Adil Basha

Background: Spinal cord injury (SCI) is a pervasive issue that impacts the lives of almost 250,000 to 500,000 patients globally, with almost 282,000 people living with SCI in the United States alone.^1,4 SCIs can be caused by traumatic injury to the spinal cord brought on by fractured vertebrae or masses such as epidural hematomas or abscesses, compromised blood flow, inflammatory processes, metabolic issues, or exposure to toxins.² Spinal cord injury is an important issue because of the limited regenerative capacity of the nervous system. Many injuries lead to permanent loss of function in people who are affected, which is why finding mechanisms to bolster repair and recovery are important in restoring the autonomy and mobility of SCI patients.¹ A novel therapy for SCI is being developed that combines neuronal stem cell transplantation with immunomodulation, specifically targeting complement C5a.^4,5 By blocking the inflammatory cascade, the stem cell graft uptake and integration will improve, and reversal of the damage could result in a return of function.

Objective: In this narrative review, we reviewed the mechanisms of the complement pathway and how blocking C5a affected the neural stem cell graft uptake in the mouse model.

Search Method: An online search in the PubMed database was conducted from 2016 to 2020 using the following keywords: “spinal cord injury”, “complement C5a”, neuronal stem cells”, and “transplantation”.

Results: Results showed that the injection of C5a receptor antagonist in SCID-Beige mice resulted in increased levels of pro-inflammatory cytokines such as IL-1b, IL-6, TNF-alpha, and pro-inflammatory cells such as neutrophils and macrophages.³ Furthermore, graft uptake and cell survival was detected via fluorescence to be higher in the C5ARA and transplant (TP) group compared to the PBS groups, indicated by the GFP marker. Additionally, mice locomotor function was restored in the therapeutic group, measured via increases in rotor-rod and stride length tests, and a decrease in paw angle measurements. There were no statistically significant differences measured in the differentiation profile of grafted neuronal stem cells between the C5aRA +TP and the PBS + TP group.³

Conclusion: The study highlighted that antagonizing the C5a receptor and adding hiPSC-NS/PC transplanted cells in the treatment of thoracic spinal cord injury in mice was superior to the NS/PC transplantation alone or no transplantation at all.³ It showcased that C5a’s chemoattraction of leukocytes such as neutrophils, eosinophils and macrophages was diminished, which reduced the invasion of leukocytes into the site of injury, and subsequently reduced a deleterious inflammatory response that would lead to chronic disability.³  Future research efforts should focus on additional lymphocyte depression as T and NK cells can also produce C5a and may have impacted the findings in this study. Additionally, the CCX-168 C5a receptor antagonist should also be looked into for implementation due to its efficacy and compatibility in human clinical trials.³

Works Cited:

1. Burns AS, Marino RJ, Flanders AE, Flett H. Clinical diagnosis and prognosis following spinal cord injury. Handb Clin Neurol. 2019;109:47-62. doi:10.1016/B978-0-444-52137-8.00003-6
2. Ding W, Hu S, Wang P, et al. Spinal Cord Injury: The Global Incidence, Prevalence, and Disability From the Global Burden of Disease Study 2019. Spine (Phila Pa 1976). 2022;47(21):1532-1540. doi:10.1097/BRS.0000000000004417
3. Shibata R, Nagoshi N, Kajikawa K, et al. Administration of C5a Receptor Antagonist Improves the Efficacy of Human Induced Pluripotent Stem Cell-Derived Neural Stem/Progenitor Cell Transplantation in the Acute Phase of Spinal Cord Injury. J Neurotrauma. 2022;39(9-10):667-682. doi:10.1089/neu.2021.0225
4. van Den Hauwe L, Sundgren PC, Flanders AE. Spinal Trauma and Spinal Cord Injury (SCI). In: Hodler J, Kubik-Huch RA, von Schulthess GK, eds. Diseases of the Brain, Head and Neck, Spine 2020–2023: Diagnostic Imaging. Cham (CH): Springer; February 15, 2020.231-240.
5. Curtis E, Martin JR, Gabel B, et al. A First-in-Human, Phase I Study of Neural Stem Cell Transplantation for Chronic Spinal Cord Injury. Cell Stem Cell. 2018;22(6):941-950.e6. doi:10.1016/j.stem.2018.05.014