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.

Proteomic Characterization of Human Neural Stem Cells and Their Secretome During in vitro Differentiation

“…NSCs/NPCs are among cell sources considered or already used in clinical trials for cell-based therapies in neurological conditions including neurodegenerative diseases, e.g., Alzheimer's disease (Oliver and Reddy, 2019 ; Hayashi et al, 2020 ; Liu et al, 2020 ), Parkinson's disease (Díaz, 2019 ; Oliver and Reddy, 2019 ; Harris et al, 2020 ), amyotrophic lateral sclerosis (Abati et al, 2019 ), spinal cord injuries (Ahuja et al, 2020 ), stroke (Suda et al, 2020 ), or multiple sclerosis (Cuascut and Hutton, 2019 ; Pluchino et al, 2020 ). Currently, 40 studies employing NSCs/NPCs are Active or Completed according to ClinicalTrials.gov .…”

One Raft to Guide Them All, and in Axon Regeneration Inhibit Them

“…Therapeutic approaches are mainly focused on blocking inhibitory components present in the glial scar, neuronal replacement and axon growth enhancement. These strategies comprise the design of inhibitory compounds to block the Nogo receptors or CSPGs [ 83 , 155 ], the application of new cell-based therapies to replace the damaged tissue, the promotion of neuroprotection, modulation of the immune response [ 156 , 157 , 158 ], and the use of bioactive materials that will be combined with cells and soluble molecules to recreate developmental environments that enhance neuronal regrowth and restore its functionality [ 159 , 160 , 161 ]. Among the limitations of neural transplantation therapies are the poor rate of survival, as well as the lack of plasticity and integration of transplanted cells.…”

Comparison of the effects of two therapeutic strategies based on olfactory ensheathing cell transplantation and repetitive magnetic stimulation after spinal cord injury in female mice

“…Spinal cord injury (SCI) is an incurable disease, which leads to a permanent loss of motor, and sensitive functions below the injury site (Ahuja et al., 2020). Indeed, SCI induces an interruption of the afferent and efferent pathways due to the disruption of axonal tracts.…”

“…The second approach is based on promoting neuroregeneration by enhancing axonal regrowth or replacing lost cells (Ahuja et al., 2020). Indeed, based on several experimental paradigms, studies have reported that functional recoveries can be promoted after SCI in rodents by using neurotrophic factors infusion, cell transplantation, peripheral nerve graft, or combination of different treatments (Decherchi et al., 1997; Kanno et al., 2014; Thornton et al., 2018).…”

“…In Humans this second approach is mainly based on cell transplantation. Thereby, several trials have been already conducted using autologous stem or differentiated cells (Ahuja et al., 2020; Badner et al., 2017).…”