Tao Jiawang, Wu Zichao, Liang Yanran, Wang Jiongliang, Tang Miaoxiu, Huang Sunan, Jiang Fan, Zhou Guangqi, Guo Lin, Yuan Shengxian, Li Yinxiong, Wang Jie
Center for Biomedical Digital Science, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
University of Chinese Academy of Sciences, Beijing, China.
Hepatology. 2024 Dec 18. doi: 10.1097/HEP.0000000000001201.
Promoting liver regeneration while inhibiting fibrogenesis represented an attractive strategy for treating liver diseases, with 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.
Through comparing acute and chronic liver injury mouse models induced by CCl 4 injections, we revealed that HSCs exhibited dual functionality, expressing pro-regenerative and profibrogenic 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, 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. In addition, Lhx2 overexpression not only promoted hepatocyte proliferation but also exhibited an antifibrogenic function after chronic injury. Mechanistically, Lhx2 suppressed multiple functions of activated HSCs, including fibrogenesis, proliferation, and migration, and upregulated SMAD6 to block the TGF-β signaling pathway. Moreover, Lhx2 was an upstream regulator of various pro-regenerative factors, especially HGF, which is crucial for liver regeneration.
We demonstrated that Lhx2 had pro-regenerative and antifibrogenic functions, and elucidated its regulatory mechanism. The study provided a potential target with dual effects for treating liver diseases.
促进肝再生同时抑制肝纤维化是治疗肝脏疾病的一个有吸引力的策略，肝星状细胞（HSCs）在这两个过程中都起着关键作用。本研究旨在确定HSCs中同时促进再生和抑制纤维化的特定靶点，并阐明其分子机制。
通过比较四氯化碳注射诱导的急性和慢性肝损伤小鼠模型，我们发现HSCs具有双重功能，在损伤后表达促再生和促纤维化基因。分析这些模型中分离的原代HSCs的RNA测序数据，以及公开的HSCs单细胞RNA测序数据，我们确定了转录因子Lhx2，它特异性地在HSCs中表达，是双重功能的潜在调节因子。值得注意的是，在小鼠和人类模型中，与纤维化肝脏相比，Lhx2在健康肝脏组织的HSCs中表达显著更高。急性肝损伤后，敲低Lhx2会损害肝功能恢复和细胞增殖。在HSC特异性过表达Lhx2的小鼠中观察到了一致的变化。此外，Lhx2过表达不仅促进肝细胞增殖，还在慢性损伤后表现出抗纤维化功能。机制上，Lhx2抑制活化HSCs的多种功能，包括纤维化、增殖和迁移，并上调SMAD6以阻断TGF-β信号通路。此外，Lhx2是多种促再生因子的上游调节因子，尤其是对肝再生至关重要的HGF。
我们证明了Lhx2具有促再生和抗纤维化功能，并阐明了其调节机制。该研究为治疗肝脏疾病提供了一个具有双重作用的潜在靶点。
