title: The orphan nuclear receptor COUP-TFII coordinates hypoxia-independent proangiogenic responses in hepatic stellate cells.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  ArrayExpress accession E-MTAB-1795.
authors.affiliation: 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.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Ceni
authors.affiliation: 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.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Mello
authors.affiliation: 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.
authors.forename: Simone
authors.initials: S
authors.lastname: Polvani
authors.affiliation: INSERM, U1016, Institut Cochin, Paris, France.
authors.forename: Mireille
authors.initials: M
authors.lastname: Vasseur-Cognet
authors.affiliation: 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.
authors.forename: Mirko
authors.initials: M
authors.lastname: Tarocchi
authors.affiliation: Gastroenterology Research Unit, Department of Experimental and Clinical Biochemical Sciences, University of Florence, Florence, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Tempesti
authors.affiliation: Department of Biology, University of Florence, Florence, Italy.
authors.forename: Duccio
authors.initials: D
authors.lastname: Cavalieri
authors.affiliation: Translational Genomics Unit, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Beltrame
authors.affiliation: Gastroenterology Research Unit, Department of Experimental and Clinical Biochemical Sciences, University of Florence, Florence, Italy.
authors.forename: Giada
authors.initials: G
authors.lastname: Marroncini
authors.affiliation: UCL Institute for Liver and Digestive Health, University College London, Royal Free Hospital Campus U3, Rowland Hill Street, London NW3 2PF, UK.
authors.forename: Massimo
authors.initials: M
authors.lastname: Pinzani
authors.affiliation: 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.
authors.forename: Stefano
authors.initials: S
authors.lastname: Milani
authors.affiliation: 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.
authors.forename: Andrea
authors.initials: A
authors.lastname: Galli
mesh_terms: D000818:Animals; D051837:COUP Transcription Factor II / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002450:Cell Communication; D002465:Cell Movement; D049109:Cell Proliferation; D054338:Cell Transdifferentiation; D018920:Coculture Techniques; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D055166:Hepatic Stellate Cells / Q000166:cytology / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D006801:Humans; D000860:Hypoxia / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000235:genetics; D015854:Up-Regulation; D014945:Wound Healing / Q000235:genetics / Q000502:physiology
chemical_list: D051837:COUP Transcription Factor II; C497587:Nr2f2 protein, mouse; C095569:NR2F2 protein, human
keywords: Angiogenesis; COUP transcription factor II; Cell transdifferentiation; Fibrosis; HIF; Hepatic stellate cells; Hypoxia; NF-κB; Notch; Wound healing