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Background <p>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).</p> Methods <p>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&amp;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<sup>2+</sup>) assessed ferroptosis. Enzyme-linked immunosorbent assay (ELISA) detected cytokines in supernatant.</p> Results <p>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.</p> Conclusion <p>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.</p>

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Human umbilical cord mesenchymal stem cells ameliorate liver fibrosis by inhibiting hepatocyte ferroptosis and macrophage polarization via the miR-455-3p/PLAU axis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月30日

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  • Yong Zhang,
  • Jin Dou,
  • Shipeng Dai,
  • Yuchen Xie,
  • Hongyu Wang,
  • Zhongda Chen,
  • Haiwen Zhuang,
  • Sanrong Xu

摘要

Background

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).

Methods

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 (Fe2+) assessed ferroptosis. Enzyme-linked immunosorbent assay (ELISA) detected cytokines in supernatant.

Results

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.

Conclusion

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.