Abstract

After CNS injury, axon regeneration is blocked by an inhibitory environment consisting of the highly upregulated tenascin-C and chondroitin sulfate proteoglycans (CSPGs). Tenascin-C promotes growth of axons if they express a tenascin-binding integrin, particularly α9β1. Additionally, integrins can be inactivated by CSPGs, and this inhibition can be overcome by the presence of a β1-binding integrin activator, kindlin-1. We examined the synergistic effect of α9 integrin and kindlin-1 on sensory axon regeneration in adult rat spinal cord after dorsal root crush and adeno-associated virus transgene expression in dorsal root ganglia. After 12 weeks, axons from C6-C7 dorsal root ganglia regenerated through the tenascin-C-rich dorsal root entry zone into the dorsal column up to C1 level and above (>25 mm axon length) through a normal pathway. Animals also showed anatomical and electrophysiological evidence of reconnection to the dorsal horn and behavioral recovery in mechanical pressure, thermal pain, and ladder-walking tasks. Expression of α9 integrin or kindlin-1 alone promoted much less regeneration and recovery. The study demonstrates that long-distance sensory axon regeneration over a normal pathway and with sensory and sensory-motor recovery can be achieved. This was achieved by expressing an integrin that recognizes tenascin-C, one of the components of glial scar tissue, and an integrin activator. This enabled extensive long-distance (>25 mm) regeneration of both myelinated and unmyelinated sensory axons with topographically correct connections in the spinal cord. The extent of growth and recovery we have seen would probably be clinically significant. Restoration of sensation to hands, perineum, and genitalia would be a significant improvement for a spinal cord-injured patient.

Highlights

  • After injury, CNS axons fail to regenerate because of the presence of inhibitory factors, the lack of growth-promoting factors in Received March 17, 2016; revised May 5, 2016; accepted May 30, 2016

  • We examined the synergistic effect of ␣9 integrin and kindlin-1 on sensory axon regeneration in adult rat spinal cord after dorsal root crush and adeno-associated virus transgene expression in dorsal root ganglia

  • The aim of this study was to examine whether the expression of the tenascin-binding ␣9 integrin with an integrin activator, kindlin-1, could promote extensive sensory axon regeneration in the spinal cord

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Summary

Introduction

CNS axons fail to regenerate because of the presence of inhibitory factors, the lack of growth-promoting factors in Received March 17, 2016; revised May 5, 2016; accepted May 30, 2016. The combination of CSPGs, tenascin-C, Nogo-A, semaphorin 3A, and other inhibitory molecules forms an inhibitory environment for axon regeneration (Milev et al, 1997; Probstmeier et al, 2000; Pasterkamp and Verhaagen, 2006; Kwok et al, 2014). Of these molecules, tenascin-C is of particular

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