Lhx2 specifically expressed in hepatic stellate cells promotes liver regeneration and inhibits liver fibrosis

IF 12.9 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY
Jiawang Tao, Zichao Wu, Yanran Liang, Jiongliang Wang, Miaoxiu Tang, Sunan Huang, Fan Jiang, Guangqi Zhou, Lin Guo, Shengxian Yuan, Yinxiong Li, Jie Wang
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引用次数: 0

Abstract

Background and Aims: Promoting liver regeneration while inhibiting fibrogenesis represented an attractive strategy for treating liver diseases, with hepatic stellate cells (HSCs) being crucial to both processes. This study aimed to identify specific targets in HSCs that simultaneously facilitated regeneration and suppressed fibrosis, and elucidated their molecular mechanisms. Approach and Results: Through comparing acute and chronic liver injury mouse models induced by CCl4 injections, we revealed that HSCs exhibited dual functionality, expressing pro-regenerative and pro-fibrogenic genes following injury. Analyzing RNA-seq data from primary HSCs of these models, along with publicly available single-cell RNA-seq data of HSCs, we identified transcription factor Lhx2, specifically expressed in HSCs, emerged as a potential regulator of the dual functions. Notably, Lhx2 showed significantly higher expression in HSCs from healthy liver tissue compared to fibrotic liver, in both mouse and human models. Lhx2 knockdown impaired liver function recovery and cellular proliferation after acute liver injury. Consistent changes were observed in mice with HSC-specific Lhx2 overexpression. Additionally, Lhx2 overexpression not only promoted hepatocyte proliferation but also exhibited an anti-fibrogenic function after chronic injury. Mechanistically, Lhx2 suppressed multiple functions of activated HSCs, including fibrogenesis, proliferation and migration, and up-regulated SMAD6 to block TGF-β signaling pathway. Moreover, Lhx2 was an upstream regulator of various pro-regenerative factors, especially HGF, which is crucial for liver regeneration. Conclusions: We demonstrated that Lhx2 had pro-regenerative and anti-fibrogenic functions, and elucidated its regulatory mechanism. The study provided a potential target with dual effects for treating liver diseases.
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来源期刊
Hepatology
Hepatology 医学-胃肠肝病学
CiteScore
27.50
自引率
3.70%
发文量
609
审稿时长
1 months
期刊介绍: HEPATOLOGY is recognized as the leading publication in the field of liver disease. It features original, peer-reviewed articles covering various aspects of liver structure, function, and disease. The journal's distinguished Editorial Board carefully selects the best articles each month, focusing on topics including immunology, chronic hepatitis, viral hepatitis, cirrhosis, genetic and metabolic liver diseases, liver cancer, and drug metabolism.
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