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Combined treatment with enteric neural stem cells and chondroitinase ABC reduces spinal cord lesion pathology

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Benjamin Jevans, Nicholas D. James, Emily Burnside, Conor J. McCann, Nikhil Thapar, Elizabeth J. Bradbury, Alan J. Burns

Original languageEnglish
Article number10
JournalStem Cell Research and Therapy
Volume12
Issue number1
DOIs
PublishedDec 2021

Bibliographical note

Funding Information: This work was funded by a grant from the Anatomical Society awarded to AJB, and the UK Medical research Council (SNCF G1002055) awarded to EJB. NT was supported by the Great Ormond Street Hospital Children’s Charity (GOSHCC - V1258). Funding Information: The authors gratefully acknowledge Professor Joost Verhaagen (Netherlands Institute for Neuroscience) for the use of the ChABC lentiviral construct. We would also like to thank Dr. Ayad Eddaoudi and Ms. Stephanie Canning (UCL Great Ormond Street Institute of Child Health Flow Cytometry Facility) and Dr. Dale Moulding (UCL Great Ormond Street Institute of Child Health Imaging Facility) for technical assistance. The authors would like to acknowledge the NIHR Great Ormond Street Hospital Biomedical Research Centre which supports all research at Great Ormond Street Hospital NHS Foundation Trust and UCL Great Ormond Street Institute of Child Health. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. Publisher Copyright: © 2020, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

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Abstract

Background: Spinal 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. Methods: ENSCs 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. Results: ENSC 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. Conclusions: Regenerative 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.

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