillakaratne N, Recktenwald NR, Hodgson JA, Roy RR. Use-dependent plasticity in spinal stepping and standing. of outstanding interest Adv Neurol. 72:1997;233-248 The authors demonstrate the very important finding that not only is there plasticity in the spinal cord circuitry caudal to a transection, but also that the function of that circuitry can be modified by sensory-motor input and training. This opens a very exciting avenue for future studies in animals and humans to define the contribution of various rehabilitation strategies to recovery of motor function after spinal cord injury.
53. Harkema SJ, Hurley SL, Patel UK, Requejo S, Dobkin BH, Edgerton VR. Human lumbosacral spinal cord interprets loading during stepping. J Neurophysiol. 77:1998;797-811.
54. Chau C, Barbeau H, Rossignol S. Early locomotor training with clonidine in spinal cats. of outstanding interest J Neurophysiol. 79:1998;392-409 In this study, the authors examined the effect of combined pharmacological intervention and intensive training on recovery after spinal cord transection. The exciting observation here is that early training combined with pharmacological intervention to facilitate stepping led to increased recovery of locomotion in spinal cats. Thus, from both cell biological (see main text of review) and functional perspectives, the combination of treatment strategies leads to greater improvements than do individual treatments. It is going to be critical to understand the manner in which particular interventions after spinal cord injury facilitate or restrict axonal regrowth and recovery of function.
55. Barbeau H, Rossignol S. Initiation and modulation of the locomotor pattern in the adult chronic spinal cat by noradrenergic, serotonergic and dopaminergic drugs. Brain Res. 546:1991;250-260.
56. Chau C, Barbeau H, Rossignol S. Effects of intrathecal alpha1 and alpha2 noradrenergic agonists and norepinephrine on locomotion in chronic spinal cats. of outstanding interest J Neurophysiol. 79:1998;2941-2963 This important study shows that the administration of different subclasses of noradrenergic drugs has very specific effects on locomotor function. This finding suggests that treatment strategies may be designed to target specific aspects of locomotor deficits in patients after spinal cord injury. Again, much work needs to be done to understand the way in which particular pathways contribute to the recovery of movement after injury. It will be critical to understand the way in which even limited descending input (or substitutes for that input) interacts with the segmental circuitry caudal to the injury (see [52,54]).