Regenerative replacement of neural cells for treatment of spinal cord injury

ABSTRACT

Introduction: Traumatic Spinal Cord Injury (SCI) results from primary physical injury to the spinal cord, which initiates a secondary cascade of neural cell death. Current therapeutic approaches can attenuate the consequences of the primary and secondary events, but do not address the degenerative aspects of SCI. Transplantation of neural stem/progenitor cells (NPCs) for the replacement of the lost/damaged neural cells is suggested here as a regenerative approach that is complementary to current therapeutics.

Areas Covered: This review addresses how neurons, oligodendrocytes, and astrocytes are impacted by traumatic SCI, and how current research in regenerative-NPC therapeutics aims to restore their functionality. Methods used to enhance graft survival, as well as bias progenitor cells towards neuronal, oligodendrogenic, and astroglia lineages are discussed.

Expert Opinion: Despite an NPC’s ability to differentiate into neurons, oligodendrocytes, and astrocytes in the transplant environment, their potential therapeutic efficacy requires further optimization prior to translation into the clinic. Considering the temporospatial identity of NPCs could promote neural repair in region specific injuries throughout the spinal cord. Moreover, understanding which cells are targeted by NPC-derived myelinating cells can help restore physiologically-relevant myelin patterns. Finally, the duality of astrocytes is discussed, outlining their context-dependent importance in the treatment of SCI.

KEYWORDS:

• Neural progenitor cells (NPCS)
• astrocytes
• neurons
• oligodendrocytes
• spinal cord injury (SCI)
• stem cell therapy

Article highlights

• Spinal cord injury elicits damage to the three major cell types of the central nervous system: neurons, oligodendrocytes, and astrocytes. Current clinical practices are incapable of regenerating the cells that have been lost.

• Neural progenitor cells exhibit a promising therapeutic strategy to complement clinical practice by replacing the three cell types that are lost after injury.

• Restoring synaptic connectivity between the spared circuitry and grafted cellular domains is essential to promote functional recovery. Considering the molecular regional identity of graft-derived neurons, as well as the resulting neuronal subtypes, can optimize integration and target-specific behavioral outcomes.

• Transplanting myelinating cells aims to promote signal transduction and axonal survival. Myelinating cells, including neural progenitor cells and oligodendrocyte precursor cells, can be further manipulated in culture in order to enhance the extent of remyelination.

• Astrocytes are often considered to be maladaptive to regeneration; however, their therapeutic potential has been previously overlooked. By modifying their state in vitro, different astrocyte subpopulations may be beneficial when transplanted in different stages of spinal cord injury.

This box summarizes key points contained in the article.

Acknowledgments

All figures have been made using BioRender. We thank Dr. Tim Worden (University Health Network, Canada) for editing the manuscript.

Declaration of interest

WB McIntyre is supported by the Unilever/Lipton Graduate Fellowship in Neurosciences. K Pieczonka is supported by the Institute of Medical Science, University of Toronto, Open Fellowship. M Khazaei is supported by grants from Wings for Life, Krembil Foundation and Canadian Institutes of Health Research (CIHR). MG Fehlings is supported by is supported by the Halbert Chair in Neural Repair and Regeneration and the Dezwirek Foundation. The author(s) have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper is not funded.