Endothelial GATA4 controls liver fibrosis and regeneration by preventing a pathogenic switch in angiocrine signaling

• DOI: 10.1016/j.jhep.2020.08.033
• Publication Date: 2020-09-09T08:37:46Z
• Authors: Manuel Winkler; Theresa Staniczek; Sina Wietje Kürsc...; Christian David S...; Hiltrud Schönhaber; Julio Cordero; Linda Kessler; Arthur Mathes; Carsten Sticht; Michelle Neßling; Alexey Uvarovskii; Simon Anders; Xue-jun Zhang; Guido von Figura; Daniel Hartmann; Carolin Mogler; Gergana Dobreva; Kai Schledzewski; Cyrill Géraud; Philipp-Sebastian...; Sergij Goerdt
• Keywords: Hepatic stellate cell; Liver Regeneration; PDGFB; Kupffer cell; Hepatic fibrosis

Angiocrine signaling by liver sinusoidal endothelial cells (LSECs) regulates hepatic functions such as growth, metabolic maturation, and regeneration. Recently, we identified GATA4 the master regulator of LSEC specification during development. Herein, studied role in adult pathogenesis.We generated Clec4g-icretg/0xGata4fl/fl (Gata4LSEC-KO) mice with LSEC-specific depletion Gata4. Livers were analyzed histology, electron microscopy, immunohistochemistry/immunofluorescence, situ hybridization, LSECs isolated for gene expression profiling, ChIP- ATAC-sequencing. Partial hepatectomy was performed to assess We used choline-deficient, l-amino acid-defined (CDAA) diet chronic carbon tetrachloride exposure model fibrosis. Human single cell RNA-seq data sets alterations healthy cirrhotic livers.Genetic Gata4 deficiency caused perisinusoidal fibrosis, hepatopathy impaired Sinusoidal capillarization LSEC-to-continuous transdifferentiation accompanied a profibrotic angiocrine switch involving de novo stellate cell-activating cytokine PDGFB. Increased chromatin accessibility amplification activated MYC mediated Pdgfb expression. As observed Gata4LSEC-KO livers, CDAA diet-induced fibrosis associated repression, activation LSECs. Comparison CDAA-fed control demonstrated that indeed protects against dietary-induced In human GATA4-positive target genes reduced, while non-LSEC including PDGFB enriched.Endothelial repressing at level. Therapies targeting GATA4/MYC/PDGFB/PDGFRβ axis offer promising strategy prevention treatment fibrosis.The vasculature is supposed play major development cirrhosis, which can lead failure cancer. discovered structural transcriptional changes induced genetic deletion transcription factor endothelium sufficient cause Activation "angiocrine" growth downstream drivers potential therapeutic targets this potentially fatal disease.