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.

中文翻译：

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在肝星状细胞中特异性表达的 Lhx2 促进肝脏再生并抑制肝纤维化


背景和目的： 促进肝脏再生同时抑制纤维化是治疗肝脏疾病的一种有吸引力的策略，肝星状细胞 （HSC） 对这两个过程都至关重要。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，并阐明它们的分子机制。方法和结果： 通过比较 CCl4 注射诱导的急性和慢性肝损伤小鼠模型，我们发现 HSCs 表现出双重功能，在损伤后表达促再生和促纤维化基因。分析来自这些模型的原代 HSC 的 RNA-seq 数据，以及公开可用的 HSC 单细胞 RNA-seq 数据，我们确定了在 HSC 中特异性表达的转录因子 Lhx2 成为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 在健康肝组织的 HSC 中的表达显著更高。Lhx2 敲低损害急性肝损伤后肝功能恢复和细胞增殖。在 HSC 特异性 Lhx2 过表达的小鼠中观察到一致的变化。此外，Lhx2 过表达不仅促进肝细胞增殖，而且在慢性损伤后表现出抗纤维化功能。从机制上讲，Lhx2 抑制了活化 HSC 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 是各种促再生因子的上游调节因子，尤其是对肝脏再生至关重要的 HGF。结论： 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效果的潜在靶点。