MSC-Derived Extracellular Vesicles Activate Mitophagy to Alleviate Renal Ischemia/Reperfusion Injury via the miR-223-3p/NLRP3 Axis

Abstract

Background. MSC-derived extracellular vehicles (EVs) exhibit a protective functional role in renal ischemia/reperfusion injury (RIRI). Recent studies have revealed that mitophagy could be a potential target process in the treatment of RIRI. However, whether MSC-derived EVs are involved in the regulation of mitophagy in RIRI remains largely unknown to date. Methods. RIRI model was established in vivo in mice by subjecting them to renal ischemia/reperfusion. TCMK-1 cells were subjected to hypoxia/reoxygenation (H/R) stimulation to mimic RIRI in vitro. BMSCs and BMSC-derived EVs were isolated and identified. Renal injury was assessed using H&E staining. The qPCR and western blot analyses were conducted to detect the mRNA and protein levels. Apoptosis was evaluated using the TUNEL assay and flow cytometry analysis. The EVs, autophagosomes, and mitochondria were observed using TEM. The colocalization of autophagosomes with mitochondria was confirmed through the confocal assay. The direct binding of miR-223-3p to NLRP3 was validated through the dual-luciferase assay. Results. BMSCs and BMSC-derived EVs were successfully isolated from mice and identified. The protective effect of BMSC-derived EVs against RIRI was validated both in vitro and in vivo, which was indicated by a decrease in apoptosis and inflammasome activation and an increase in mitophagy. However, this protective effect was impaired in the miR-223-3p-depleted EVs, suggesting that miR-223-3p mediated this protective effect. Further mechanistic investigation revealed that miR-223-3p suppressed inflammasome activation to enhance mitophagy by directly targeting NLRP3. Conclusion. In conclusion, the protective role of BMSC-derived EVs and exosome-delivered miR-223-3p in RIRI was validated. Exogenous miR-223-3p directly targeted NLRP3 to attenuate inflammasome activation, thereby promoting mitophagy.

Exosomal miR-223-3p from bone marrow mesenchymal stem cells targets HDAC2 to downregulate STAT3 phosphorylation to alleviate HBx-induced ferroptosis in podocytes

“…Most studies on miR-223-3p have focused on acute kidney injury and chronic kidney disease, and few studies have investigated miR-223-3p for the treatment of HBV-GN. However, in previous studies, miR-223-3p demonstrated an amelioration of renal ischemia/reperfusion-induced injury ( Yuan et al, 2017 ; Sun et al, 2022 ) and HBx induced downregulation of miR-223 levels ( Yu et al, 2016 ), which was speculated that it might play a protective role in the development of HBV-GN. In this current study, we employed miR-223-3p-deficient BMSC-Exo to validate the renoprotective role of miR-223-3p in restraining ferroptotic damage in podocytes of HBx transgenic mice.…”

Profiling plasma extracellular vesicle-derived microRNAs for noninvasive diagnosis of alpha-1 antitrypsin deficiency associated liver disease

“…In this regard, miR- 223, miR-23a, miRNA-15b, and miR374a have been previously shown to be correlated with liver fibrosis, regulating lipid and cholesterol homeostasis (69, 76–78). Furthermore, miRNA-15b has been reported to regulate ATP levels and mitochondrial ROS production (79, 80), while miR223-3p increases mitophagy in cells with dysfunctional mitochondria (81). Interestingly, serum levels of miR-15b, miR-23a, miR-374a, and let-7a have been recently reported to have great potential as diagnostic biomarkers of nonalcoholic liver fibrosis (82).…”

Comprehensive overview of the role of mitochondrial dysfunction in the pathogenesis of acute kidney ischemia-reperfusion injury: a narrative review

“…Regarding mitophagy, overexpression of BNIP3 is sufficient to overcome kidney IR injury [ 44 , 80 ]. Mesenchymal stem cell-derived extracellular vesicles containing miR-223-3p can activate mitophagy and improve kidney IR injury by inhibiting NLRP3 [ 81 ]. Collectively, these findings highlight the potential of mitophagy as a viable target for the treatment of IR injury.…”