Winkler Manuel, Staniczek Theresa, Suhayda Maximilian, Kürschner-Zacharias Sina Wietje, Hoffmann Johannes, Cordero Julio, Kraske Linda, Maude Hannah, Nagy Dorka, Manco Rita, Sticht Carsten, Neßling Michelle, Richter Karsten, Dobreva Gergana, Randi Anna Maria, Cebola Inês, Schledzewski Kai, Reiners-Koch Philipp-Sebastian, Goerdt Sergij, Schmid Christian David
Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University, and Center of Excellence in Dermatology, Mannheim, Germany.
Department of Anatomy and Developmental Biology, European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
JHEP Rep. 2025 Jun 6;7(9):101475. doi: 10.1016/j.jhepr.2025.101475. eCollection 2025 Sep.
BACKGROUND & AIMS: Liver sinusoidal endothelial cells (LSECs) are highly specialized components of the hepatic vascular niche, regulating liver function and disease pathogenesis through angiocrine signaling. Recently, we identified GATA4 as a key transcription factor controlling LSEC development and protecting against liver fibrosis. As the transcription factor c-Maf was strongly downregulated in -deficient LSECs, we hypothesized that c-Maf might be an important downstream effector of GATA4 in LSEC differentiation and liver fibrogenesis.
( ) mice with LSEC-specific deficiency were generated and liver tissue was analyzed histologically. LSECs were isolated for bulk RNA-seq, ATAC-seq, and single-cell (sc) RNA-seq analysis. livers were analyzed after MASH diet feeding. The expression of and its targets was analyzed in published human scRNA-seq data.
Endothelial deficiency resulted in perisinusoidal liver fibrosis (Sirius red 0.46% . 2.92%; <0.05) without affecting metabolic liver zonation, accompanied by a switch from sinusoidal to continuous endothelial cell identity, which was aggravated upon MASH diet feeding ( <0.01). Furthermore, endothelial deficiency caused LSEC proliferation (0.05) and expression of profibrotic angiocrine factors including , , , among which FLRT2 ( <0.01) and CXCL12 ( <0.001) activated hepatic stellate cells . scRNA-seq revealed replacement of zonated LSEC subpopulations with capillarized, proliferative, sprouting and secretory endothelial cell subsets that promote liver fibrogenesis and angiogenesis. This fundamental dysregulation of LSEC gene expression and differentiation was caused by changes in chromatin accessibility and transcription factor activity following loss of . Notably, endothelial expression was also significantly reduced in human cirrhotic livers (0.0001).
Hepatic endothelial c-Maf protects against metabolic dysfunction-associated steatohepatitis-like liver fibrosis and regulates endothelial differentiation and zonation by controlling chromatin opening.
This work builds on the known importance of liver sinusoidal endothelial cells in liver function and disease. Here, transcription factor c-Maf is identified as a master regulator in maintaining normal differentiation and zonation of liver sinusoidal endothelial cells, thereby protecting against the development of liver fibrosis/cirrhosis. The findings are significant for researchers and clinicians focusing on liver disease, as they suggest potential new targets for therapeutic intervention. These findings could instruct the development of novel preventive treatment options and antifibrotic therapy regimens as well as liver repair strategies, benefiting patients, clinicians and policy makers in the management of liver disease.
肝窦内皮细胞（LSECs）是肝血管微环境中高度特化的组成部分，通过血管内分泌信号调节肝功能和疾病发病机制。最近，我们确定GATA4是控制LSECs发育和预防肝纤维化的关键转录因子。由于转录因子c-Maf在GATA4缺陷的LSECs中强烈下调，我们推测c-Maf可能是GATA4在LSECs分化和肝纤维化形成中的重要下游效应因子。
构建LSEC特异性c-Maf缺陷的小鼠，并对肝脏组织进行组织学分析。分离LSECs进行批量RNA测序、ATAC测序和单细胞（sc）RNA测序分析。在给予MASH饮食后分析小鼠肝脏。在已发表的人类scRNA测序数据中分析c-Maf及其靶标的表达。
内皮细胞c-Maf缺陷导致肝窦周围肝纤维化（天狼星红0.46%对2.92%；P<0.05），而不影响肝脏代谢分区，同时伴随着从窦状内皮细胞向连续性内皮细胞身份的转变，在给予MASH饮食后这种转变加剧（P<0.01）。此外，内皮细胞c-Maf缺陷导致LSECs增殖（P<0.05）以及包括FLRT2、CXCL12、FGF1和ANGPTL4在内的促纤维化血管内分泌因子表达，其中FLRT2（P<0.01）和CXCL12（P<0.001）激活肝星状细胞。scRNA测序显示，具有促肝纤维化和血管生成作用的毛细血管化、增殖、芽生和分泌性内皮细胞亚群取代了分区化的LSEC亚群。LSEC基因表达和分化的这种根本失调是由于c-Maf缺失后染色质可及性和转录因子活性的变化所致。值得注意的是，在人类肝硬化肝脏中内皮细胞c-Maf的表达也显著降低（P<0.0001）。
肝内皮细胞c-Maf可预防代谢功能障碍相关的脂肪性肝炎样肝纤维化，并通过控制染色质开放来调节内皮细胞分化和分区。
这项工作建立在已知肝窦内皮细胞在肝功能和疾病中的重要性基础之上。在此，转录因子c-Maf被确定为维持肝窦内皮细胞正常分化和分区的主要调节因子，从而预防肝纤维化/肝硬化的发展。这些发现对专注于肝病的研究人员和临床医生具有重要意义，因为它们提示了潜在的治疗干预新靶点。这些发现可为新型预防性治疗方案、抗纤维化治疗方案以及肝脏修复策略的开发提供指导，使患者、临床医生和政策制定者在肝病管理中受益。
