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Published on: February 10, 2018
Bone marrow mesenchymal stem cells alleviate liver fibrosis after rat liver transplantation through JAK1/STAT5
Zhuyuan Si1,2, Shengqiao Zhao2, Zhixin Zhang2
1Department of Organ Transplantation, Qilu Hospital of Shandong University, Jinan, China.
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.
Insights
Bone marrow mesenchymal stem cells (BMSCs) alleviate liver fibrosis after transplantation by inhibiting the IL7R/JAK1/STAT5 pathway. This reduces hepatic stellate cell activation and improves liver function, offering a potential therapeutic strategy.
Area of Science:
- Regenerative Medicine
- Hepatology
- Immunology
Background:
- Liver fibrosis is a significant complication following liver transplantation.
- The therapeutic potential of bone marrow mesenchymal stem cells (BMSCs) in post-transplantation liver fibrosis remains largely unexplored.
- Understanding the underlying molecular mechanisms is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the efficacy of BMSCs in mitigating liver fibrosis post-liver transplantation (LT).
- To elucidate the role of the Janus-activated kinase (JAK) 1/signal transducer and activator of transcription (STAT) 5 pathway in BMSC-mediated therapeutic effects.
- To explore the interaction between BMSCs, hepatic stellate cells (HSCs), and the IL-7 signaling axis.
Main Methods:
- A rat model of post-LT liver fibrosis was established using cold ischemia-reperfusion injury.
- BMSCs were administered via the portal vein.
- In vitro studies involved co-culturing HSCs with BMSCs under hypoxia-reoxygenation, with interventions using JAK1 inhibitors/agonists and anti-IL7/IL7Rα antibodies.
Main Results:
- BMSC transplantation significantly reduced liver fibrosis and collagen deposition (COL1A1, ACTA2) in vivo.
- BMSCs decreased the activation of JAK1/STAT5 signaling and HSC activation in vitro and in vivo.
- Inhibition of the IL7R/JAK1/STAT5 pathway mimicked BMSC effects, while its activation exacerbated fibrosis.
Conclusions:
- BMSCs effectively alleviate liver fibrosis after LT by reducing hepatic cell damage.
- BMSCs downregulate IL-7 production and the IL7R/JAK1/STAT5 pathway in HSCs.
- This mechanism suppresses HSC activation, ultimately mitigating liver fibrosis post-transplantation.
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