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Published on: May 4, 2020
MiR-203a-3p in extracellular vesicles derived from mesenchymal stem cells alleviates BPD-associated apoptosis and
Hyunji An1,2, Young-Eun Kim3,4, Seong Dong Jeong2,5
1Department of MetaBioHealth, SKKU Institute for Convergence, Sungkyunkwan University, Suwon-si, Gyeonggi-do, 16419, Republic of Korea.
Insights
Mesenchymal stem cell-derived extracellular vesicles (EVs) show therapeutic potential for bronchopulmonary dysplasia (BPD). MicroRNA-203a-3p within these EVs is key to their anti-apoptotic and anti-inflammatory effects, offering a novel treatment strategy for BPD.
Area of Science:
- Neonatal Medicine
- Regenerative Medicine
- Molecular Biology
Background:
- Bronchopulmonary dysplasia (BPD) is a leading cause of mortality and morbidity in premature infants.
- Hyperoxia-induced lung injury and inflammation are primary contributors to BPD pathogenesis.
- Extracellular vesicles (EVs) mediate cell-cell communication and are explored for BPD therapy.
Purpose of the Study:
- To investigate the therapeutic effects of mesenchymal stem cell-derived EVs (MSC-EVs) in a BPD model.
- To elucidate the molecular mechanisms underlying MSC-EVs' protective actions against BPD.
- To identify specific microRNAs within MSC-EVs responsible for therapeutic efficacy.
Main Methods:
- Established a BPD animal model to assess MSC-EV efficacy.
- Utilized miRNA sequencing to identify differentially expressed miRNAs in MSC-EVs.
- Employed Western blot, RT-qPCR, Ago2 RIP, and luciferase assays to confirm miRNA-target interactions.
- Overexpressed miR-203a-3p in EVs to evaluate enhanced therapeutic effects.
Main Results:
- MSC-EVs demonstrated protective effects against hyperoxia-induced lung injury in vivo.
- MicroRNA-203a-3p within MSC-EVs inhibited apoptosis by targeting inhibitor of differentiation 4.
- miR-203a-3p also reduced inflammation by targeting myeloid differentiation primary response 88.
- EVs overexpressing miR-203a-3p exhibited superior anti-apoptotic and anti-inflammatory effects.
Conclusions:
- miR-203a-3p is a crucial component of MSC-EVs mediating their therapeutic benefits for BPD.
- MSC-EVs exert anti-apoptotic and anti-inflammatory effects in BPD through miR-203a-3p.
- This study highlights miR-203a-3p as a key therapeutic factor in MSC-EV-based BPD treatment.
Background:
Bronchopulmonary dysplasia (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. Extracellular vesicles (EV) are known to function as a powerful cell-cell communicator by delivering their cargo including proteins, lipids, and nucleic acids such as microRNAs. 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 H2O2-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.
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.
