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 adipose-derived 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 circ-Rps5-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 stroke-induced brain injury via delivery of circ-Rps5 and promoted M2 microglia/macrophage polarization.