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TGF-β1 signaling activates hepatic stellate cells through Notch pathway

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Abstract

Hepatic stellate cells (HSCs), as the most important stromal cells in the liver microenvironment, play crucial roles in hepatic fibrosis, hepatocellular carcinoma, liver regeneration and fetal liver development after transdifferentiating into myofibroblasts (MFs). Transforming growth factor β1 (TGF-β1), as an important polyergic cytokine, is involved in HSCs activation process. However, the specific mechanisms of HSCs transdifferentiation process are not clearly demonstrated. Here we added exogenous recombinant TGF-β1 protein and transforming growth factor β receptor 1 (TGF-βR1) inhibitor SB431542 into mouse HSCs to detect the detailed impact of TGF-β1 signaling on HSCs activation. TGF-β1 signaling significantly increased phosphorylated (P)-Smad2/3 level and promoted Smad2/3 translocation from the cytoplasm to the nucleus, which also caused transdifferentiation of HSCs into MFs. Importantly, TGF-β1 signaling also resulted in high expression of Notch pathway markers Notch1, Jagged1, Hes1 in HSCs. In contrast, expression of those above markers in mouse HSCs were obviously decreased after hampering TGF-β1 signaling via TGF-βR1 inhibitor SB431542. To further examine the effect of Notch pathway on HSCs activation process, TGF-β1-stimulated HSCs and control HSCs were treated with or without LY450139, a specific inhibitor of Notch pathway. LY450139 evidently decreased the expression of Notch1 and MFs marker α-smooth muscle actin (α-SMA) expression in HSCs. These above results may provide a novel insight that TGF-β1 signaling controls HSCs activation process through regulating the expression of Notch pathway markers.

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Acknowledgements

The authors would like to acknowledge the technical support from State Key Laboratory on Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Xinjiang Medical University. This study was supported by the Postgraduate Scientific Research Innovation Project of Xinjiang Medical University (Grant No. CXCY2018025), Xinjiang Uyghur Autonomous Region Key Laboratory Open Research Program (Grant No. 2017D04004) and Xinjiang Uyghur Autonomous Region Key Project (Grant No. 201430123).

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Author notes

  1. Yasen Aimaiti and Maimaitinijiati Yusufukadier contributed equally to this work

Authors and Affiliations

  1. Xinjiang Medical University, Urumqi, 830011, Xinjiang Uyghur Autonomous Region, People’s Republic of China

    Yasen Aimaiti, Maimaitinijiati Yusufukadier & Aisan Meiheriayi

  2. State Key Laboratory on Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Xinjiang Medical University, 393 Xin Yi Road, Urumqi, 830011, Xinjiang Uyghur Autonomous Region, People’s Republic of China

    Yasen Aimaiti, Maimaitinijiati Yusufukadier, Wending Li, Apar Shadike, Aini Abudusalamu, Hui Wang & Hao Wen

  3. Department of Liver and Laparoscopic Surgery, Digestive and Vascular Surgery Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011, Xinjiang Uyghur Autonomous Region, People’s Republic of China

    Yasen Aimaiti, Wending Li, Tusun Tuerhongjiang, Apar Shadike,  Gulisitan & Aini Abudusalamu

  4. Department of Hepatobiliary and Hydatid Disease, Digestive and Vascular Surgery Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011, Xinjiang Uyghur Autonomous Region, People’s Republic of China

    Yasen Aimaiti, Maimaitinijiati Yusufukadier, Aji Tuerganaili & Yingmei Shao

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  1. Yasen Aimaiti
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Contributions

YA: Conception and design; provision of study material; collection and assembly of data; Manuscript writing and revision. MY: Collection and assembly of data; manuscript writing and revision. WL: Data Collection. TT: Provision of study material; collection and assembly of data. AS: Provision of study material; Collection and assembly of data. AM and G: Data collection. AA: Provision of study material. HW: Provision of study material; collection and assembly of data. AT: Conception and design; administrative support. YSS: Conception and design; administrative support. WH: Conception and design; administrative support; Final approval of manuscript.

Corresponding author

Correspondence to Hao Wen.

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The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

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Aimaiti, Y., Yusufukadier, M., Li, W. et al. TGF-β1 signaling activates hepatic stellate cells through Notch pathway. Cytotechnology 71, 881–891 (2019). https://doi.org/10.1007/s10616-019-00329-y

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  • DOI: https://doi.org/10.1007/s10616-019-00329-y

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