Rongjun Xiao, Qingsong Wang, Jun Peng, Xiqi Hu, Min Chen, Ying Xia
{"title":"ucmscs衍生的外泌体SLIT2通过β-catenin/TCF4/USP20信号通路缓解缺血性卒中。","authors":"Rongjun Xiao, Qingsong Wang, Jun Peng, Xiqi Hu, Min Chen, Ying Xia","doi":"10.1080/00207454.2025.2497936","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":14161,"journal":{"name":"International Journal of Neuroscience","volume":" ","pages":"1-16"},"PeriodicalIF":1.7000,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"UCMSCs-derived exosomal SLIT2 alleviates ischemic stroke through the β-catenin/TCF4/USP20 signaling pathway.\",\"authors\":\"Rongjun Xiao, Qingsong Wang, Jun Peng, Xiqi Hu, Min Chen, Ying Xia\",\"doi\":\"10.1080/00207454.2025.2497936\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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.</p>\",\"PeriodicalId\":14161,\"journal\":{\"name\":\"International Journal of Neuroscience\",\"volume\":\" \",\"pages\":\"1-16\"},\"PeriodicalIF\":1.7000,\"publicationDate\":\"2025-04-30\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"International Journal of Neuroscience\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1080/00207454.2025.2497936\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q4\",\"JCRName\":\"NEUROSCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"International Journal of Neuroscience","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1080/00207454.2025.2497936","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q4","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
UCMSCs-derived exosomal SLIT2 alleviates ischemic stroke through the β-catenin/TCF4/USP20 signaling pathway.
Background: 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.
Methods: 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 USP20 promoter was investigated by chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assys.
Results: 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 USP20 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.
Conclusion: 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.
期刊介绍：
The International Journal of Neuroscience publishes original research articles, reviews, brief scientific reports, case studies, letters to the editor and book reviews concerned with problems of the nervous system and related clinical studies, epidemiology, neuropathology, medical and surgical treatment options and outcomes, neuropsychology and other topics related to the research and care of persons with neurologic disorders. The focus of the journal is clinical and transitional research. Topics covered include but are not limited to: ALS, ataxia, autism, brain tumors, child neurology, demyelinating diseases, epilepsy, genetics, headache, lysosomal storage disease, mitochondrial dysfunction, movement disorders, multiple sclerosis, myopathy, neurodegenerative diseases, neuromuscular disorders, neuropharmacology, neuropsychiatry, neuropsychology, pain, sleep disorders, stroke, and other areas related to the neurosciences.
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