Multi-target approaches to CNS repair: olfactory mucosa-derived cells and heparan sulfates

Abstract

Spinal cord injury (SCI) remains one of the biggest challenges in the development of neuroregenerative therapeutics. Cell transplantation is one of numerous experimental strategies that have been identified and tested for efficacy at both preclinical and clinical levels in recent years. In this Review, we briefly discuss the state of human olfactory cell transplantation as a therapy, considering both its current clinical status and its limitations. Furthermore, we introduce a mesenchymal stromal cell derived from human olfactory tissue, which has the potential to induce multifaceted reparative effects in the environment within and surrounding the lesion. We argue that no single therapy will be sufficient to treat SCI effectively and that a combination of cell-based, rehabilitation and pharmaceutical interventions is the most promising approach to aid repair. For this reason, we also introduce a novel pharmaceutical strategy based on modifying the activity of heparan sulfate, an important regulator of a wide range of biological cell functions. The multi-target approach that is exemplified by these types of strategies will probably be necessary to optimize SCI treatment.

Key points

  • The development of neuroregenerative therapeutics for spinal cord injury (SCI) is hampered by the limited ability of the CNS to regenerate, primarily owing to the non-permissive extracellular environment that is created following damage.

  • Approaches that target multiple biological pathways are likely to be the way forward for SCI treatment; potential multi-target therapeutic strategies include olfactory mucosa-derived mesenchymal stromal cells (OM-MSCs) and heparan sulfate mimetics.

  • OM-MSCs might offer advantages over conventional olfactory tissue transplantation approaches owing to their pro-reparative properties and ease of growth.

  • Heparan sulfates are known to bind many proteins, and their mimetics could affect numerous pathways after SCI, thereby enabling a polypharmacological approach to treatment.

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Fig. 1: Timeline of events following spinal cord injury.
Fig. 2: The olfactory system.
Fig. 3: Reparative effects of mesenchymal stromal cells.
Fig. 4: Cellular expression of CSPGs and HSPGs in the CNS.
Fig. 5: Regulation of cell signalling pathways by HSPGs.

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Acknowledgements

The authors’ work was supported by Medical Research Scotland (G.A.M., grant number MRS PhD-769-2014) and the Multiple Sclerosis Society of Great Britain (S.L.L., grant number 56).

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All authors researched data for the article and wrote the manuscript. S.L.L., G.A.M. and S.C.B. made substantial contributions to discussions of the content and edited and/or reviewed the manuscript before submission. A.G.W. researched and wrote the clinical section.

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Correspondence to Susan C. Barnett.

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Glossary

Epimerization

A structural change in an epimer, which is one of a pair of stereoisomers. For example, glucose and galactose are epimers of each other, as they differ only in the position of the hydroxyl group at C4 (chiral carbon atom).

1C4 chair

A cyclohexane conformation is any of several three-dimensional shapes that a cyclohexane molecule can assume while maintaining the integrity of its chemical bonds. The most important shapes are called chair, half-chair, boat and skew/twist-boat. The numbers on the C represent its position in the conformation: the superscript number is above the plane and the subscript number is below the plane. The chair conformation is the most stable conformer.

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Lindsay, S.L., McCanney, G.A., Willison, A.G. et al. Multi-target approaches to CNS repair: olfactory mucosa-derived cells and heparan sulfates. Nat Rev Neurol 16, 229–240 (2020). https://doi.org/10.1038/s41582-020-0311-0

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