Preclinical insights into cholangiopathies: disease modeling and emerging therapeutic targets

Abstract

The common predominant clinical features of cholangiopathies such as primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC), and biliary atresia (BA) are biliary damage/senescence and liver fibrosis. Curative therapies are lacking, and liver transplantation is the only option. An understanding of the mechanisms and pathogenesis is needed to develop novel therapies. Previous studies have developed various disease-based research models and have identified candidate therapeutic targets. Areas covered: This review summarizes recent studies performed in preclinical models of cholangiopathies and the current understanding of the pathophysiology representing potential targets for novel therapies. A literature search was conducted in PubMed using the combination of the searched term 'cholangiopathies' with one or two keywords including 'model', 'cholangiocyte', 'animal', or 'fibrosis'. Papers published within five years were obtained. Expert opinion: Access to appropriate research models is a key challenge in cholangiopathy research; establishing more appropriate models for PBC is an important goal. Several preclinical studies have demonstrated promising results and have led to novel therapeutic approaches, especially for PSC. Further studies on the pathophysiology of PBC and BA are necessary to identify candidate targets. Innovative therapeutic approaches such as stem cell transplantation have been introduced, and those therapies could be applied to PSC, PBC, and BA.

Keywords: Cholangiopathy; bile duct; cholangiocyte; inflammation; liver fibrosis.

Figure 1.. The strategy for novel therapies in cholangiopathies.

Cholangiocytes express various membrane receptors such as G protein-coupled bile acid receptor (TGR5), secretin receptor (SR), and sphingosine-1-phosphate receptor 2 (S1PR2). During cholangiopathies, secreted levels of triggering agents including bile acids and secretin (Sct) are increased and they bind to those receptors. This activates specific signaling pathways inducing cholangiocyte proliferation, ductular reaction, and fibrogenesis. Current studies target those signaling pathways to interrupt activation of signaling by administration of drugs binding those receptors. JTE-013 and Sec 5–27 are antagonists for S1PR2 and SR, respectively that bind to these receptors inhibiting downstream signaling. However, functional roles of some receptors such as TGR5 are still undefined during cholangiopathies; therefore, further studies are required to elucidate the potential utilization of agonists/antagonists as novel therapies targeting those receptors. Extracellular vesicles (EVs) can carry mediators such as RNAs and proteins that can be delivered into cholangiocytes. Internalized EVs transfer cargo mediators into recipient cholangiocytes and regulate physiological events leading to improved liver conditions, representing promising potentials of EVs as a tool of novel therapies.