Regenerative Medicine of the Bile Duct: Beyond the Myth

Cholangiopathies are rare diseases of the bile duct with high mortality rates. The current treatment for cholangiopathies is liver transplantation, but there are significant obstacles including a shortage of donors and a high risk of complications. Currently, there is only one available medicine on the market targeting cholangiopathies, and the results have been inadequate in clinical therapy. To overcome these obstacles, many researchers have used human induced pluripotent stem cells (hPSC) as a source for cholangiocyte-like cell generation and have incorporated advances in bioprinting to create artificial bile ducts for implantation and transplantation. This has allowed the field to move dramatically forward in studies of biliary regenerative medicine. In this review, the authors provide an overview of cholangiocytes, the organogenesis of the bile duct, cholangiopathies, and the current treatment and advances that have been made that are opening new doors to the study of cholangiopathies.

Bile Acid Transporters Are Expressed and Heterogeneously Distributed in Rat Bile Ducts

BACKGROUND/AIMS: Cholangiocytes are capable of reabsorbing bile salts from bile, but the pathophysiological significance of this process is unclear. To this end, we detected the expression and distribution of bile acid transport proteins in cholangiocytes from normal rat liver and analyzed the possible pathophysiological significance. METHODS: Bile duct tissues of Sprague-Dawley rats were isolated by enzymatic digestion and mechanical isolation, and then divided into large and small bile duct tissues. Immunohistochemistry, real-time polymerase chain reaction and Western blotting were used to determine the expression of the apical sodium-dependent bile acid transporter (ASBT), ileal bile acid binding protein (IBABP), and basolateral organic solute transporter α (Ostα) in the biliary tract system of rats. Differences in the expression and distribution of these proteins were analyzed. RESULTS: In cholangiocytes, ASBT and IBABP were mainly expressed in cholangiocytes of the large bile ducts, in which the expression of both was significantly higher than that in the small ducts (p0.05). CONCLUSIONS: Bile acid transporters are expressed and heterogeneously distributed in rat bile ducts, indicating that bile acid reabsorption by cholangiocytes might mainly occur in the large bile ducts. These findings may help explore the physiology of bile ducts and the pathogenesis of various cholangiopathies.

The rat model of graft cholangiopathies established by cold preservation or chronic rejection / 中华肝胆外科杂志

Objective To develop rat models of graft cholangiopathies and evaluated their values.Methods Four groups were constructed.The long-term cold preservation group(n=24) contained homogeneic inbred rat liver orthotopic transplantations (ROLT) performed in a rat combination of ♂ Wistar→ ♂ Wistar with the donor liver preserved in 4℃ UW for 12 h,the vessels reconstructed by the two-cuff method,and the hepatic artery and extrahepatic bile duct rebuilt by a stent.The chronic rejection group (n=24)(CsA 1 mg · kg-1 · d-1,cold preserved for 1 h) was allogeneic inbred ♂ DA→♂ Lewis rats induced for ROLT,and the revascularization methods were the same as the longterm cold preservation group.The control group (n=24) (cold preserved for 1 h) was homogeneic inbred ♂ Wistar→♂ Wistar rats with ROLT techniques the same as above.The sham group (n=24)was ♂ Wistar rats that had an exploratory laparotomy.The animals were followed for 16 weeks,complications were compared,and liver tissues were harvested.Histopathological and morphometric techniques were used to construct a time course of histological changes after liver transplantation.Results In both the long-term cold preservation group and chronic rejection group,the rats recovered slowly,the incidence of complications and mortality were higher than those of other groups,and the intrahepatic bile duct proliferation and immune cell infiltration were noticeable after the operation.In 16 weeks,the hepatic lobules were separated by the proliferating bile ducts,the normal structure of hepatic lobules disappeared,many biliary epithelial cells necrosed with disappearing cytoplasms,and there was immune cell infiltration and obliterative arteriopathy.Conclusions The rat models of graft cholangiopathies induced by long-term cold preservation or chronic rejection donor livers are stable and easily standardized.This model is ideal for studying the pathogenesis and prevention of graft cholangiopathies.

The Crucial Role of Cholangiocytes in Cholangiopathies

Cholangiopathies are diseases involving the intrahepatic biliary tree. They appear to involve, chronic inflammation of the bile ducts, which can lead to the development of bile duct cholestasis, proliferation/ductopenia, biliary fibrosis, and malignant transformation. Sustained stimulatory insults to biliary epithelial cells can induce a ductular reaction, which has a key role in the initiation and progression of cholangiopathies. The epithelial-mesenchymal interaction between reactive cholangiocytes and mesenchymal cells with the inflammatory infiltrates plays a major role in this pathogenesis. Cytokines, chemokines, growth factors and morphogens mediate these interactions in an autocrine or paracrine manner. The main hepatic myofibroblasts (MFs) in cholangiopathies originate from portal fibroblasts. Hepatic stellate cells and fibrocytes also transform into MFs. Whether cholangiocytes or hepatocytes are a source of MFs via the epithelial-mesenchymal transition (EMT) remains a matter of controversy. Although there have been numerous indirect findings supporting the theory of a cholangiocyte EMT in human tissues, recent studies using lineage tracing methods have demonstrated strong evidence against the EMT. Understanding the pathogenic mechanisms involved in cholangiopathies can allow for better-targeted anti-fibrotic therapies in animal models. Before anti-fibrotic therapies can translate into clinical trials, improved monitoring of the fibrotic progression of cholangiopathies and an accurate assessment regarding the effectiveness of the proposed treatments must be achieved.