Zhizhong Xiong, Xianzhe Li, Minghao Xie, Jianping Guo, Shi Yin, Dayin Huang, Longyang Jin, Caiqin Wang, Fengxiang Zhang, Chaobin Mao, Huaxian Chen, Dandong Luo, Haijie Tang, Xijie Chen, Lei Lian
{"title":"源自脂肪间充质干细胞的小细胞外囊泡通过MFGE8抑制FAK/Akt信号通路，从而缓解肠纤维化。","authors":"Zhizhong Xiong, Xianzhe Li, Minghao Xie, Jianping Guo, Shi Yin, Dayin Huang, Longyang Jin, Caiqin Wang, Fengxiang Zhang, Chaobin Mao, Huaxian Chen, Dandong Luo, Haijie Tang, Xijie Chen, Lei Lian","doi":"10.1007/s00535-024-02152-5","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Intestinal fibrosis is one of the most frequent and severe complications of Crohn's disease. Accumulating studies have reported that adipose mesenchymal stem cell-derived small extracellular vesicles (AMSC-sEVs) could alleviate renal fibrosis, hepatic fibrosis, etc., while their potential for treating intestinal fibrosis remains uncertain. Therefore, this study aims to determine the therapeutic effects of AMSC-sEVs on intestinal fibrosis and identify the mechanisms underlying these effects.</p><p><strong>Methods: </strong>AMSC-sEVs were characterized using transmission electron microscopy, nanoparticle tracking analysis, and western blot. Whether AMSC-sEVs exert antifibrotic effects was investigated in two different murine models of intestinal fibrosis. Besides, AMSC-sEVs were co-cultured with primary human fibroblasts and CCD18co during transforming growth factor (TGF)-β1 stimulation. Label-free proteomics and rescue experiments were performed to identify candidate molecules in AMSC-sEVs. Transcriptome sequencing revealed changes in mRNA levels among different groups. Lastly, proteins related to relevant signaling pathways were identified by western blotting, and their expression and activation status were assessed.</p><p><strong>Results: </strong>AMSC-sEVs positively expressed CD63 and Alix and presented a classical \"rim of a cup\" and granule shape with approximately 43-100 nm diameter. AMSCs significantly alleviated intestinal fibrosis through secreted sEVs in vitro and in vivo. The milk fat globule-EGF factor 8 (MFGE8) was stably enriched in AMSC-sEVs and was an active compound contributing to the treatment of intestinal fibrosis by AMSCs. Mechanistically, AMSC-sEV-based therapies attenuated intestinal fibrosis by inhibiting the FAK/Akt signaling pathway.</p><p><strong>Conclusions: </strong>MFGE8-containing AMSC-sEVs attenuate intestinal fibrosis, partly through FAK/Akt pathway inhibition.</p>","PeriodicalId":16059,"journal":{"name":"Journal of Gastroenterology","volume":" ","pages":"1092-1106"},"PeriodicalIF":6.9000,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Small extracellular vesicles derived from adipose mesenchymal stem cells alleviate intestinal fibrosis by inhibiting the FAK/Akt signaling pathway via MFGE8.\",\"authors\":\"Zhizhong Xiong, Xianzhe Li, Minghao Xie, Jianping Guo, Shi Yin, Dayin Huang, Longyang Jin, Caiqin Wang, Fengxiang Zhang, Chaobin Mao, Huaxian Chen, Dandong Luo, Haijie Tang, Xijie Chen, Lei Lian\",\"doi\":\"10.1007/s00535-024-02152-5\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Intestinal fibrosis is one of the most frequent and severe complications of Crohn's disease. Accumulating studies have reported that adipose mesenchymal stem cell-derived small extracellular vesicles (AMSC-sEVs) could alleviate renal fibrosis, hepatic fibrosis, etc., while their potential for treating intestinal fibrosis remains uncertain. Therefore, this study aims to determine the therapeutic effects of AMSC-sEVs on intestinal fibrosis and identify the mechanisms underlying these effects.</p><p><strong>Methods: </strong>AMSC-sEVs were characterized using transmission electron microscopy, nanoparticle tracking analysis, and western blot. Whether AMSC-sEVs exert antifibrotic effects was investigated in two different murine models of intestinal fibrosis. Besides, AMSC-sEVs were co-cultured with primary human fibroblasts and CCD18co during transforming growth factor (TGF)-β1 stimulation. Label-free proteomics and rescue experiments were performed to identify candidate molecules in AMSC-sEVs. Transcriptome sequencing revealed changes in mRNA levels among different groups. Lastly, proteins related to relevant signaling pathways were identified by western blotting, and their expression and activation status were assessed.