Exosomes from hypoxic pre-treated BMSCs protect against lipopolysaccharide-induced acute lung injury via delivery of circ-LRP6

Abstract

The role of circular RNAs (circRNAs) derived from exosomes of mesenchymal stem cells in acute lung injury (ALI) is poorly understood. This study aimed to determine whether exosomal circRNAs can influence ALI and to uncover the underlying mechanisms. Bone marrow mesenchymal stem cells (BM-MSCs) were pretreated under hypoxic or normoxic conditions, from which exosomes were extracted (normoxic BM-MSC-derived exosomes (Nor Exo) and hypoxic BM-MSC-derived exosomes (Hypo Exo). To assess their in vitro effects on ALI, lipopolysaccharide (LPS)-treated MLE-12 cells were incubated with these exosomes. An ALI mouse model was established through airway perfusion with LPS, and exosomes were administered via the tail vein to evaluate their in vivo effects. The results showed that blocking exosome production could reverse the protective effect of the BM-MSC supernatant on LPS-induced injury in vitro. The exosomes attenuated LPS-induced ALI, with Hypo Exo demonstrating a more pronounced therapeutic effect than Nor Exo, both in vitro and in vivo. Additionally, a higher level of circ-LRP6 was detected in Hypo Exo compared with that in Nor Exo. Mechanistically, circ-LRP6 was found to regulate Claudin 4 levels in the context of ALI. These findings provide new insights into the potential of exosomal circ-LRP6 as a treatment for ALI.