Extrinsic and intrinsic mechanisms of axon regeneration: the need for spinal cord injury treatment strategies to address both.

Abstract

Spinal cord injury (SCI) causes disturbances in motor and sensory functions leading to paralysis, the severity of which depends on the spinal level of the injury. Traumatic lesions of spinal cord axon projection tracts are untreatable in human patients, although numerous research groups worldwide are studying putative treatment strategies. Both extrinsic factors in the environment of the axons as well as intrinsic factors in the neurons themselves play important roles in the regeneration process (Chew et al., 2012). The peripheral nervous system (PNS) provides a good example where the extrinsic and intrinsic factors play optimally together to allow regeneration. Schwann cells dedifferentiate and form new endoneurial tubes for the axons to grow through. Together with macrophages they clear the debris and produce growth factors and cytokines that positively stimulate the neurons. In parallel, the neurons intrinsically react to the injury by activating a regeneration-associated gene expression program. Most PNS axons produce a new growth cone and start growing within 3 hours (Bradke et al., 2012), eventually reinnervating their targets. In contrast, the projection neurons in the central nervous system (CNS) do not spontaneously activate regeneration-associated genes (RAGs) (van Kesteren et al., 2011). The axons first die back several hundreds of micrometers, tend to make retraction bulbs rather than growth cones, and seem unable to navigate in the correct direction (Bradke et al., 2012). Those CNS axons that do regenerate encounter a highly inhibitory scar that further blocks their growth (Fawcett et al., 2012). So, in the CNS both intrinsic and extrinsic mechanisms negatively influence regeneration. This is further corroborated by the observation that some spinal cord axons are able to regenerate through a peripheral nerve graft (van Kesteren et al., 2011) indicating again that the PNS environment is favorable to growth. However, the majority of injured neurons in the spinal cord do not regenerate spontaneously, so that peripheral nerve grafts still need to be combined with treatments such as cAMP, increasing the intrinsic regeneration capacity (Bunge, 2008). In this paper, I will address the extrinsic and intrinsic regeneration mechanisms with respect to treatments for SCI.