Characterization of animal models for primary sclerosing cholangitis (PSC)

Abstract

Summary Primary sclerosing cholangitis (PSC) is a chronic cholangiopathy characterized by biliary fibrosis, development of cholestasis and end stage liver disease, high risk of malignancy, and frequent need for liver transplantation. The poor understanding of its pathogenesis is also reflected in the lack of effective medical treatment. Well-characterized animal models are utterly needed to develop novel pathogenetic concepts and study new treatment strategies. Currently there is no consensus on how to evaluate and characterize potential PSC models, which makes direct comparison of experimental results and effective exchange of study material between research groups difficult. The International Primary Sclerosing Cholangitis Study Group (IPSCSG) has therefore summarized these key issues in a position paper proposing standard requirements for the study of animal models of PSC.

Animal models of biliary injury and altered bile acid metabolism

“…Based on these considerations, to study the early pathological alterations occurring in chronic cholestatic diseases, such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), is essential to rely on an animal model with slow development of biliary injury [15–17]. Chronic DDC-feeding in mice is a well-established model of cholestatic liver injury originally proposed to study Mallory-Denk body formation, which is specifically associated with metabolic liver injury, as observed in alcoholic and nonalcoholic steatohepatitis, based on DDC ability to induce chronic oxidative cell stress [18–20].…”

“…Conversely, cholestatic effects exerted by DDC depends upon the ability to stimulate biliary porphyrin secretion that after a 4-week treatment leads to the generation of intraductal pigment plugs. Due to these properties, chronic DDC feeding has been proposed also as a model for xenobiotic-induced cholangiopathy, featuring ductular proliferation, intense pericholangitis associated with onion skin-type periductal fibrosis, which slowly progressed over time, leading to portal-portal bridging, and extending to the large bile ducts, thus recapitulating specific pathological hallmarks of human PSC [15,19]. This type of progressive biliary injury is initially characterized by specific transporter abnormalities, involving canalicular expression of Sodium/Taurocholate Cotransporter (Ntcp), organic anion transporting polypeptide (Oatp4), and Multidrug Resistance-Associated Protein 2 (Mrp2), responsible for reduced biliary excretion of glutathione (GSH) and phospholipids, occurring before phenotypic changes of cholangiocytes (‘reactive cholangiocyte’) [19].…”

“…The Mdr2 knockout (Mdr2-KO) mouse is one of the best-characterized models of fibrosing cholangiopathy (although caused primarily by hepatocyte dysfunction), generated by Smit and colleague [43,44] which in the last few years has gained considerable interest as surrogate model of PSC [15,16]. The multidrug resistance gene (Mdr2 in rodents/ MDR3 in humans) belongs to the group of ABC transporters (ATP binding cassette subfamily B member 4 or Abcb4) [45] and encodes a canalicular flippase (translocase) expressed by hepatocytes, mediating the transport of biliary phospholipids, mainly phosphatidylcholine, into the outer leaflet of the canalicular cell membrane, which facilitates their subsequent excretion into the bile [44,46].…”

Fibrin deposition following bile duct injury limits fibrosis through an αMβ2-dependent mechanism

“…8 The xenobiotic a-naphthylisothiocyanate (ANIT) is a chemical that selectively injures BDECs. [11][12][13][14] Long-term exposure of rodents to ANIT recapitulates many clinical and histopathological features of sclerosing cholangitis, 4,9,15,16 including coagulation cascade activation, robust fibrin(ogen) deposition, bile duct hyperplasia, and peribiliary fibrosis. 2,5,6,17 Complete fibrin(ogen) deficiency in ANIT-exposed mice provoked an atypical increase in focal liver necrosis, a unique lesion that was recapitulated in mice expressing mutant fibrin(ogen) unable to engage platelet integrin a IIb b 3.…”

Activation of biliary tree stem cells within peribiliary glands in primary sclerosing cholangitis

“…A high risk of biliary malignancies is associated with this condition and most patients develop liver cirrhosis [1,2]. The aetiology and pathogenesis of PSC are still largely unknown, and the mechanisms responsible for these characteristic bile duct (BD) strictures are poorly understood [3,4].…”