{"title":"骨髓间充质干细胞通过JAK1/STAT5通路缓解大鼠肝移植后肝纤维化。","authors":"Zhuyuan Si, Shengqiao Zhao, Zhixin Zhang, Tianran Chen, Ruofan Wang, Chong Dong, Kai Wang, Chao Sun, Zhuolun Song, Zhongyang Shen, Wei Gao","doi":"10.1186/s13287-025-04353-y","DOIUrl":null,"url":null,"abstract":"<p><strong>Objective: </strong>The effectiveness of bone marrow mesenchymal stem cells (BMSCs) in post-transplantation liver fibrosis has not been studied. The aim of this study was to investigate the effect of BMSCs on liver fibrosis and their role in the Janus-activated kinase (JAK) 1/ signal transducer and activator of transcription (STAT) 5 pathway after liver transplantation (LT).</p><p><strong>Methods: </strong>A rat model of post-LT liver fibrosis induced by cold ischemia injury was successfully established. BMSCs were injected into the rats through the portal vein. Hepatic stellate cell (HSC)-T6 were co-cultured with BMSCs in vitro after hypoxia-reoxygenation. JAK1 inhibitor Abrocitinib and JAK1 agonist RO8191 were used to study the JAK1/STAT5 signaling pathway.</p><p><strong>Results: </strong>BMSCs significantly alleviated liver fibrosis caused by cold ischemia-reperfusion injury after rat LT in vivo. After BMSCs transplantation, the levels of JAK1 and p-STAT5 in rat liver were significantly reduced. After using Abrocitinib, the stage of liver fibrosis and the levels of collagen type I alpha 1 chain (COL1A1) and actin alpha 2 (ACTA2) decreased. After using RO8191, the stage of liver fibrosis and the levels of COL1A1 and ACTA2 increased. BMSCs significantly reduced the activation of HSC-T6 after hypoxia-reoxygenation in vitro. After co-culturing with BMSCs after HSC-T6 hypoxia-reoxygenation, the levels of JAK1 and p-STAT5 were significantly reduced. After the addition of Abrocitinib, the levels of COL1A1 and ACTA2 decreased in HSC-T6; in contrast, after adding RO8191, the levels of COL1A1 and ACTA2 increased in HSC-T6 after hypoxia-reoxygenation. After using anti-IL7 antibody or anti-IL7Rα in vivo and in vitro, the stage of liver fibrosis and the levels of COL1A1 and ACTA2 decreased as well as the phosphorylation level of STAT5.</p><p><strong>Conclusions: </strong>BMSCs alleviate hepatic cell damage, reduce hepatic cell-derived IL7, downregulate IL7R/JAK1/STAT5 in HSCs, thereby reducing HSCs' activation and ultimately alleviating liver fibrosis after liver transplantation.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"16 1","pages":"217"},"PeriodicalIF":7.1000,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12044927/pdf/","citationCount":"0","resultStr":"{\"title\":\"Bone marrow mesenchymal stem cells alleviate liver fibrosis after rat liver transplantation through JAK1/STAT5 pathway.\",\"authors\":\"Zhuyuan Si, Shengqiao Zhao, Zhixin Zhang, Tianran Chen, Ruofan Wang, Chong Dong, Kai Wang, Chao Sun, Zhuolun Song, Zhongyang Shen, Wei Gao\",\"doi\":\"10.1186/s13287-025-04353-y\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Objective: </strong>The effectiveness of bone marrow mesenchymal stem cells (BMSCs) in post-transplantation liver fibrosis has not been studied. The aim of this study was to investigate the effect of BMSCs on liver fibrosis and their role in the Janus-activated kinase (JAK) 1/ signal transducer and activator of transcription (STAT) 5 pathway after liver transplantation (LT).</p><p><strong>Methods: </strong>A rat model of post-LT liver fibrosis induced by cold ischemia injury was successfully established. BMSCs were injected into the rats through the portal vein. Hepatic stellate cell (HSC)-T6 were co-cultured with BMSCs in vitro after hypoxia-reoxygenation. JAK1 inhibitor Abrocitinib and JAK1 agonist RO8191 were used to study the JAK1/STAT5 signaling pathway.</p><p><strong>Results: </strong>BMSCs significantly alleviated liver fibrosis caused by cold ischemia-reperfusion injury after rat LT in vivo. After BMSCs transplantation, the levels of JAK1 and p-STAT5 in rat liver were significantly reduced. After using Abrocitinib, the stage of liver fibrosis and the levels of collagen type I alpha 1 chain (COL1A1) and actin alpha 2 (ACTA2) decreased. After using RO8191, the stage of liver fibrosis and the levels of COL1A1 and ACTA2 increased. BMSCs significantly reduced the activation of HSC-T6 after hypoxia-reoxygenation in vitro. After co-culturing with BMSCs after HSC-T6 hypoxia-reoxygenation, the levels of JAK1 and p-STAT5 were significantly reduced. After the addition of Abrocitinib, the levels of COL1A1 and ACTA2 decreased in HSC-T6; in contrast, after adding RO8191, the levels of COL1A1 and ACTA2 increased in HSC-T6 after hypoxia-reoxygenation. After using anti-IL7 antibody or anti-IL7Rα in vivo and in vitro, the stage of liver fibrosis and the levels of COL1A1 and ACTA2 decreased as well as the phosphorylation level of STAT5.