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Int J Biol Sci 2021; 17(9):2135-2146. doi:10.7150/ijbs.60056 This issue Cite

Research Paper

Disruption of myofibroblastic Notch signaling attenuates liver fibrosis by modulating fibrosis progression and regression

Zhensheng Yue^1,2*, Zijian Jiang^1*, Bai Ruan^1,3, Juanli Duan¹, Ping Song¹, Jingjing Liu¹, Hua Han^4,5✉, Lin Wang^1✉

1. Department of Hepatobiliary Surgery, Xi-Jing Hospital, Fourth Military Medical University, Xi'an 710032, China.
2. Department of Ophthalmology, Xi-Jing Hospital, Fourth Military Medical University, Xi'an 710032, China.
3. Aerospace Clinical Medical Center, School of Aerospace Medicine, Fourth Military Medical University, Xi'an 710032, China.
4. State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an 710032, China.
5. Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an 710032, China.
*These authors contributed equally to this work.

✉ Corresponding authors: Lin Wang, Department of Hepatobiliary Surgery, Xi-Jing Hospital, Fourth Military Medical University, Chang-Le Xi Street #127, Xi'an 710032, China, E-mail: fierywangcom; Hua Han, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Chang-Le Xi Street #169, Xi'an 710032, China, E-mail, huahanedu.cn. More

Abstract

The phenotypic transformation of hepatic myofibroblasts (MFs) is involved in the whole process of the progression and regression of liver fibrosis. Notch signaling has been demonstrated to modulate the fibrosis. In this study, we found that Notch signaling in MFs was overactivated and suppressed with the progression and regression of hepatic fibrosis respectively, by detecting Notch signaling readouts in MFs. Moreover, we inactivated Notch signaling specifically in MFs with Sm22α^CreER-RBPj^flox/flox mice (RBPj^MF-KO), and identified that MFs-specific down-regulation of Notch signaling significantly alleviated CCl₄-induced liver fibrosis during the progression and regression. During the progression of liver fibrosis, MFs-specific blockade of Notch signaling inhibited the activation of HSCs to MFs and increases the expression of MMPs to reduce the deposition of ECM. During the regression of fibrosis, blocking Notch signaling in MFs increased the expression of HGF to promote proliferation in hepatocytes and up-regulated the expression of pro-apoptotic factors, Ngfr and Septin4, to induce apoptosis of MFs, thereby accelerating the reversal of fibrosis. Collectively, the MFs-specific disruption of Notch signaling attenuates liver fibrosis by modulating fibrosis progression and regression, which suggests a promising therapeutic strategy for liver fibrosis.

Keywords: Myofibroblasts, hepatic stellate cells, Notch signaling, liver fibrosis progression, liver fibrosis regression

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