骨髓间充质干细胞通过JAK1/STAT5信号通路减轻大鼠肝移植后的肝纤维化。

Bone marrow mesenchymal stem cells alleviate liver fibrosis after rat liver transplantation through JAK1/STAT5 pathway.

作者信息

Si Zhuyuan, Zhao Shengqiao, Zhang Zhixin, Chen Tianran, Wang Ruofan, Dong Chong, Wang Kai, Sun Chao, Song Zhuolun, Shen Zhongyang, Gao Wei

机构信息

Department of Organ Transplantation, Qilu Hospital of Shandong University, Jinan, China.

Department of Liver Transplantation, Organ Transplantation Center, Tianjin First Central Hospital, Tianjin, China.

出版信息

Stem Cell Res Ther. 2025 May 1;16(1):217. doi: 10.1186/s13287-025-04353-y.

DOI:10.1186/s13287-025-04353-y

PMID:40312752

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12044927/

Abstract

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.

摘要

目的

尚未研究骨髓间充质干细胞（BMSCs）在肝移植后肝纤维化中的有效性。本研究旨在探讨BMSCs对肝纤维化的影响及其在肝移植（LT）后Janus激酶（JAK）1/信号转导和转录激活因子（STAT）5通路中的作用。

方法

成功建立冷缺血损伤诱导的大鼠LT后肝纤维化模型。通过门静脉将BMSCs注入大鼠体内。缺氧复氧后，将肝星状细胞（HSC）-T6与BMSCs进行体外共培养。使用JAK1抑制剂阿布昔替尼和JAK1激动剂RO8191研究JAK1/STAT5信号通路。

结果

BMSCs显著减轻大鼠LT后体内冷缺血再灌注损伤所致的肝纤维化。BMSCs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，肝纤维化分期以及I型胶原α1链（COL1A1）和肌动蛋白α2（ACTA2）水平降低。使用RO8191后，肝纤维化分期以及COL1A1和ACTA2水平升高。BMSCs显著降低体外缺氧复氧后HSC-T6的活化。HSC-T6缺氧复氧后与BMSCs共培养，JAK1和p-STAT5水平显著降低。加入阿布昔替尼后，HSC-T6中COL1A1和ACTA2水平降低；相反，加入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IL7Rα后，肝纤维化分期以及COL1A1和ACTA2水平降低，STAT5磷酸化水平也降低。