The leading edge: Emerging neuroprotective and neuroregenerative cell-based therapies for spinal cord injury

Abstract

Spinal cord injuries (SCIs) are associated with tremendous physical, social, and financial costs for millions of individuals and families worldwide. Rapid delivery of specialized medical and surgical care has reduced mortality; however, long-term functional recovery remains limited. Cell-based therapies represent an exciting neuroprotective and neuroregenerative strategy for SCI. This article summarizes the most promising preclinical and clinical cell approaches to date including transplantation of mesenchymal stem cells, neural stem cells, oligodendrocyte progenitor cells, Schwann cells, and olfactory ensheathing cells, as well as strategies to activate endogenous multipotent cell pools. Throughout, we emphasize the fundamental biology of cell-based therapies, critical features in the pathophysiology of spinal cord injury, and the strengths and limitations of each approach. We also highlight salient completed and ongoing clinical trials worldwide and the bidirectional translation of their findings. We then provide an overview of key adjunct strategies such as trophic factor support to optimize graft survival and differentiation, engineered biomaterials to provide a support scaffold, electrical fields to stimulate migration, and novel approaches to degrade the glial scar. We also discuss important considerations when initiating a clinical trial for a cell therapy such as the logistics of clinical-grade cell line scale-up, cell storage and transportation, and the delivery of cells into humans. We conclude with an outlook on the future of cell-based treatments for SCI and opportunities for interdisciplinary collaboration in the field.

Keywords: clinical trials; neuroprotection; neuroregeneration; spinal cord injury; stem cells.

FIGURE 1

Pathophysiology of traumatic spinal cord injury. “(a) The initial mechanical trauma to the spinal cord initiates a secondary injury cascade that is characterized in the acute phase (that is, 0–48 hours after injury) by oedema, haemorrhage, ischaemia, inflammatory cell infiltration, the release of cytotoxic products and cell death. This secondary injury leads to necrosis and/or apoptosis of neurons and glial cells, such as oligodendrocytes, which can lead to demyelination and the loss of neural circuits. (b) In the subacute phase (2–4 days after injury), further ischaemia occurs owing to ongoing oedema, vessel thrombosis and vasospasm. Persistent inflammatory cell infiltration causes further cell death, and cystic microcavities form, as cells and the extracellular architecture of the cord are damaged. In addition, astrocytes proliferate and deposit extracellular matrix molecules into the perilesional area. (c) In the intermediate and chronic phases (2 weeks to 6 months), axons continue to degenerate and the astroglial scar matures to become a potent inhibitor of regeneration. Cystic cavities coalesce to further restrict axonal regrowth and cell migration.” Republished with permission from Ahuja et al ¹⁵

FIGURE 2

A simplified schematic representation of a proposed endogenous neural stem cell (NCS) lineage. Within the central nervous system, the proposed lineage suggests two types of NSCs are present. Primitive NSCs (pNSCs) are a population of rare, leukemia inhibitory factor (LIF) responsive cells that give rise to more abundant definitive NSCs (dNSCs). dNSCs are responsive to EGF and FGF2 (EFH). NSC progeny (progenitor cells) give rise to neurons, astrocytes, and oligodendrocytes upon differentiation. This pathway is exploited for ESC‐ and iPSC‐based generation of NSCs, neurons and glia. Direct reprogramming allows somatic cells to enter the NSC or later stage without passing through the pluripotent state

FIGURE 3

Potential considerations during intraparenchymal transplant of stem cells into the spinal cord. These considerations apply to perilesional parenchymal transplants; however, other considerations apply when transplanting directly into lesion or cavity sites where parenchymal volume and cord architecture are already lost. A, Stem cell grafts can be delivered by fine needles or catheters to the gray matter (ventral horn, dorsal horn, etc.) or white matter (dorsal tracts, lateral tracts, ventral tracts, etc.). The spinal cord is most commonly approached dorsally, however, dorsolateral and ventral techniques are also possible depending on the surgical approach. B, Multiple factors affect graft delivery. Higher syringe injection speeds lead to compressive forces on the graft, however, lower speeds increase operative time and allow cell‐cell adhesion to occur which can clog the needle or cause membrane disruption. Thin needles can causes greater shearing forces on cells as they exit the tip, whereas thick needles cause greater parenchymal damage and potentially allow a wider needle tract for graft efflux. Larger transplant volumes allow larger doses of cells, however, volumes are limited by surrounding tissue. Respiratory and cardiac cycles typically continue during grafting, which can potentially cause microtrauma and cell efflux around the transplant needle