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.
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.
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)Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Journal of HepatologyAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Primary sclerosing cholangitis.Lancet. 2013; 382: 1587-1599
- Update on primary sclerosing cholangitis.J Hepatol. 2013; 59: 571-582
- Cholangiocyte senescence by way of N-ras activation is a characteristic of primary sclerosing cholangitis.Hepatology. 2014; 59: 2263-2275
- Characterization of animal models for primary sclerosing cholangitis (PSC).J Hepatol. 2014; 60: 1290-1303
- The biliary tree: a reservoir of multipotent stem cells.Nat Rev Gastroenterol Hepatol. 2012; 9: 231-240
- Liver regeneration by stem/progenitor cells.Hepatology. 2014; 59: 1617-1626
- Biliary tree stem/progenitor cells in glands of extrahepatic and intraheptic bile ducts: an anatomical in situ study yielding evidence of maturational lineages.J Anat. 2012; 220: 186-199
- Biliary tree stem cells, precursors to pancreatic committed progenitors: evidence for possible life-long pancreatic organogenesis.Stem Cells. 2013; 31: 1966-1979
- Multipotent stem/progenitor cells in human biliary tree give rise to hepatocytes, cholangiocytes, and pancreatic islets.Hepatology. 2011; 54: 2159-2172
- Microstructure and development of the normal and pathologic biliary tract in humans, including blood supply.Microsc Res Tech. 1997; 38: 552-570
- Staging of chronic nonsuppurative destructive cholangitis (syndrome of primary biliary cirrhosis).Virchows Arch A Pathol Anat Histol. 1978; 379: 103-112
- Histological subclassification of cirrhosis using the Laennec fibrosis scoring system correlates with clinical stage and grade of portal hypertension.J Hepatol. 2011; 55: 1004-1009
- Evidence for multipotent endodermal stem/progenitor cell populations in human gallbladder.J Hepatol. 2014; 60: 1194-1202
- Hepatic progenitor cells activation, fibrosis, and adipokines production in pediatric nonalcoholic fatty liver disease.Hepatology. 2012; 56: 2142-2153
- Hedgehog signaling in the liver.J Hepatol. 2011; 54: 366-373
- Loss of liver E-cadherin induces sclerosing cholangitis and promotes carcinogenesis.Proc Natl Acad Sci U S A. 2014; 111: 1090-1095
- Telomere shortening in the damaged small bile ducts in primary biliary cirrhosis reflects ongoing cellular senescence.Hepatology. 2008; 48: 186-195
- Sal-like protein 4 (SALL4), a stem cell biomarker in liver cancers.Hepatology. 2013; 57: 1469-1483
- Long-term culture of genome-stable bipotent stem cells from adult human liver.Cell. 2015; 160: 299-312
- Identification of intramural epithelial networks linked to peribiliary glands that express progenitor cell markers and proliferate after injury in mice.Hepatology. 2013; 58: 1486-1496
- Possible involvement of CCL1-CCR8 interaction in lymphocytic recruitment in IgG4-related sclerosing cholangitis.J Hepatol. 2013; 59: 1059-1064
- Regeneration of human extrahepatic biliary epithelium: the peribiliary glands as progenitor cell compartment.Liver Int. 2012; 32: 554-559
- Injury to peribiliary glands and vascular plexus before liver transplantation predicts formation of non-anastomotic biliary strictures.J Hepatol. 2014; 60: 1172-1179
- Fas/Fas ligand apoptosis pathway underlies immunomodulatory properties of Human Biliary Tree Stem/Progenitor Cells.J Hepatol. 2014; 61: 1097-1105
- Induction of colitis in cftr-/- mice results in bile duct injury.Am J Physiol Gastrointest Liver Physiol. 2004; 287: G491-G496
- A biliary HCO3- umbrella constitutes a protective mechanism against bile acid-induced injury in human cholangiocytes.Hepatology. 2012; 55: 173-183
- Transit-amplifying cells orchestrate stem cell activity and tissue regeneration.Cell. 2014; 157: 935-949
- Lung epithelial stem cells and their niches: Fgf10 takes center stage.Fibrogenesis Tissue Repair. 2014; 7: 8
- Autophagy and senescence in fibrosing cholangiopathies.J Hepatol. 2015; 62: 934-945
- The biliary HCO(3)(-) umbrella: experimental evidence revisited.Curr Opin Gastroenterol. 2012; 28: 253-257
- Inhibition of hedgehog signaling attenuates carcinogenesis in vitro and increases necrosis of cholangiocellular carcinoma.Hepatology. 2013; 57: 1035-1045
- The intrahepatic signalling niche of hedgehog is defined by primary cilia positive cells during chronic liver injury.J Hepatol. 2014; 60: 143-151
- Non-canonical Hedgehog signaling contributes to chemotaxis in cholangiocarcinoma.J Hepatol. 2014; 60: 599-605
- GammaH2AX and cancer.Nat Rev Cancer. 2008; 8: 957-967
Article info
Publication history
Published online: June 25, 2015
Accepted:
June 19,
2015
Received in revised form:
June 8,
2015
Received:
January 28,
2015
See Editorial, pages 1062–1063Identification
Copyright
© 2015 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved.
