Stem Cell Usage in Spinal Cord Injury Treatment

Spinal cord injury (SCI) is a devastating and complex condition characterized by spinal cord damage caused by sudden or sustained trauma. This can lead to a variety of neurological impairments such as axonal damage and neurological cell death (De Almeida et al., 2023) (Figure 1). Advances in medical research have resulted in the development of various therapeutic avenues aimed at promoting recovery and improving patient outcomes. Notable examples include the use of Chondroitinase ABC treatment and minocycline, induced pluripotent stem cells, as well as riluzole. This essay aims to evaluate the current and potential therapeutic avenues used in SCI research, with a specific focus on these experimental examples. 

Current Therapeutic Avenues 

1. Chondroitinase ABC treatment 

SCI is strongly linked with the upregulation of inhibitory chondroitin sulfate proteoglycans (CSPGs) present within glial scars. This upregulation can result in the loss of locomotor function and inhibition of axonal regeneration. To overcome this problem, glial scars can be removed using Chondroitinase ABC (ChABC) treatment, which degrades the glycosaminoglycan side chains of CSPGs, improving functional recovery and axonal regeneration (De Almeida et al., 2023) (Figure 2.). Bradbury and colleagues' research using a contusion model backs up this claim (Bradbury et al., 2002). Adult rats were used in the study to simulate the mechanical trauma seen in SCI, with a focus on the thoracic level (T3) of the spinal cord. The rats were then split into two groups, one receiving ChABC treatment and the other serving as a control by receiving a control solution (penicillinase/saline). Histological analysis revealed that rats given the ChABC treatment had a significantly higher number of regenerating axons than the control group. Furthermore, using behavioural assessments such as the tape removal test and locomotor tasks, it was demonstrated that ChABC treatment resulted in improved motor function and increased sensitivity to tactile stimuli (Bradbury et al., 2002). Therefore, these findings provide important evidence supporting the potential therapeutic use of ChABC in the context of spinal cord contusion injuries. However, there were some limitations to this study. For instance, it lacked a group that received no treatment or a vehicle control, which hinders the ability to differentiate the specific effects of ChABC treatment from potential nonspecific effects of the treatment procedure. Moreover, the study’s use of behavioural assessments, such as tape removal tests, focus on one aspect of sensory perception (tactile sensation) and may not accurately capture the full spectrum of sensory functions affected by SCI, such as nociception and proprioception (Fagoe et al., 2016). 

2. Minocycline

While ChABC treatment shows promise in promoting axonal regeneration and functional recovery, other therapeutic avenues that target different aspects of SCI must be explored. Other drugs, such as minocycline, have also been studied in preclinical studies to see how they affect the inflammatory response. Minocycline reduces oligodendrocyte death, which may prevent early demyelination and axon degeneration (Almad et al., 2011) (Figure 2). This was highlighted in a preclinical study using a dorsal column transection model in adult rats to investigate the effects of minocycline treatment on various aspects of secondary injury response (Stirling, 2004). Animal footprints (splodges) were measured, as well as toe spread, angle of rotation of the foot, and limb coordination (Stirling, 2004). The effects of minocycline and saline were also compared, and it was discovered that minocycline improved limb coordination over saline. This implies that the functional outcomes observed in the foot analysis were improved, highlighting the therapeutic benefits of minocycline in the context of SCI. These promising preclinical results provided the rationale for conducting a human clinical trial to assess the efficacy and safety of minocycline in patients with acute traumatic SCI (Casha et al., 2012). It was discovered that patients who received minocycline had better motor recovery than those who received a placebo. This finding, however, was not statistically significant and should be interpreted with caution. Furthermore, when compared to the placebo group, cervical injured patients in the minocycline group had a significant improvement in motor function. More importantly, no such changes were observed in thoracic injured patients, implying that the therapeutic effects of minocycline may be influenced by the location and severity of the SCI. As a result, different treatment approaches for thoracic injured patients may be required.

Potential Therapeutic Avenues 

1. Induced pluripotent stem cells 

In light of the variable outcomes observed with minocycline and its potential dependency on the location and severity of SCI, exploring alternative therapeutic approaches becomes crucial. A promising area of research is the use of induced pluripotent stem cells (iPSCs). In animal models, administration of stem cells after traumatic SCI reduces neuronal loss and improves functional recovery (Villanova Junior et al., 2020). In a preclinical study, the effect of human iPSC-derived neural stem cells (hiPSC-NSCs) and umbilical cord-derived mesenchymal stem cells (huMSCs) on an acute SCI mouse model was tested (Kong et al., 2021) (Figure 3). The injury was performed, and the two different types of cells were then transported. The hiPSC-NSC group consistently outperformed the mice treated with MSCs and the control (saline) group on the Basso Mouse Scale (BMS) test (Kong et al., 2021). This suggests that iPSC transplantation improved hind limb motor function, locomotor function, and coordination significantly. The hiPSC-NSC group also outperformed the huMSC and control groups in terms of functional recovery. Furthermore, the muscles in the lower limbs and buttocks of mice in the hiPSC-NSC group showed less atrophy, indicating better muscle mass and function preservation (Kong et al., 2021). 

