title: Activation of biliary tree stem cells within peribiliary glands in primary sclerosing cholangitis.
abstract: OBJECTIVE
  Primary sclerosing cholangitis (PSC) is characterised by fibro-stenosing strictures involving extrahepatic and/or large intrahepatic bile ducts. Mechanisms leading to bile duct injury are poorly understood. We aimed to study the biliary tree stem cell compartment located in peribiliary glands of extrahepatic and large intrahepatic bile ducts and its role in the pathogenesis of biliary fibrosis in PSC.
  
  
  METHODS
  Specimens containing extrahepatic or large intrahepatic bile ducts were obtained from normal liver (n=6), liver explants from patients with PSC (n=11), and primary biliary cirrhosis (n=6). Specimens were processed for histology, immunohistochemistry and immunofluorescence.
  
  
  RESULTS
  In PSC samples, progressive hyperplasia and mucinous metaplasia of peribiliary glands were observed in large ducts with fibrosis, but not in inflamed ducts without fibrosis. Peribiliary gland hyperplasia was associated with progressive biliary fibrosis and the occurrence of dysplastic lesions. Hyperplasia of peribiliary glands was determined by the expansion of biliary tree stem cells, which sprouted towards the surface epithelium. In PSC, peribiliary glands and myofibroblasts displayed enhanced expression of Hedgehog pathway components. Peribiliary glands in ducts with onion skin-like fibrosis expressed epithelial-to-mesenchymal transition traits associated with components of Hedgehog pathway, markers of senescence and autophagy.
  
  
  CONCLUSIONS
  The biliary tree stem cell compartment is activated in PSC, its activation contributes to biliary fibrosis, and is sustained by the Hedgehog pathway. Our findings suggest a key role for peribiliary glands in the progression of bile duct lesions in PSC and could explain the associated high risk of cholangiocarcinoma.
authors.affiliation: Department of Movement, Human and Health Sciences, Division of Health Sciences, University of Rome "Foro Italico", Rome, Italy.
authors.forename: Guido
authors.initials: G
authors.lastname: Carpino
authors.affiliation: Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Cardinale
authors.affiliation: Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Italy.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Renzi
authors.affiliation: Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Cancer, Surgery and Transplantation, Oslo University Hospital Rikshospitalet, Norway; Research Institute of Internal Medicine, Division of Cancer, Surgery and Transplantation, Oslo University Hospital Rikshospitalet, Norway; K.G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Johannes R
authors.initials: JR
authors.lastname: Hov
authors.affiliation: Department of General Surgery and Organ Transplantation, Sapienza University of Rome, Rome, Italy.
authors.forename: Pasquale Bartolomeo
authors.initials: PB
authors.lastname: Berloco
authors.affiliation: Department of General Surgery and Organ Transplantation, Sapienza University of Rome, Rome, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Rossi
authors.affiliation: Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Cancer, Surgery and Transplantation, Oslo University Hospital Rikshospitalet, Norway; Research Institute of Internal Medicine, Division of Cancer, Surgery and Transplantation, Oslo University Hospital Rikshospitalet, Norway; K.G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Tom H
authors.initials: TH
authors.lastname: Karlsen
authors.affiliation: Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Alvaro
authors.affiliation: Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Italy. Electronic address: eugenio.gaudio@uniroma1.it.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Gaudio
mesh_terms: D001659:Biliary Tract / Q000166:cytology* / Q000378:metabolism; D001706:Biopsy; D015209:Cholangitis, Sclerosing / Q000378:metabolism / Q000473:pathology*; D018450:Disease Progression; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism
chemical_list: D053823:Hedgehog Proteins
keywords: Biliary fibrosis; Dysplasia; Epithelial-to-mesenchymal transition; Senescence; Sonic Hedgehog