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内皮c-Maf通过调节染色质可访问性来抑制致病微血管细胞子集来预防类似MASLD的肝纤维化

Manuel Winkler¹, Theresa Staniczek¹, Maximilian Suhayda¹

¹Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University, and Center of Excellence in Dermatology, Mannheim, Germany.

JHEP reports : innovation in hepatology

|August 14, 2025

概括

转录因子c-Maf对于肝侧内皮细胞 (LSEC) 的分化和功能至关重要. 在LSEC中c-Maf的损失促进肝纤维化,改变内皮细胞的身份,突出其在肝病中的保护作用.

科学领域:

肝病学和血管生物学
分子和细胞生物学分子和细胞生物学
转录条例转录条例转录条例

背景情况:

肝脏状内皮细胞 (LSEC) 对于肝脏功能和疾病至关重要,调解血管分泌信号.
GATA4是LSEC发育和预防肝纤维化的一个关键转录因子.
假设c-Maf是GATA4的下游效应因子,在LSEC分化和纤维化中起作用.

研究的目的:

研究转录因子c-Maf在LSEC分化和肝脏纤维化中的作用.
确定c-Maf是否是LSEC中GATA4的下游目标.
探索LSEC特异性c-Maf缺乏对肝脏健康和疾病的影响.

主要方法:

产生了特定于LSEC的c-Maf淘汰赛小鼠 (Maf^LSEC-KO).
在LSEC上进行了组织学分析,大量RNA-seq,ATAC-seq和单细胞RNA-seq.
在MASH饮食条件下分析了Maf^LSEC-KO肝脏,并检查了人类肝硬化肝脏数据.

主要成果:

内皮细胞c-Maf缺乏导致周状肝纤维化,并转换为连续的内皮细胞身份.
在MASH饮食下,Maf缺乏症加剧了纤维化,诱导了LSEC增殖,并上调了益纤维素因子 (例如,FLRT2,CXCL12).
单细胞RNA-seq揭示了LSEC亚群向亲纤维化和血管性表型的转变,这与改变的染色质可访问性有关.

结论:

肝脏内皮c-Maf对于维持LSEC分化和区分至关重要,可以防止肝纤维化.
c-Maf通过控制染色质可访问性来调节内皮细胞的身份和功能.
人类肝硬化肝脏内皮内膜MAF表达的减少强调了其临床相关性.

关键词:

在ATAC-Seq分析中,毛细化毛细化毛细化肝硬化是肝硬化的一种.肝脏的阴侧内皮细胞 (LSEC)单细胞RNA-Seq分析

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