Seth Johnston

Background: Spinal cord injury (SCI) is a costly disease with comorbidities that impact every major organ system. Traditionally, many spinal cord injuries (SCI) result in permanent injuries with little positive prognosis. Many injuries involve young male adults, which not only affects their physical and mental state, but negatively impacts their family and caretakers². This creates a hopelessness and burden on patients and their families. SCI’s are split into two injuries; a primary injury, typically due to a mechanical injury of some kind, and a secondary, the after effects of the primary injury, including spinal ischemia, neuroinflammation, apoptosis, necrosis, and scar formations.³  Damage from an SCI is best mitigated during the acute phase (within 18 months of the onset) before it progresses to the chronic phase (post 18 months).¹ SCI prognosis depends upon the criteria they fulfill. Neurological and Functional Classification Standard of the American Spinal Injury Association (ASIA) Impairment Scale (AIS) is the standard for analyzing the extent of the damage and can be an indicator of prognosis.¹ Many treatments are used for these patients, but there is little positive success of recovery beyond physical therapy. One such promising treatment is Neural Stem Cell therapy, which is explored in further detail below.³

Objective: In this review, we explore the current research for treatment of SCI with Neural Stem Cell therapy  therapy and possible augmentation with Brain Derived Neurotrophic Factor (BDNF) through the TrkB pathway and other mechanisms.⁶

Research Methods: An online search in PubMed database for articles published between 2018-2023.

Results: Current use of Neural Stem Cell therapy in primates shows promising growth of axons and recovery of neural tissue. However, gross motor function was not significantly improved¹¹. In order to augment this therapy, researchers added BDNF to a Neural Stem Cell graft in primates, which works through the TrkB pathway to cause cell growth and differentiation. While motor function did improve, the greatest result was a 5.5 fold increase of neurons and 20 fold increase in neural connections to host neurons⁵. These results demonstrated the possibility of augmenting Neural Stem Cell therapy to improve overall outcomes. Route of administration can impact overall improvement of the therapy. In two different studies, grafts overexpressed BDNF so it did not have to be administered separately⁷. Additionally, one graft was injected in a distant site in extracellular small vesicles that homed to ischemic tissue ⁸. Two other studies demonstrated co-administering an anti-inflammatory and a gene knock out for the thrombin cascade that resulted in improved motor function for subjects ^9,10.

Conclusion: These studies demonstrate that while Neural Stem Cell therapy has current limitations in therapy, augmentation can make it a viable option for the future of treating SCI.

Works Cited:

1. Hu X, Xu W, Ren Y, et al. Spinal cord injury: molecular mechanisms and therapeutic interventions. Signal Transduct Target Ther. 2023;8(1):245. Published 2023 Jun 26. doi:10.1038/s41392-023-01477-6
2. Cofano F, Boido M, Monticelli M, et al. Mesenchymal Stem Cells for Spinal Cord Injury: Current Options, Limitations, and Future of Cell Therapy. Int J Mol Sci. 2019;20(11):2698. Published 2019 May 31. doi:10.3390/ijms20112698
3. Anjum A, Yazid MD, Fauzi Daud M, et al. Spinal Cord Injury: Pathophysiology, Multimolecular Interactions, and Underlying Recovery Mechanisms. Int J Mol Sci. 2020;21(20):7533. Published 2020 Oct 13. doi:10.3390/ijms21207533
4. National Spinal Cord Injury Statistical Center, Traumatic Spinal Cord Injury Facts and Figures at a Glance. Birmingham, AL: University of Alabama at Birmingham, 2023.
5. Li Y, Tran A, Graham L, Brock J, Tuszynski MH, Lu P. BDNF guides neural stem cell-derived axons to ventral interneurons and motor neurons after spinal cord injury. Exp Neurol. 2023;359:114259. doi:10.1016/j.expneurol.2022.114259
6. Kowiański P, Lietzau G, Czuba E, Waśkow M, Steliga A, Moryś J. BDNF: A Key Factor with Multipotent Impact on Brain Signaling and Synaptic Plasticity. Cell Mol Neurobiol. 2018;38(3):579-593. doi:10.1007/s10571-017-0510-4
7. Chang DJ, Cho HY, Hwang S, et al. Therapeutic Effect of BDNF-Overexpressing Human Neural Stem Cells (F3.BDNF) in a Contusion Model of Spinal Cord Injury in Rats. Int J Mol Sci. 2021;22(13):6970. Published 2021 Jun 28. doi:10.3390/ijms22136970
8. Zhou X, Deng X, Liu M, et al. Intranasal delivery of BDNF-loaded small extracellular vesicles for cerebral ischemia therapy. J Control Release. 2023;357:1-19. doi:10.1016/j.jconrel.2023.03.033
9. Triplet EM, Kim HN, Yoon H, et al. The thrombin receptor links brain derived neurotrophic factor to neuron cholesterol production, resiliency and repair after spinal cord injury. Neurobiol Dis. 2021;152:105294. doi:10.1016/j.nbd.2021.105294
10. Zhang H, Huang Z, Guo M, et al. Effect of combination therapy with neural stem cell transplantation and tetramethylpyrazine in rats following acute spinal cord injury. Neuroreport. 2021;32(16):1311-1319. doi:10.1097/WNR.0000000000001725
11. Rosenzweig ES, Brock JH, Lu P, et al. Restorative effects of human neural stem cell grafts on the primate spinal cord. Nat Med. 2018;24(4):484-490. doi:10.1038/nm.4502