Putting the spinal cord together again.

Abstract

Demonstration of successful spinal cord regeneration in experimental models is nontrivial. It requires unambiguous proof that injured and not neighboring intact neurons have grown, that novel functional synapses have been established, and that these are responsible for any improvement in functional recovery and that any such recovery is not accompanied by maladaptive function. Very few studies fulfill all these criteria, and consequently there is often uncertainty as to how much regeneration has occurred and its functional significance. The rate of recent progress indicates, though, that we are likely to learn soon why regeneration fails in the adult CNS and may be able to devise technical approaches to use this knowledge to further enhance regeneration.The therapeutic strategies necessary to achieve successful spinal cord regeneration are shown in Table 1Table 1. Given the complexity and diverse response of the CNS to injury, it is extremely unlikely that a single approach will suffice. Multiple interventions will be required at coordinated times to initiate, maintain, and guide regeneration of injured neurons from their site of injury to the appropriate target neurons, and to reestablish functional synaptic contact. Although cautious optimism is beginning to be appropriate, there are great scientific challenges that still need to be met before it is time to focus on or initiate clinical therapies.*To whom correspondence should be addressed (e-mail: woolf.clifford@mgh.harvard.edu).Table 1Strategies for Promoting Spinal Cord RegenerationObjectivesneuronal death/atrophyglial cell reaction/extracellular matrix formationdecrease inhibitory environment provide permissive environmentincrease growth response decrease response to inhibitory influences provide axon guidance cues ensure contact with appropriate target neuron promote synaptic differentiation prevent maladaptive connectivityTechniquesanti-inflammatory agents—methyl prednisoloneneuroprotection—glutamate receptor antagonists/ion channel blockers/growth factorstarget glial cell reactionvaccination against myelin proteins neutralizing antibodies/receptor bodies targeted at inhibitory proteins (Nogo, etc.) receptor antagonistsabort growth cone collapse—intracellular signal transduction modifierssupporting cell bridges—peripheral nerve grafts embryonic tissue/stem cell grafts Schwann cells/olfactory ensheathing glia acellular matrix conduitsadminister molecules that increase intrinsic growth capacity activate growth cone signal transduction cascades potassium channel blockers—optimizing conduction replace neurons—stem cell transplantsprovide guidance cues and ensure specific target recognition