Elisabetta Ceni1, Tommaso Mello1, Simone Polvani1, Mireille Vasseur-Cognet2, Mirko Tarocchi1, Sara Tempesti3, Duccio Cavalieri4, Luca Beltrame5, Giada Marroncini3, Massimo Pinzani6, Stefano Milani1, Andrea Galli7. 1. Gastroenterology Research Unit, Department of Experimental and Clinical Biochemical Sciences, University of Florence, Florence, Italy; Center of Excellence for Research, Transfer and High Education, DENOthe, University of Florence, Italy. 2. INSERM, U1016, Institut Cochin, Paris, France. 3. Gastroenterology Research Unit, Department of Experimental and Clinical Biochemical Sciences, University of Florence, Florence, Italy. 4. Department of Biology, University of Florence, Florence, Italy. 5. Translational Genomics Unit, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy. 6. UCL Institute for Liver and Digestive Health, University College London, Royal Free Hospital Campus U3, Rowland Hill Street, London NW3 2PF, UK. 7. Gastroenterology Research Unit, Department of Experimental and Clinical Biochemical Sciences, University of Florence, Florence, Italy; Center of Excellence for Research, Transfer and High Education, DENOthe, University of Florence, Italy; FiorGen Foundation, Florence, Italy. Electronic address: a.galli@dfc.unifi.it.
Abstract
BACKGROUND & AIMS: Hepatic stellate cell (HSC) transdifferentiation into collagen-producing myofibroblasts is a key event in hepatic fibrogenesis, but the transcriptional network that controls the acquisition of the activated phenotype is still poorly understood. In this study, we explored whether the nuclear receptor chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) is involved in HSC activation and in the multifunctional role of these cells during the response to liver injury. METHODS: COUP-TFII expression was evaluated in normal and cirrhotic livers by immunohistochemistry and Western blot. The role of COUP-TFII in HSC was assessed by gain and loss of function transfection experiments and by generation of mice with COUP-TFII deletion in HSC. Molecular changes were determined by gene expression microarray and RT-qPCR. RESULTS: We showed that COUP-TFII is highly expressed in human fibrotic liver and in mouse models of hepatic injury. COUP-TFII expression rapidly increased upon HSC activation and it was associated with the regulation of genes involved in cell motility, proliferation and angiogenesis. Inactivation of COUP-TFII impairs proliferation and invasiveness in activated HSC and COUP-TFII deletion in mice abrogate HSC activation and angiogenesis. Finally, co-culture experiments with HSC and liver sinusoidal endothelial cells (SEC) showed that COUP-TFII expression in HSC influenced SEC migration and tubulogenesis via a hypoxia-independent and nuclear factor kappaB-dependent mechanism. CONCLUSION: This study elucidates a novel transcriptional pathway in HSC that is involved in the acquisition of the proangiogenic phenotype and regulates the paracrine signals between HSC and SEC during hepatic wound healing. LAY SUMMARY: In this study, we identified an important regulator of HSC pathobiology. We showed that the orphan receptor COUP-TFII is an important player in hepatic neoangiogenesis. COUP-TFII expression in HSC controls the crosstalk between HSC and endothelial cells coordinating vascular remodelling during liver injury. TRANSCRIPT PROFILING: ArrayExpress accession E-MTAB-1795.
BACKGROUND & AIMS: Hepatic stellate cell (HSC) transdifferentiation into collagen-producing myofibroblasts is a key event in hepatic fibrogenesis, but the transcriptional network that controls the acquisition of the activated phenotype is still poorly understood. In this study, we explored whether the nuclear receptor chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) is involved in HSC activation and in the multifunctional role of these cells during the response to liver injury. METHODS:COUP-TFII expression was evaluated in normal and cirrhotic livers by immunohistochemistry and Western blot. The role of COUP-TFII in HSC was assessed by gain and loss of function transfection experiments and by generation of mice with COUP-TFII deletion in HSC. Molecular changes were determined by gene expression microarray and RT-qPCR. RESULTS: We showed that COUP-TFII is highly expressed in humanfibrotic liver and in mouse models of hepatic injury. COUP-TFII expression rapidly increased upon HSC activation and it was associated with the regulation of genes involved in cell motility, proliferation and angiogenesis. Inactivation of COUP-TFII impairs proliferation and invasiveness in activated HSC and COUP-TFII deletion in mice abrogate HSC activation and angiogenesis. Finally, co-culture experiments with HSC and liver sinusoidal endothelial cells (SEC) showed that COUP-TFII expression in HSC influenced SEC migration and tubulogenesis via a hypoxia-independent and nuclear factor kappaB-dependent mechanism. CONCLUSION: This study elucidates a novel transcriptional pathway in HSC that is involved in the acquisition of the proangiogenic phenotype and regulates the paracrine signals between HSC and SEC during hepatic wound healing. LAY SUMMARY: In this study, we identified an important regulator of HSC pathobiology. We showed that the orphan receptor COUP-TFII is an important player in hepatic neoangiogenesis. COUP-TFII expression in HSC controls the crosstalk between HSC and endothelial cells coordinating vascular remodelling during liver injury. TRANSCRIPT PROFILING: ArrayExpress accession E-MTAB-1795.
Authors: Gan Zhao; Aaron I Weiner; Katherine M Neupauer; Maria Fernanda de Mello Costa; Gargi Palashikar; Stephanie Adams-Tzivelekidis; Nilam S Mangalmurti; Andrew E Vaughan Journal: Sci Adv Date: 2020-11-25 Impact factor: 14.136
Authors: Li Li; Pierre Galichon; Xiaoyan Xiao; Ana C Figueroa-Ramirez; Diana Tamayo; Jake J-K Lee; Marian Kalocsay; David Gonzalez-Sanchez; Maria S Chancay; Kyle W McCracken; Nathan N Lee; Takaharu Ichimura; Yutaro Mori; M Todd Valerius; Julia Wilflingseder; Dario R Lemos; Elazer R Edelman; Joseph V Bonventre Journal: EMBO Rep Date: 2021-05-25 Impact factor: 9.071