Kelly Dickerson

Background: Traumatic Brain Injury (TBI) occurs when an external force injures the brain, leading to temporary or permanent impairment.¹ Common causes include falls, car accidents, blunt force trauma, self-harm, and assault.¹ Symptoms can emerge shortly after the injury and include loss of consciousness, memory loss, persistent headaches, nausea, vomiting, and seizures.¹ Severe cases may result in coma, vegetative state, or brain death.¹ During the acute phase of TBI, there is an immediate excessive release of excitatory neurotransmitters due to the tearing of brain tissue. The chronic phase is triggered by the acute phase and contributes to further brain damage. Microglia contribute to the chronic phase by increasing the production of reactive oxidative species and pro-inflammatory cytokines. TBIs also heighten the risk of Alzheimer’s and Parkinson’s diseases, particularly with repeated or severe injuries.¹ There are currently no approved treatments. Human Mesenchymal stem cells (hMSCs) possess the ability to differentiate into various mesenchymal lineages, proliferate rapidly, and are easily isolated, making them an attractive treatment option.^2,3 MSC-EVs (Mesenchymal Stem cell-extracellular vesicles) are structures filled with proteins, lipids, carbohydrates, and nucleic acids, facilitating cell-to-cell communication.^2,3 These vesicles have been utilized to deliver therapeutic substances such as microRNAs, anti-inflammatory agents, and growth factors to injury sites.^2,3 Extracellular vesicle-based therapies have demonstrated efficacy in reducing neuron damage, promoting neuro-regeneration, and enhancing cognitive function following Traumatic Brain Injury (TBI).

Objective: In this narrative review, we explored the mechanisms by which mesenchymal stem cell derived extracellular vesicles utilize to reduce inflammation and unfavorable TBI outcomes.

Search Methods: An online search in the PubMed database was conducted from 2015 to 2024 using the following keywords: “Traumatic Brain Injury”, “Mesenchymal stem cells”, “extracellular vesicles”, “tbi pathogenesis”.

Results: Adult mice induced with TBI then treated with intranasal hMSC-EVs containing “activated microglia-modulating miRNAs” demonstrated a reduction in both the immediate and prolonged effects of Traumatic Brain Injury (TBI).³ The intranasally administered hMSC-Evs incorporated into neurons and microglia in the brain on both the ipsilateral and contralateral sides of the controlled cortical impact injury.³ Through small RNA sequencing, hMSC-EVs were capable of modulating the proinflammatory microglia and inhibiting NLRP3 inflammasome activation both in the acute and chronic phase of TBI injury.³ Specifically, this treatment effectively suppressed the ongoing activation of the NLRP3-p38/MAPK signaling pathway post-TBI, resulting in diminished brain damage and preservation of cognitive function in the adult mice.³ In a separate experiment, a group of rats treated with umbilical cord MSC-EVs after induced TBI exhibited significantly decreased sensorimotor deficits as measured by the modified Neurological Severity Score (mNSS).⁴ Additionally, this group showed increased expression of Bcl-2/Bax and decreased expression of GFAP and IBA1 mRNA, indicating a reduction in inflammation through the inhibition of microglia and astrocyte activation by MSC-EVs.⁴

Conclusion: Extracellular vesicle- based therapeutics have shown to reduce neuron damage, neuro-regeneration, and improve cognitive function after TBI. There are multiple pathways that MSC-EVs target to lower inflammation, apoptosis, and the activation of microglia and astrocytes. MSC-EV treatment for TBI patients is promising and can be used for functional recovery in the future.

Works Cited:

1. Capizzi A, Woo J, Verduzco-Gutierrez M. Traumatic Brain Injury: An Overview of Epidemiology, Pathophysiology, and Medical Management. Med Clin North Am. 2020;104(2):213-238. doi:10.1016/j.mcna.2019.11.001
2. Kou M, Huang L, Yang J, et al. Mesenchymal stem cell-derived extracellular vesicles for immunomodulation and regeneration: a next generation therapeutic tool?. Cell Death Dis. 2022;13(7):580. Published 2022 Jul 4. doi:10.1038/s41419-022-05034-x
3. Xiong Y, Mahmood A, Chopp M. Mesenchymal stem cell-derived extracellular vesicles as a cell-free therapy for traumatic brain injury via neuroprotection and neurorestoration. Neural Regen Res. 2024;19(1):49-54. doi:10.4103/1673-5374.374143
4. Kodali M, Madhu LN, Reger RL, et al. Intranasally administered human MSC-derived extracellular vesicles inhibit NLRP3-p38/MAPK signaling after TBI and prevent chronic brain dysfunction. Brain Behav Immun. 2023;108:118-134. doi:10.1016/j.bbi.2022.11.014
5. Cui L, Luo W, Jiang W, et al. Human umbilical cord mesenchymal stem cell-derived exosomes promote neurological function recovery in rat after traumatic brain injury by inhibiting the activation of microglia and astrocyte. Regen Ther. 2022;21:282-287. Published 2022 Aug 28. doi:10.1016/j.reth.2022.07.005