Preclinical insights into cholangiopathies: disease modeling and emerging therapeutic targets

ABSTRACT

Introduction: 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

Article Highlights

• Cholangiopathies are bile duct disorders characterized by bile duct damage and inflammation

• Treatments for cholangiopathies are limited to liver transplantation

• Various animal models have been established and are available for researchers

• Previous studies have identified candidate signaling pathways that could be targets for novel therapies

• Injection of stem cells or extracellular vesicles could be utilized as a novel therapeutic approach for cholangiopathies

This box summarizes the key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

Portions of these discussed studies were supported by Baylor Scott & White Institute, the Hickam Endowed Chair, Gastroenterology, Medicine, Indiana University, a VA Research Senior Career Scientist Award and a VA Merit award to G Alpini [5I01BX000574], H Francis [1I01BX003031], F Meng [1I01BX001724], and S Liangpunsakul [I01CX000361] as well as the NIH grants DK054811, DK076898, DK107310, DK110035, DK062975, DK108959, DK107682, AA025997, AA025157, AA025208, AA026917, and AA026903 to G Alpini, F Meng, H Francis, S Glaser, and S Liangpunsakul. G. Alpini and K Sato were awarded funding from PSC Partners Seeking a Cure, Colorado, USA.