These findings suggest that iPSCs have therapeutic potential due to their ability to alleviate secondary damage and promote functional recovery in the injured spinal cord. However, some limitations should be considered. The specific timing of treatment in relation to the injury and transplantation is not specified, making it challenging to determine the optimal therapeutic window for stem cell intervention. Additionally, the absence of significant differences in the left/right stepping score between groups during the BMS observation period raises concerns about the actual potential of iPSCs in SCI treatment.

2. Riluzole 

Shifting focus to another potential therapeutic avenue, riluzole is a sodium channel blocker used in the treatment of amyotrophic lateral sclerosis. Riluzole slows the progression of this condition by increasing glutamate uptake, decreasing glutamate excitotoxicity, and exerting neuroprotective effects (Srinivas et al., 2019). Therefore, riluzole carries therapeutic potential for SCI, as demonstrated by Ates's preclinical study (Ates et al., 2007). Adult male rats were given Riluzole and other sodium channel blockers (Mexiletine, Phenytoin) after injury. Using the Basso, Beattie, and Bresnahan (BBB) locomotor rating scale, it was found that motor function score dropped significantly after SCI, indicating impaired motor function. Furthermore, when comparing those who received the vehicle (no drug) versus those who received any of the sodium channel blockers, the sodium channel blockers significantly improved motor function recovery over time. A plausible explanation for these findings is that excitotoxicity was reduced, which helps protect neurons and promote functional recovery (Ates et al., 2007). Additionally, when the drugs were administered intraperitoneally immediately following weight drop trauma to evaluate acute effects, Phenytoin and Riluzole caused significantly less SCI damage. This suggests that both of these drugs have neuroprotective effects by reducing the initial damage caused by the trauma. Despite these encouraging results, there are some limitations that should be considered. For instance, only male mice were used in the study, limiting its applicability to human populations. Because SCI affects both sexes, excluding female mice fails to account for potential gender differences in SCI response and treatment effectiveness (Klein et al., 2015). 

Overall, these findings suggest that Riluzole has therapeutic potential by not only protecting against initial injury but also by promoting regeneration and repair processes during the chronic stage of SCI. However, these positive results are contradicted by a recent study conducted by Nguyen and colleagues, which revealed pharmacokinetic issues with riluzole in the acute stage of SCI (Nguyen et al., 2021). The dynamic nature of traumatic SCI, characterized by significant changes and secondary injury processes, can greatly impact riluzole's bioavailability, thereby affecting its effectiveness. To address this issue, future studies should build upon these findings to develop a rational and optimal Riluzole dosing scheme in SCI patients, taking into account the time-dependent modifications required to maintain the required therapeutic exposure. This will help ensure that patients receive an appropriate and effective dose of Riluzole throughout the acute stage of SCI, maximising its potential benefits in promoting neuroprotection and functional recovery (Nguyen et al., 2021). 

Conclusion

Current SCI therapeutic options, such as ChABC treatment, show promise in improving functional recovery and axonal regeneration by degrading inhibitory CSPGs within glial scars. Minocycline, which has been shown to reduce cell death and improve limb coordination in dorsal column transection models, also shows promise. However, limitations in study design and the need for different treatment approaches for different types of SCI should be considered. Looking ahead, iPSCs and Riluzole hold promise as potential therapeutic options. iPSCs have been shown to improve motor function and preserve muscle mass in animal models. Riluzole showed neuroprotective effects and the potential to promote regeneration and repair in SCI models. Several constraints, however, must be considered, including optimising the timing and dosing of these treatments. Overall, current, and potential therapeutic approaches offer hope for improving recovery and the lives of individuals with SCI, but more research is needed to fully understand their effectiveness and implementation in clinical conditions.

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Yasmin Ouali is a twenty-one-year-old Neuroscience graduate from the United Kingdom, with a passion for both cats and reading research revolved around neurological disorders, neurotrauma, and their potential therapeutic avenues. In particular, she likes to critically analyse research findings and use illustrative material to showcase her understanding. In her free time, Yasmin enjoys reading drama and romance novels, piano and travelling – something she hopes to do more of during her gap year.

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