</p><p><strong>Results: </strong>AMSC-sEVs positively expressed CD63 and Alix and presented a classical \\\"rim of a cup\\\" and granule shape with approximately 43-100 nm diameter. AMSCs significantly alleviated intestinal fibrosis through secreted sEVs in vitro and in vivo. The milk fat globule-EGF factor 8 (MFGE8) was stably enriched in AMSC-sEVs and was an active compound contributing to the treatment of intestinal fibrosis by AMSCs. Mechanistically, AMSC-sEV-based therapies attenuated intestinal fibrosis by inhibiting the FAK/Akt signaling pathway.</p><p><strong>Conclusions: </strong>MFGE8-containing AMSC-sEVs attenuate intestinal fibrosis, partly through FAK/Akt pathway inhibition.</p>\",\"PeriodicalId\":16059,\"journal\":{\"name\":\"Journal of Gastroenterology\",\"volume\":\" \",\"pages\":\"1092-1106\"},\"PeriodicalIF\":6.9000,\"publicationDate\":\"2024-12-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Gastroenterology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1007/s00535-024-02152-5\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/9/21 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"GASTROENTEROLOGY & HEPATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Gastroenterology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s00535-024-02152-5","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/9/21 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"GASTROENTEROLOGY & HEPATOLOGY","Score":null,"Total":0}
Small extracellular vesicles derived from adipose mesenchymal stem cells alleviate intestinal fibrosis by inhibiting the FAK/Akt signaling pathway via MFGE8.
Background: Intestinal fibrosis is one of the most frequent and severe complications of Crohn's disease. Accumulating studies have reported that adipose mesenchymal stem cell-derived small extracellular vesicles (AMSC-sEVs) could alleviate renal fibrosis, hepatic fibrosis, etc., while their potential for treating intestinal fibrosis remains uncertain. Therefore, this study aims to determine the therapeutic effects of AMSC-sEVs on intestinal fibrosis and identify the mechanisms underlying these effects.
Methods: AMSC-sEVs were characterized using transmission electron microscopy, nanoparticle tracking analysis, and western blot. Whether AMSC-sEVs exert antifibrotic effects was investigated in two different murine models of intestinal fibrosis. Besides, AMSC-sEVs were co-cultured with primary human fibroblasts and CCD18co during transforming growth factor (TGF)-β1 stimulation. Label-free proteomics and rescue experiments were performed to identify candidate molecules in AMSC-sEVs. Transcriptome sequencing revealed changes in mRNA levels among different groups. Lastly, proteins related to relevant signaling pathways were identified by western blotting, and their expression and activation status were assessed.
Results: AMSC-sEVs positively expressed CD63 and Alix and presented a classical "rim of a cup" and granule shape with approximately 43-100 nm diameter. AMSCs significantly alleviated intestinal fibrosis through secreted sEVs in vitro and in vivo. The milk fat globule-EGF factor 8 (MFGE8) was stably enriched in AMSC-sEVs and was an active compound contributing to the treatment of intestinal fibrosis by AMSCs. Mechanistically, AMSC-sEV-based therapies attenuated intestinal fibrosis by inhibiting the FAK/Akt signaling pathway.
期刊介绍：
The Journal of Gastroenterology, which is the official publication of the Japanese Society of Gastroenterology, publishes Original Articles (Alimentary Tract/Liver, Pancreas, and Biliary Tract), Review Articles, Letters to the Editors and other articles on all aspects of the field of gastroenterology. Significant contributions relating to basic research, theory, and practice are welcomed. These publications are designed to disseminate knowledge in this field to a worldwide audience, and accordingly, its editorial board has an international membership.
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