Exosomes from hypoxic pre-treated ADSCs attenuate acute ischemic stroke-induced brain injury via delivery of circ-Rps5 and promote M2 microglia/macrophage polarization

Background: Previous investigations have shown that exosome secretion from hypoxic pre-treated adiposederived stem cells (ADSCs) affect ischemic injury treatment; however, the therapeutic effect relative to circRNA delivery is unclear. Methods: In the present investigation inflammatory factors, nerve injury, and cognitive function were assessed using a middle cerebral artery occlusion mouse model. The isolated exosomes were identified using transmission electron microscopy and further tested by leveraging exosome particles in a nanoparticle tracking approach. Differences in circRNA expression between exosomes and hypoxic pre-treated ADSC exosomes were analyzed by high-throughput sequencing. The phenotypic transformation of microglia was detected by immunofluorescence. The circRNA and downstream target were analyzed by bioinformatics, RT-qPCR, and luciferase report. Results: Exosomes from hypoxic pre-treated ADSCs improved cognitive function by reducing neuronal damage in the hippocampus after cerebral infarction. Exosomes from hypoxic pre-treated ADSCs improved cognitive function via delivery of circ-Rps5. SIRT7 and miR-124-3p were circ-Rps5 downstream targets, which was confirmed by luciferase report analysis. miR-124-3p overexpression or SIRT7 downregulation reversed the circRps5-mediated M2 microglial shift under LPS conditions. Circ-Rps5-modified ADSC exosome improved cognitive function by decreasing neuronal damage and shifting microglia from an M1 to M2 phenotype in the hippocampus. Conclusion: The study showed that exosomes from hypoxic pre-treated ADSCs attenuated acute ischemic strokeinduced brain injury via delivery of circ-Rps5 and promoted M2 microglia/macrophage polarization.