Lyophilized MSC-EVs attenuates COVID-19 pathogenesis by regulating the JAK/STAT pathway.

BACKGROUND: The JAK/STAT signaling pathway plays a crucial role in the release of interferons (IFNs) and the proinflammatory response during SARS-CoV-2 infection, contributing to the cytokine storm characteristic of severe COVID-19 cases. STAT3, a key protein in this pathway, has been implicated in promoting inflammation, making its inhibition a potential therapeutic strategy to mitigate disease severity. Mesenchymal Stem Cell-derived Extracellular Vesicles (MSC-EVs), enriched with immunomodulatory and antiviral miRNAs, offer a promising therapeutic approach by modulating gene expression and regulating inflammatory responses. This study investigates the ability of Lyophilized MSC-EVs to inhibit the JAK/STAT pathway, highlighting their potential application in COVID-19 management. METHODS: Male Syrian hamsters were used as an experimental model, housed under controlled laboratory conditions. SARS-CoV-2 (hCoV-19/Egypt/NRC-03/2020) was propagated in Vero E6 cells, and viral titers were determined using plaque assays. Hamsters were intranasally challenged with the virus and treated intraperitoneally with 0.5 mL of lyophilized human Wharton's jelly-derived MSC-extracellular vesicles (MSC-EVs). Histopathological evaluations were performed on lung tissues using H&E, Masson's trichrome, and immunohistochemical staining. Morphometric analyses were conducted to assess lung injury and fibrosis. Western blotting was employed to evaluate protein expression. All procedures adhered to ethical and biosafety guidelines. RESULTS: The administration of MSC-EVs significantly upregulated the expression levels of miRNA-146a, miRNA-124, miRNA-155, miRNA-29b, miRNA-7, miRNA-145 and miRNA-18a compared to their levels in the COVID-19 group, suggesting a targeted release of miRNA-cargo from the MSC-EVs into the lung tissue of the animals. MSC-EVs impaired the activation of the STAT3/STAT1 signaling pathway and reduced the cytokine storm and coagulopathy associated with COVID-19. CONCLUSIONS: These findings suggest that MSC-EVs have the potential to effectively mitigate the pathogenesis of COVID-19 by targeting the JAK/STAT signaling pathway. Further research is needed to fully understand the mechanisms underlying the therapeutic effects of MSC-EVs and their clinical application in combating the COVID-19 pandemic.