Zhang Yong, Dou Jin, Dai Shipeng, Xie Yuchen, Wang Hongyu, Chen Zhongda, Zhuang Haiwen, Xu Sanrong
Department of General Surgery, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu Province, China.
Division of Gastrointestinal Surgery, Department of General Surgery, The Affiliated Huai'an Hospital of Xuzhou Medical UniversityHuai'an Second People's Hospital, Huai'an, Jiangsu Province, China.
Stem Cell Res Ther. 2025 Jul 30;16(1):412. doi: 10.1186/s13287-025-04526-9.
Peripheral infusion of human umbilical cord mesenchymal stem cells (hUC-MSCs) may therapeutically treat liver fibrosis. hUC-MSCs can influence liver fibrosis progression and immune microenvironment remodeling via microRNAs (miRNAs).
Bioinformatics showed the miR-455-3p/PLAU axis might regulate ferroptosis in liver fibrosis and affect the immune microenvironment. hUC-MSCs were transplanted into CCL4 induced liver-fibrotic male C57BL/6 mice. Liver tissues were stained (Hematoxylin and eosin (H&E), Masson, Sirius Red) to assess fibrosis; Alpha-smooth muscle actin (α-SMA) expression was detected by immunohistochemistry (IHC). Macrophage polarization was measured by immunofluorescence (IF), quantitative real-time polymerase chain reaction (qRT-PCR), and flow cytometry. Dual-luciferase and RNA pull-down assays verified miR-455-3p/PLAU regulation. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TBIL) evaluated liver function. Reactive oxygen species (ROS), glutathione peroxidase 4 (GPX4), iron content, and ferrous iron (Fe) assessed ferroptosis. Enzyme-linked immunosorbent assay (ELISA) detected cytokines in supernatant.
In fibrotic vs. normal liver tissues, miR-455-3p was down-regulated, PLAU up-regulated, and ferroptosis increased. hUC-MSCs transplantation improves CCL4 induced liver fibrosis by inhibiting ferroptosis of hepatocytes through the miR-455-3p/PLAU axis. It also alleviated macrophage M1 polarization and liver damage.
hUC-MSCs inhibit hepatocyte ferroptosis via the miR-455-3p/PLAU axis, alleviate macrophage M1 polarization, and slow liver fibrosis. These findings offer insights for future liver fibrosis research and treatment.
外周输注人脐带间充质干细胞（hUC-MSCs）可能对肝纤维化具有治疗作用。hUC-MSCs可通过微小RNA（miRNAs）影响肝纤维化进展和免疫微环境重塑。
生物信息学分析显示，miR-455-3p/PLAU轴可能调控肝纤维化中的铁死亡并影响免疫微环境。将hUC-MSCs移植到CCl4诱导的肝纤维化雄性C57BL/6小鼠体内。对肝组织进行苏木精-伊红（H&E）染色、Masson染色、天狼星红染色以评估纤维化程度；通过免疫组织化学（IHC）检测α-平滑肌肌动蛋白（α-SMA）的表达。通过免疫荧光（IF）、定量实时聚合酶链反应（qRT-PCR）和流式细胞术检测巨噬细胞极化情况。双荧光素酶报告基因检测和RNA下拉实验验证miR-455-3p/PLAU调控关系。检测丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（AST）和总胆红素（TBIL）评估肝功能。检测活性氧（ROS）、谷胱甘肽过氧化物酶4（GPX4）、铁含量和亚铁（Fe）评估铁死亡情况。通过酶联免疫吸附测定（ELISA）检测上清液中的细胞因子。
与正常肝组织相比，纤维化肝组织中miR-455-3p表达下调，PLAU表达上调，铁死亡增加）。hUC-MSCs移植通过miR-455-3p/PLAU轴抑制肝细胞铁死亡，从而改善CCl4诱导的肝纤维化。它还减轻了巨噬细胞M1极化和肝损伤。
hUC-MSCs通过miR-455-3p/PLAU轴抑制肝细胞铁死亡，减轻巨噬细胞M1极化，减缓肝纤维化。这些发现为未来肝纤维化的研究和治疗提供了思路。
