Endothelial c-Maf prevents MASLD-like liver fibrosis by regulating chromatin accessibility to suppress pathogenic microvascular cell subsets
Year: 2025
Type: article
Abstract: Background and Aims Liver sinusoidal endothelial cells (LSEC) are highly specialized within the hepatic vascular niche, controlling liver function and disease pathogenesis by angiocrine signaling. Recently, we identified GATA4 as a major transcription factor controlling LSEC development and protecting against liver fibrosis. As the transcription factor c-Maf was strongly downregulated in Gata4 -deficient LSEC, we hypothesized that c-Maf might be an important downstream effector of GATA4 in LSEC differentiation and liver fibrogenesis. Methods Clec4g-iCre/Maf fl/fl ( Maf LSEC-KO ) mice with LSEC-specific Maf deficiency were generated and liver tissue was analyzed histologically. LSEC were isolated for bulk RNA-seq, ATAC-seq, and single-cell (sc) RNA-seq analysis. Maf LSEC-KO livers were analyzed after MASH diet. The expression of MAF and its targets was analyzed in published human scRNA-seq data. Results Endothelial Maf deficiency resulted in perisinusoidal liver fibrosis (Sirius Red 0.46% vs . 2.92%; p <0.05) without affecting metabolic liver zonation, accompanied by a switch from sinusoidal to continuous endothelial cell identity, which was aggravated upon feeding a MASH diet ( p <0.01). Furthermore, endothelial Maf deficiency caused LSEC proliferation ( p <0.05) and expression of profibrotic angiocrine factors such as Pdgfb , Igfbp5 , Flrt2, and Cxcl12 , of which FLRT2 ( p <0.01) and CXCL12 ( p <0.001) activated hepatic stellate cells in vitro . scRNA-seq revealed replacement of zonated LSEC subpopulations by capillarized, proliferative, sprouting and secretory endothelial cell subsets promoting 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 Maf . Notably, endothelial MAF expression was also significantly reduced in human liver cirrhosis patients ( p <0.0001). Conclusions Hepatic endothelial c-Maf protects against metabolic dysfunction-associated steatohepatitis-like liver fibrosis and regulates endothelial differentiation and zonation by controlling chromatin opening. Impact and Implications This work builds on the known importance of liver sinusoidal endothelial cells (LSEC) in liver function and disease. Here, transcription factor c-Maf is identified as a master regulator in maintaining normal LSEC differentiation and zonation, thereby protecting against 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.
Source: JHEP Reports
Authors: Manuel Winkler, Theresa Staniczek, Maximilian Suhayda, Sina Wietje Kürschner-Zacharias, Johannes Hoffmann, Julio Cordero, Linda Kraske, Hannah Maude, Dorka Nagy, Rita Manco, Carsten Sticht, Michelle Neßling, Karsten Richter, Gergana Dobreva, Anna Maria Randi, Inês Cebola, Kai Schledzewski, Philipp-Sebastian Reiners-Koch, Sergij Goerdt, Christian David Schmid
Language: English
Subfield: Hepatology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,110
Awards: G1268980531, G1692958442, G2428190716, G2867604408, G3253862789, Discovery of NAFLD gene regulatory networks with multi-omics, G4724125240, G4783087731, G5284521312, G6233569528, G6461157608, Discovery of NAFLD gene regulatory networks with multi-omics, Schnittstellen und Interventionen bei komplexen chronischen Erkrankungen, Endothelial transciptional networks in the control of angiogenesis and tissue homeostasis (renewal), G6584887909, G7704527074, SFB 1366: Vaskuläre Kontrolle der Organfunktion, ICL 4th intake 2020 – 4-year PhD Studentship (4th) Scheme: Ms Maike Haensal; Ms Zuzanna Jablonska; Ms Anies Makhdomi- Sohi; Ms Dorka Nagy, GRK 2099: Hallmarks of Skin Cancer: TumorMikromilieu und MelanomImmunologie, G8597422617
OpenAlex ID: W4411079169