MSC-derived (EVs) showed protective effects against hyperoxia-induced lung injuries in a animal model.
-203a-3p (miR-203a-3p) in MSC-derived EVs inhibited cell death caused by high oxygen levels.
miR-203a-3p reduced inflammation by targeting specific proteins involved in the inflammatory response.
Experiments indicated that the presence of miR-203a-3p enhanced the therapeutic effects of MSC-derived EVs compared to control EVs.
The study suggests that miR-203a-3p is a significant factor contributing to the protective effects of MSC-derived EVs in treating BPD.
Simplified
BACKGROUND: (BPD) is the most well-known disease contributing to mortality and long-term morbidity in premature infants. Although the pathogenesis of BPD is multifactorial, hyperoxia-induced lung injury and inflammation are recognized as major causes of BPD. (EV) are known to function as a powerful cell-cell communicator by delivering their cargo including proteins, lipids, and nucleic acids such as . EVs derived from mesenchymal stem cells (MSC) are recently reported as promising and effective therapeutic modalities for BPD.
METHODS: The therapeutic effects of MSC-derived EV were examined using a BPD animal model. Differentially expressed miRNAs were selected through miRNA sequencing. The regulation of target genes by miRNA was investigated by Western blot, RT-qPCR, Ago2 RNA immunoprecipitation, and luciferase reporter assay. The increase in therapeutic efficacy of EVs by miRNA was demonstrated by confirming the anti-apoptotic and anti-inflammatory effects of EVs secreted by HEK293 cells overexpressing miR-203a-3p.
RESULTS: Through an in vivo BPD animal model, MSC-derived EVs exhibited protective effects against hyperoxia-induced lung injuries. To define the molecular mechanisms by which MSC-derived EVs alleviate BPD, anti-apoptotic and anti-inflammatory effects were examined. MicroRNA-203a-3p (miR-203a-3p) present in MSC-derived EVs exhibited inhibitory effects on HO-induced apoptotic cell death by targeting inhibitor of differentiation 4, as well as on lipopolysaccharide-induced inflammatory cytokine expression by targeting myeloid differentiation primary response 88. Experiments with miR-203a-3p inhibitor revealed that miR-203a-3p was responsible for mitigative effects of MSC-derived EVs. Compared to EVs containing control mimic, EVs containing miR-203a-3p mimic exhibited higher anti-apoptotic and anti-inflammatory effects. 2 2
CONCLUSIONS: Our findings revealed that miR-203a-3p in MSC-derived EVs inhibited apoptotic cell death and inflammation, demonstrating that miR-203a-3p is a key player enabling MSC-derived EVs to exhibit therapeutic effects for BPD.
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Declarations. Ethics approval and consent to participate: Human Wharton’s jelly-derived MSCs were obtained from a single donor with written informed consent, under protocols approved by the Institutional Review Board of Samsung Medical Center (IRB approval number: 2016-07102-043; approval date: September 20, 2016; approval expiration date: September 15, 2025; title: Study on the selection of optimal mesenchymal stem cells from different sources for the treatment of chronic/intractable diseases including Alzheimer’s disease and musculoskeletal disorders). All animal procedures were reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) of Samsung Medical Center (approval number: 20241016001) and were conducted in accordance with the National Institutes of Health Guidelines for Laboratory Animal Care as well as the institutional guidelines. All animal procedures were reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) of Samsung Medical Center (Approval number: 20241016001; Approval date: October 24, 2024; Title: Investigation of the therapeutic effects and mechanisms of MSC-derived EVs in hyperoxia-induced lung injury in newborn rats) and were conducted in accordance with the National Institutes of Health Guidelines for Laboratory Animal Care as well as the institutional guidelines. Competing interests: The authors declare no competing interests.
