盼盼
(2024-12-31 21:44):
#paper doi:10.1097/HEP.0000000000001201 2024年12月,Hepatology在线发表了最新研究成果“Lhx2 specifically expressed in hepatic stellate cells promotes liver regeneration and inhibits liver fibrosis”,该研究通过比较小鼠急性和慢性肝损伤模型,结合RNA-seq和单细胞RNA-seq数据分析,发现Lhx2在肝星状细胞中特异性表达,具有促进肝脏再生和抑制纤维化的双重功能。hx2能够通过上调SMAD6阻断TGF-β信号通路,抑制HSCs的激活,同时促进肝细胞生长因子HGF的表达,加速肝细胞增殖。这一发现为开发治疗肝脏疾病的新策略提供了潜在靶点,具有重要的临床意义。
Hepatology,
2024-12-18.
DOI: 10.1097/HEP.0000000000001201
Lhx2 specifically expressed in hepatic stellate cells promotes liver regeneration and inhibits liver fibrosis
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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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