Extracellular vesicles derived from mesenchymal stem cells ameliorate sulfur mustard-induced lung injury by regulating apoptosis via miR-146a-5p

Sulfur mustard (SM) is an extremely toxic chemical warfare agent. Although SM-induced toxicity has long been studied, due to its complexity, the characterization of the precise molecular pathway it targets has been remaining an ongoing area of research. Extracellular vesicles derived from human umbilical cord mesenchymal stem cells (hucMSC-EVs) are natural substances that participate in intercellular communication by delivering microRNA to target cells. Importantly, the microRNA content in EVs can be modified. MiR-146a-5p delivered by EVs were utilized and hucMSCs were further modified with miR-146a-5p mimics or inhibitors to collect EVs that over-(miR-146a-5p+-EVs) or underexpress (miR-146a-5p--EVs) miR-146a-5p. Transcriptome sequencing was used to identify potential mediators of the effects of miR-146a-5p delivered by hucMSC-EVs. Our results showed that hucMSC-EVs reduced SM-induced lung injury by mitigating apoptosis. These effects were enhanced by miR146a-5p+-EVs and weakened by miR-146a-5p--EVs. Meanwhile, the relationship between apoptosis enhancing nuclease (AEN) and miR-146a-5p was discovered, a novel target of miR-146a-5p. Our study showed that hucMSC-EVs ameliorating sulfur mustard induced lung injury through miR-146a-5p, and AEN was one of the functional molecules in this process.