Background & Aims
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.
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.
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.
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.
Abbreviations:PSC (Primary Sclerosing Cholangitis), BD (Bile Duct), BTSCs (Biliary Tree Stem Cells), PBG (Peribiliary Gland), EHBD (Extrahepatic Bile Duct), IHBD (Intrahepatic Bile Duct), PBC (Primary Biliary Cirrhosis), SR (Sirius Red), PAS (Periodic Acid-Schiff), DAPI (4′,6-diamidino-2-phenylindole), K (keratin), SOX (Sry-related HMG box), EpCAM (epithelial cell adhesion molecule), PCNA (Proliferating Cell Nuclear Antigen), CFTR (Cystic Fibrosis Transmembrane conductance Regulator), LGR5 (Leucine-rich repeat containing G protein-coupled receptor 5), OCT4A (octamer-binding transcription factor 4 A), α-SMA (alpha-Smooth Muscle Actin), EMT (Epithelial-to-Mesenchymal Transition), Hh (Hedgehog), Shh (Sonic Hedgehog), Ptc (Patched), Gli-1 (glioma-associated oncogene homolog 1), γH2A.x (γH2A histone family, member x), PDX1 (Pancreatic and Duodenal homeobox 1)
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Published online: June 25, 2015
Accepted: June 19, 2015
Received in revised form: June 8, 2015
Received: January 28, 2015See Editorial, pages 1062–1063
© 2015 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved.