Peripheral nerve regeneration.

The success of peripheral nerve regeneration is dependent on the survival of axotomized neurons, the efficacy of axonal outgrowth from those neurons, and the specificity of reinnervation of peripheral targets by those neurons. Experimental evidence indicates that following peripheral injury, primary sensory (DRG) neurons and in some cases, motoneurons are lost. This cell death, which can involve one third or more of the axotomized neurons, suggests that some neurons in the adult are dependent on nerve or target-derived neurotrophic factors. One of these factors, NGF, when supplied to the cut proximal stump of the sciatic nerve, can save 100% of the DRG neurons that would normally succumb to axonal injury. But not all neurons are NGF-dependent, and other factors, including gonadal hormones, may be important to their survival following axotomy. Axonal elongation following peripheral nerve injury is dependent upon molecules in the extracellular matrix as well as secreted molecules from nonneuronal cells within the distal stump of the nerve. Extracellular matrix molecules such as laminin provide an adhesive substrate for axonal growth; but Schwann cells in the distal stump, which have been shown to synthesize increased amounts of NGF following peripheral nerve injury, appear to be essential for axonal elongation. Although neuronal survival and the efficacy of axonal elongation are important to peripheral nerve regeneration, the most important determinant of the success of peripheral nerve regeneration is the specificity of reinnervation. There remains some debate over whether regenerating axons are physically guided to the appropriate targets by mechanical guides in the form of basal laminar tubes, or whether they are lured by neurotropic factors derived from the distal nerve stump and targets. There is evidence that both factors are operative in the adult PNS. However, although recent data suggest that neurotropic factors within the adult nerve can influence the sorting of regenerating axons, clinical and experimental data indicate that physical constraints of nerve cytoarchitecture can override those tropic factors. Finally, although some degree of specificity of reinnervation of peripheral targets has been demonstrated, particularly for sensory receptors in skin and muscle, there are typically perturbations of sensation and movement due to axonal misrouting and aberrant reinnervation. Further laboratory research is needed to understand how neuron-target specificity is established during development of the PNS and to determine how the developmental mechanisms can be exploited to reestablish that specificity following peripheral nerve injury.