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

  • Stem Cell Res Ther. 2025 May 1;16(1):217. doi: 10.1186/s13287-025-04353-y.
Zhuyuan Si  #  1  2 ,  Shengqiao Zhao  #  2 ,  Zhixin Zhang  #  2 ,  Tianran Chen  2 ,  Ruofan Wang  2 ,  Chong Dong  2 ,  Kai Wang  2 ,  Chao Sun  2 ,  Zhuolun Song  2  3 ,  Zhongyang Shen  4  5 ,  Wei Gao  6  7
Affiliations
  • 1. Department of Organ Transplantation, Qilu Hospital of Shandong University, Jinan, China.
  • 2. Department of Liver Transplantation, Organ Transplantation Center, Tianjin First Central Hospital, Tianjin, China.
  • 3. Tianjin Key Laboratory of Organ Transplantation, Tianjin First Central Hospital, Tianjin, China.
  • 4. Department of Liver Transplantation, Organ Transplantation Center, Tianjin First Central Hospital, Tianjin, China. [email protected].
  • 5. Tianjin Key Laboratory of Organ Transplantation, Tianjin First Central Hospital, Tianjin, China. [email protected].
  • 6. Department of Liver Transplantation, Organ Transplantation Center, Tianjin First Central Hospital, Tianjin, China. [email protected].
  • 7. Tianjin Key Laboratory of Organ Transplantation, Tianjin First Central Hospital, Tianjin, China. [email protected].
  • # Contributed equally.
PMID: 40312752 DOI: 10.1186/s13287-025-04353-y
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.

Keywords
Bone marrow mesenchymal stem cells; Hepatic stellate cells; JAK1; Liver fibrosis; Liver transplantation; STAT5.
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