UCMSCs-derived exosomal SLIT2 alleviates ischemic stroke through the β-catenin/TCF4/USP20 signaling pathway

Ischemic stroke (IS) is a disease that causes necrosis of brain tissues by inadequate blood supply to the brain. Umbilical cord mesenchymal stem cells (UCMSCs)-derived exosomes (UCMSCs-Exo) have been reported to alleviate IS, and slit guidance ligand 2 (SLIT2) could promote neurological repair after IS. The aim of this research was to explore the potential mechanism of UCMSCs-derived exosomal SLIT2 on IS progression. The middle cerebral artery occlusion (MCAO) rat and oxygen glucose deprivation/reperfusion (OGD/R)-induced cellular models were established, and then treated with UCMSCs-Exo. Cell viability and apoptosis were explored by cell counting kit-8 (CCK-8) assay and flow cytometry, respectively. The expressions of ubiquitin specific peptidase 20 (USP20) and related apoptotic proteins were determined using Western blot. Immunofluorescence and immunohistochemistry were performed to evaluate the effect of SLIT2 on β-catenin nuclear translocation. The association between transcription factor 4 (TCF4) and <i>USP20</i> promoter was investigated by chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assys. In the OGD/R-induced cell model, UCMSCs-derived exosomal SLIT2 increased cell viability, decreased apoptosis and promoted β-catenin nuclear translocation. Besides, β-catenin agonist (SKL2001) facilitated USP20 transcription by promoting TCF4 binding to <i>USP20</i> promoter. Finally, TCF4 upregulated USP20 and inhibited OGD/R-induced cell damage. In the MCAO rat model, UCMSCs-derived exosomal SLIT2 mitigated IS by promoting β-catenin nuclear translocation, which activated the TCF4/USP20 pathway to inhibit apoptosis. UCMSCs-derived exosomal SLIT2 activated TCF4 by promoting β-catenin nuclear translocation, which transcriptionally upregulated USP20 expression, thereby attenuating OGD/R-induced neuroncell damage and ultimately leading to inhibition of IS progression. UCMSCs-derived exosomal SLIT2 inhibits the OGD/R-induced cell damage and neurological deficits in MCAO rats.UCMSCs-derived exosomal SLIT2 promotes β-catenin nuclear translocation in the IS model.TCF4 increases USP20 transcription to inhibit OGD/R-induced cell damage.UCMSCs-derived exosomal SLIT2 regulates the β-catenin/TCF4/USP20 axis to alleviate IS. UCMSCs-derived exosomal SLIT2 inhibits the OGD/R-induced cell damage and neurological deficits in MCAO rats. UCMSCs-derived exosomal SLIT2 promotes β-catenin nuclear translocation in the IS model. TCF4 increases USP20 transcription to inhibit OGD/R-induced cell damage. UCMSCs-derived exosomal SLIT2 regulates the β-catenin/TCF4/USP20 axis to alleviate IS.