</p><p><strong>Conclusions: </strong>BMSCs alleviate hepatic cell damage, reduce hepatic cell-derived IL7, downregulate IL7R/JAK1/STAT5 in HSCs, thereby reducing HSCs' activation and ultimately alleviating liver fibrosis after liver transplantation.</p>\",\"PeriodicalId\":21876,\"journal\":{\"name\":\"Stem Cell Research & Therapy\",\"volume\":\"16 1\",\"pages\":\"217\"},\"PeriodicalIF\":7.1000,\"publicationDate\":\"2025-05-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12044927/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Stem Cell Research & Therapy\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1186/s13287-025-04353-y\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CELL & TISSUE ENGINEERING\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Stem Cell Research & Therapy","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s13287-025-04353-y","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL & TISSUE ENGINEERING","Score":null,"Total":0}
引用次数: 0
摘要
目的：骨髓间充质干细胞（BMSCs）治疗移植后肝纤维化的有效性尚未得到研究。本研究旨在探讨骨髓间充质干细胞对肝移植（LT）后肝纤维化的影响及其在Janus-activated kinase (JAK) 1/ signal transducer and activator of transcription (STAT) 5通路中的作用。方法：建立冷缺血大鼠肝纤维化模型。骨髓间充质干细胞经门静脉注入大鼠体内。体外缺氧复氧培养肝星状细胞(HSC)-T6与骨髓间充质干细胞共培养。利用JAK1抑制剂Abrocitinib和JAK1激动剂RO8191研究JAK1/STAT5信号通路。结果：骨髓间充质干细胞在体内可明显减轻大鼠肝移植后冷缺血再灌注损伤引起的肝纤维化。骨髓间充质干细胞移植后，大鼠肝脏中JAK1和p-STAT5水平显著降低。使用阿布昔替尼后，肝纤维化分期及I型胶原α 1链（COL1A1）和肌动蛋白α 2 （ACTA2）水平降低。使用RO8191后，肝纤维化分期及COL1A1、ACTA2水平升高。体外缺氧再氧化后，骨髓间充质干细胞显著降低HSC-T6的活化。HSC-T6缺氧复氧后与骨髓间充质干细胞共培养，JAK1和p-STAT5水平显著降低。加用阿布昔替尼后，HSC-T6中COL1A1、ACTA2水平降低；而添加RO8191后，缺氧复氧后HSC-T6中COL1A1和ACTA2水平升高。体内和体外使用抗il7抗体或抗il7r α后，肝纤维化分期和COL1A1、ACTA2水平降低，STAT5磷酸化水平降低。结论：骨髓间充质干细胞减轻肝细胞损伤，降低肝细胞源性IL7，下调造血干细胞中IL7R/JAK1/STAT5，从而降低造血干细胞的活化，最终缓解肝移植后肝纤维化。
Bone marrow mesenchymal stem cells alleviate liver fibrosis after rat liver transplantation through JAK1/STAT5 pathway.
Objective: The effectiveness of bone marrow mesenchymal stem cells (BMSCs) in post-transplantation liver fibrosis has not been studied. The aim of this study was to investigate the effect of BMSCs on liver fibrosis and their role in the Janus-activated kinase (JAK) 1/ signal transducer and activator of transcription (STAT) 5 pathway after liver transplantation (LT).
Methods: A rat model of post-LT liver fibrosis induced by cold ischemia injury was successfully established. BMSCs were injected into the rats through the portal vein. Hepatic stellate cell (HSC)-T6 were co-cultured with BMSCs in vitro after hypoxia-reoxygenation. JAK1 inhibitor Abrocitinib and JAK1 agonist RO8191 were used to study the JAK1/STAT5 signaling pathway.
Results: BMSCs significantly alleviated liver fibrosis caused by cold ischemia-reperfusion injury after rat LT in vivo. After BMSCs transplantation, the levels of JAK1 and p-STAT5 in rat liver were significantly reduced. After using Abrocitinib, the stage of liver fibrosis and the levels of collagen type I alpha 1 chain (COL1A1) and actin alpha 2 (ACTA2) decreased. After using RO8191, the stage of liver fibrosis and the levels of COL1A1 and ACTA2 increased. BMSCs significantly reduced the activation of HSC-T6 after hypoxia-reoxygenation in vitro. After co-culturing with BMSCs after HSC-T6 hypoxia-reoxygenation, the levels of JAK1 and p-STAT5 were significantly reduced. After the addition of Abrocitinib, the levels of COL1A1 and ACTA2 decreased in HSC-T6; in contrast, after adding RO8191, the levels of COL1A1 and ACTA2 increased in HSC-T6 after hypoxia-reoxygenation. After using anti-IL7 antibody or anti-IL7Rα in vivo and in vitro, the stage of liver fibrosis and the levels of COL1A1 and ACTA2 decreased as well as the phosphorylation level of STAT5.
Conclusions: BMSCs alleviate hepatic cell damage, reduce hepatic cell-derived IL7, downregulate IL7R/JAK1/STAT5 in HSCs, thereby reducing HSCs' activation and ultimately alleviating liver fibrosis after liver transplantation.
期刊介绍：
Stem Cell Research & Therapy serves as a leading platform for translational research in stem cell therapies. This international, peer-reviewed journal publishes high-quality open-access research articles, with a focus on basic, translational, and clinical research in stem cell therapeutics and regenerative therapies. Coverage includes animal models and clinical trials. Additionally, the journal offers reviews, viewpoints, commentaries, and reports.
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