Hypoxia exposure at 1% oxygen concentration for 24 hours improves the functional capacities of sEVs.
miR-125b-5p and miR-145a-5p are identified as key molecular targets that enhance immunomodulation and regeneration.
The study reveals that WJ-sEVs influence critical molecular pathways, including the IL-6R/NFκB axis and TGF-β2/SMAD4 pathway.
These findings suggest the potential of WJ-sEVs as a promising option for personalized regenerative therapies.
Simplified
BACKGROUND: Regenerative medicine therapies offer hope for conditions previously limited to supportive care. The COVID-19 pandemic underscored the urgent need for treatments targeting systemic inflammation. Mesenchymal stem cells (MSCs) are widely recognized for their regenerative and immunomodulatory properties. Recent research shows that hypoxic priming enhances MSCs' therapeutic potential, particularly by increasing the release and modifying the cargo of their extracellular vesicles (EVs). These EVs imitate many of the regenerative and immunomodulatory effects of MSCs, making them a promising cell-free therapeutic option. This study aimed to compare the regenerative and immunomodulatory capacities of small EVs (; less than 200 nm) derived from bone marrow (BM) and wharton's jelly (WJ) MSCs, cultured under normoxic and hypoxic conditions, and decipher their underlying functional mechanisms.
METHODS: BM and WJ-MSCs were isolated and expanded. Hypoxia exposure was provided at 1% oxygen concentration for 24 h. sEV were isolated using ultracentrifugation, and in vitro functional assessments were performed using skin specific human sourced cell lines for fibroblasts, keratinocytes and macrophages. miRNA modulations were performed via transfection technique and mechanism of action of sEV were determined. Additionally, in vivo analysis was performed in a traumatic wound rat model, and molecular pathway analysis was performed in animal wound tissues.
RESULTS: Through comprehensive in vitro and in vivo evaluations, this study aimed to identify the most potent candidate for regenerative medicine while elucidating the underlying molecular mechanisms. By analysing sEV cargo and the associated molecular pathways within a traumatic wound model, the study revealed that WJ-MSCs exhibit superior regenerative potential. Furthermore, it demonstrated that enhances their therapeutic efficacy through the involvement of miR-125b-5p and miR-145a-5p, which drive immunomodulation and regeneration by targeting IL-6R/NFκB axis and TGF-β2/SMAD4 pathway, respectively. These findings underscore the significance of WJ-sEV as a promising avenue for personalized regenerative therapies, positioning miR-125b-5p and miR-145a-5p as key therapeutic targets for bioengineering of sEVs.
CONCLUSION: By exploring these comparative functions, the study provides insights into the optimization of sEV-based therapies as a cutting-edge approach in regenerative medicine, and reflects the suitability of WJ-sEV as an ideal acellular therapeutics' candidate for translational regenerative and immunomodulatory applications.
Key numbers
2.4×
Increase in release
WJ- show a 2.4× increase in release when primed under hypoxia.
36.5%
Uptake enhancement in
WJ- treatment resulted in 36.5% of internalizing .
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Declarations. Ethics approval and consent to participate: All experiments were conducted after approval from the ethics committees of All India Institute of Medical Sciences, New Delhi, India. The biological samples were collected after approval from the Institutional Committee for Stem Cell Research (Approval No. IC-SCR/120/21(R)) and Institutional Ethics Committee (Approval No. (IECPG-294/28.04.2021). Animal experiments were performed after approval from Institutional Animal Ethics Committee (Approval No. 403/IAEC-I/2022). Informed consent was obtained from all the subjects involved in the study. Consent for publication: All the authors provided their consent for the publication of this manuscript. Competing interests: The authors declare no competing interests.
PubMed
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