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@ARTICLE{Winkler:303488,
      author       = {M. Winkler and T. Staniczek and M. Suhayda and S. W.
                      Kürschner-Zacharias and J. Hoffmann and J. Cordero and L.
                      Kraske and H. Maude and D. Nagy and R. Manco and C. Sticht
                      and M. Neßling$^*$ and K. Richter$^*$ and G. Dobreva and A.
                      M. Randi and I. Cebola and K. Schledzewski and P.-S.
                      Reiners-Koch and S. Goerdt and C. D. Schmid},
      title        = {{E}ndothelial c-{M}af prevents {MASLD}-like liver fibrosis
                      by regulating chromatin accessibility to suppress pathogenic
                      microvascular cell subsets.},
      journal      = {JHEP reports},
      volume       = {7},
      number       = {9},
      issn         = {2589-5559},
      address      = {Amsterdam},
      publisher    = {Elsevier},
      reportid     = {DKFZ-2025-01679},
      pages        = {101475},
      year         = {2025},
      abstract     = {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 Gata4-deficient
                      LSECs, we hypothesized that c-Maf might be an important
                      downstream effector of GATA4 in LSEC differentiation and
                      liver fibrogenesis.Clec4g-iCre/Maf fl/fl (Maf LSEC-KO ) mice
                      with LSEC-specific Maf 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. Maf LSEC-KO livers were analyzed after MASH diet
                      feeding. The expression of MAF and its targets was analyzed
                      in published human scRNA-seq data.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 MASH diet feeding (p <0.01). Furthermore, endothelial
                      Maf deficiency caused LSEC proliferation (p <0.05) and
                      expression of profibrotic angiocrine factors including
                      Pdgfb, Igfbp5, Flrt2, and Cxcl12, among which FLRT2 (p
                      <0.01) and CXCL12 (p <0.001) activated hepatic stellate
                      cells in vitro. 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 Maf. Notably, endothelial MAF expression was also
                      significantly reduced in human cirrhotic livers (p
                      <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.},
      keywords     = {ATAC-Seq analysis (Other) / Capillarization (Other) /
                      Cirrhosis (Other) / Liver sinusoidal endothelial cells
                      (LSEC) (Other) / Single-cell RNA-Seq analysis (Other)},
      cin          = {W230},
      ddc          = {610},
      cid          = {I:(DE-He78)W230-20160331},
      pnm          = {319H - Addenda (POF4-319H)},
      pid          = {G:(DE-HGF)POF4-319H},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40810103},
      pmc          = {pmc:PMC12341620},
      doi          = {10.1016/j.jhepr.2025.101475},
      url          = {https://inrepo02.dkfz.de/record/303488},
}