Abstract

BackgroundSpinal cord injury (SCI) presents a significant challenge for the field of neurotherapeutics. Stem cells have shown promise in replenishing the cells lost to the injury process, but the release of axon growth-inhibitory molecules such as chondroitin sulfate proteoglycans (CSPGs) by activated cells within the injury site hinders the integration of transplanted cells. We hypothesised that simultaneous application of enteric neural stem cells (ENSCs) isolated from the gastrointestinal tract, with a lentivirus (LV) containing the enzyme chondroitinase ABC (ChABC), would enhance the regenerative potential of ENSCs after transplantation into the injured spinal cord.MethodsENSCs were harvested from the GI tract of p7 rats, expanded in vitro and characterised. Adult rats bearing a contusion injury were randomly assigned to one of four groups: no treatment, LV-ChABC injection only, ENSC transplantation only or ENSC transplantation+LV-ChABC injection. After 16 weeks, rats were sacrificed and the harvested spinal cords examined for evidence of repair.ResultsENSC cultures contained a variety of neuronal subtypes suitable for replenishing cells lost through SCI. Following injury, transplanted ENSC-derived cells survived and ChABC successfully degraded CSPGs. We observed significant reductions in the injured tissue and cavity area, with the greatest improvements seen in the combined treatment group. ENSC-derived cells extended projections across the injury site into both the rostral and caudal host spinal cord, and ENSC transplantation significantly increased the number of cells extending axons across the injury site. Furthermore, the combined treatment resulted in a modest, but significant functional improvement by week 16, and we found no evidence of the spread of transplanted cells to ectopic locations or formation of tumours.ConclusionsRegenerative effects of a combined treatment with ENSCs and ChABC surpassed either treatment alone, highlighting the importance of further research into combinatorial therapies for SCI. Our work provides evidence that stem cells taken from the adult gastrointestinal tract, an easily accessible source for autologous transplantation, could be strongly considered for the repair of central nervous system disorders.

Highlights

  • Spinal cord injury (SCI) presents a significant challenge for the field of neurotherapeutics

  • Combined treatment with Enteric neural stem cell (ENSC)+chondroitinase ABC (ChABC) resulted in significant improvements in the horizontal ladder test only in week 16 Rats were assessed for their ability to traverse a horizontal ladder

  • ENSCs were isolated from dissected intestines of WT Sprague Dawley rat pups (P7) via FACS using antibodies raised against p75 (Fig. 2a shows a typical FACS profile)

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Summary

Introduction

Spinal cord injury (SCI) presents a significant challenge for the field of neurotherapeutics. Neural stem cells taken from the subventricular/subgranular zones of the brain, or the ependymal canal of the spinal cord, are able to replace the cells lost due to the injury process and have resulted in significant improvements [20]. Induced pluripotent stem cells (iPSCs) are advantageous in many ways, including their extensive reprogramming potential and the possibility of autologous transplantations [23]. All of these stem cell sources show exciting promise [24,25,26,27,28,29], but no single stem cell source represents an ideal solution. Potential alternative sources should be evaluated to determine whether they represent a significant advantage over existing options

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