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Advanced Neurology Cytokine response to EV therapy in SCI

prior data is the differential expression of RANTES. In the study, our findings support the idea that MSC-EVs delivered
SCI FM+EVs5 group, RANTES levels were significantly through FM can regulate pro- and anti-inflammatory
elevated (4-fold increase) compared to the SCI group, cytokine levels in chronic SCI. This dynamic regulation
whereas the SCI FM+EVs10 group did not show this likely underlies the functional improvements observed in
excessive upregulation. This dose-dependent effect of EVs our earlier study, including enhanced motor recovery (BBB
on chemokine signaling and immune cell recruitment scores), electrophysiological restoration (MEP, SSEP), and
mirrors our earlier findings that higher doses of EVs histological preservation of spinal cord tissue. Building
were associated with improved functional recovery, likely upon our previous findings in rodent models, we extended
due to better regulation of inflammatory cell infiltration. our research to a porcine model of SCI to evaluate the
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This also aligns with our electrophysiological data, where translational potential of MSC-EVs. In this feasibility
higher EV doses led to enhanced M-wave amplitudes and study, we administered autologous MSC-EVs intrathecally
better motor conduction, suggesting a more controlled and during the subacute phase of SCI. The treatment led to
neuroprotective immune response. partial restoration of locomotor function, which was
associated with enhanced axonal remyelination and timely
MSC-EVs have been shown to significantly inhibit the
activation of the NLRP3 inflammasome and p38/MAPK reperfusion of neural tissue. These outcomes further support
the therapeutic promise of MSC-EVs in SCI recovery.
signaling pathways, both of which are critical in triggering
pro-inflammatory responses in mouse models of traumatic 5. Conclusion
brain injury. This inhibition led to reduced production
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of pro-inflammatory cytokines, including IL-1β and IL-6, Our study demonstrated that the FM itself plays a crucial
thereby exerting an overall immunomodulatory effect. role in influencing inflammatory processes, promoting
27
Furthermore, animals treated with MSC-EVs exhibited both pro-inflammatory and anti-inflammatory responses.
improved cognitive and motor functions, reduced long- This likely occurs through the activation of cells involved
term inflammation, and decreased brain damage. 26,28 in tissue repair. In addition, the application of MSC-EVs,
In a separate study involving a rodent model of SCI, encapsulated in the FM, significantly altered the levels of
administration of MSC-EVs was associated with a decrease both pro-inflammatory and anti-inflammatory cytokines
in pro-inflammatory cytokines (IL-6, IL-1β), suppression in the chronic phase of SCI, a clinically relevant and
of microglial reactivity, 29,30 and anti-apoptotic activity, understudied time point. The observed dose-dependent
leading to reduced neuroinflammation and enhanced effects, particularly with the 10 µg MSC-EVs dose, suggest
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recovery. In addition, MSC-EVs administration that this combination therapy may represent a novel
significantly reduced TNF-α and IL-1β levels and activated approach for modulating inflammatory responses and
autophagy, which further contributed to inflammation promoting tissue regeneration after SCI.
reduction and tissue regeneration. Thus, our findings Acknowledgments
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align with previous studies demonstrating that MSC-
EVs modulate inflammatory processes by lowering pro- None.
inflammatory cytokine levels and suppressing microglial
activity in traumatic CNS injury models. Funding
Taken together, these findings strongly correlate with This study was funded by the subsidy allocated to Kazan
our previous results, reinforcing the idea that MSC-EVs Federal University for state assignment (No. FZSM-2023-
12
fine-tune —rather than simply inhibit—the inflammatory 0011) in the sphere of scientific activities.
response. This study focused on the chronic phase of SCI Conflict of interest
(60 dpi), a period marked by persistent inflammation
and limited spontaneous regeneration. MSC-EVs may The authors declare that they have no competing interests.
offer unique benefits in this context by promoting long-
term immune modulation, potentially shifting microglia/ Author contributions
macrophage populations toward anti-inflammatory states Conceptualization: Yana O. Mukhamedshina
and supporting sustained tissue homeostasis. While no Data curation: Yana O. Mukhamedshina
data from the acute or subacute stages were included, future Formal analysis: Ilyas M. Kabdesh, Ekaterina E. Garanina,
studies with a temporal gradient (e.g., 7, 14, and 60 dpi) Alexander A. Kostennikov
would allow a deeper understanding of cytokine dynamics Funding acquisition: Albert A. Rizvanov
and phase-specific therapeutic effects. Furthermore, Investigation: Ilyas M. Kabdesh, Ekaterina E. Garanina,
although release kinetics were not directly assessed in this Alexander A. Kostennikov

Volume 4 Issue 4 (2025) 83 doi: 10.36922/AN025110022