Search Results (7)

Biliary atresia (BA) is characterized by rapidly progressive hepatic fibrosis with unclear mechanisms. This study aimed to investigate the role of matrix metalloproteinase 7 (MMP7) in this process and its potential for targeted therapy. Serum and liver tissue samples from BA patients were collected to analyze the correlation between MMP7 and liver fibrosis. Gene set enrichment analysis (GSEA) based on GEO datasets was performed to explore MMP7-associated biological processes. Clinical samples were further used to examine the relationship between MMP7 and epithelial–mesenchymal transition (EMT) in biliary epithelial cells (BECs). The effects of MMP7 on BECs and the underlying mechanisms were validated in vitro. Finally, the profibrotic effects and therapeutic potential of MMP7 were explored in chronic BA mice. Results showed that MMP7 was positively correlated with liver fibrosis in BA patients. GSEA revealed that MMP7 was most significantly associated with EMT, which was further validated by EMT scoring in intrahepatic BECs of patients. In vitro, MMP7 induced EMT in BECs by cleaving E-cadherin and promoting β-catenin nuclear translocation. Blockade of MMP7 alleviated EMT and liver fibrosis in BA mice. In conclusion, MMP7 promotes liver fibrosis in BA by driving EMT via the E-cadherin/β-catenin pathway, and targeting MMP7 demonstrates anti-fibrotic effects. Full article

The mechanisms involved in the regeneration of biliary epithelial cells (BECs) after liver injury remain unclear. In this study, we employed KRT19Cre^ERT/LSL-tdTomato (KT) mice and KT/TFF1KO mice to clarify the regeneration and cell fate of BECs via lineage tracing. Tamoxifen (TAM) was administered to the mice to label cytokeratin 19 (CK19)-positive BECs. The mice were subsequently fed a choline-deficient, ethionine-supplemented (CDE) diet for four weeks, after which the mouse livers were analyzed. Whereas the proportion of tdTomato⁺ cells in CK19-positive BECs decreased in the KT mice, it remained high in the KT/TFF1KO mice. Then, we analyzed hepatic progenitor cells (HPCs), the possible source of BECs. Although tdTomato-labeled HPCs were rarely found in the pretreatment mice, they were frequently found in the KT/TFF1KO mice after the CDE diet, suggesting the dedifferentiation of tdTomato-labeled BECs to HPCs. These results indicate not only that the loss of TFF1 accelerates the dedifferentiation of BECs into HPCs but also that HPCs are the source of BECs in TFF1KO mice. In addition, tdTomato-labeled HNF4α-positive hepatocytes were frequently found in the KT/TFF1KO mice, revealing the transdifferentiation of BECs to hepatocytes. The role of TFF1 as an inducer of biliary differentiation might be useful in the treatment of patients with hepatic or biliary dysfunction. Full article

Primary biliary cholangitis (PBC) is an autoimmune liver disease characterized by the production of diagnostic antimitochondrial antibodies (AMA) reactive to the pyruvate dehydrogenase complex. A human betaretrovirus (HBRV) resembling mouse mammary tumor virus has been characterized in patients with PBC. However, linking the viral infection with the disease is not a straight-forward process because PBC is a complex multifactorial disease influenced by genetic, hormonal, autoimmune, environmental, and other factors. Currently, PBC is assumed to have an autoimmune etiology, but the evidence is lacking to support this conjecture. In this review, we describe different approaches connecting HBRV with PBC. Initially, we used co-cultivation of HBRV with biliary epithelial cells to trigger the PBC-specific phenotype with cell surface expression of cryptic mitochondrial autoantigens linked with antimitochondrial antibody expression. Subsequently, we have derived layers of proof to support the role of betaretrovirus infection in mouse models of autoimmune biliary disease with spontaneous AMA production and in patients with PBC. Using Hill’s criteria, we provide an overview of how betaretrovirus infection may trigger autoimmunity and propagate biliary disease. Ultimately, the demonstration that disease can be cured with antiviral therapy may sway the argument toward an infectious disease etiology in an analogous fashion that was used to link H. pylori with peptic ulcer disease. Full article

A human betaretrovirus (HBRV) has been linked with the autoimmune liver disease, primary biliary cholangitis (PBC), and various cancers, including breast cancer and lymphoma. HBRV is closely related to the mouse mammary tumor virus, and represents the only exogenous betaretrovirus characterized in humans to date. Evidence of infection in patients with PBC has been demonstrated through the identification of proviral integration sites in lymphoid tissue, the major reservoir of infection, as well as biliary epithelium, which is the site of the disease process. Accordingly, we tested the hypothesis that patients with PBC harbor a transmissible betaretrovirus by co-cultivation of PBC patients’ lymph node homogenates with the HS578T breast cancer line. Because of the low level of HBRV replication, betaretrovirus producing cells were subcloned to optimize viral isolation and production. Evidence of infection was provided by electron microscopy, RT-PCR, in situ hybridization, cloning of the HBRV proviral genome and demonstration of more than 3400 integration sites. Further evidence of viral transmissibility was demonstrated by infection of biliary epithelial cells. While HBRV did not show a preference for integration proximal to specific genomic features, analyses of common insertion sites revealed evidence of integration proximal to cancer associated genes. These studies demonstrate the isolation of HBRV with features similar to mouse mammary tumor virus and confirm that patients with PBC display evidence of a transmissible viral infection. Full article

Cholestasis, which is impaired bile flow from the liver into the intestine, can be caused by cholangitis and/or bile duct obstruction. Cholangitis can arise from bacterial infections and cholelithiasis, however, immune-mediated cholangitis in primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) is characterized by a strong immune response targeting the biliary epithelial cells (BECs). Persistent biliary inflammation further represents a risk for biliary neoplasia, cholangiocarcinoma (CCA) by driving chronic cellular stress in the BECs. Currently, immune-mediated cholangitis is considered a Th1-Th17-dominant disease, however, the presence of Th2-related mast cells (MCs) in tissue samples from PBC, PSC and CCA patients has been described, showing that these MCs are active players in these diseases. Here, we reviewed and discussed experimental and clinical data supporting a pro-fibrotic role for MCs in immune-mediated cholangitis as well as their participation in supporting tumor growth acting as angiogenesis promoters. Thus, although MCs have classically been identified as downstream effectors of Th2 responses in allergies and parasitic infections, evidence suggests that these MCs are relevant players in biliary inflammation and neoplasia. The availability of strategies to prevent MCs’ activation represents a therapeutic opportunity in biliary diseases. Full article

Background: Chronic liver diseases are frequently accompanied with activation of biliary epithelial cells (BECs) that can differentiate into hepatocytes and cholangiocytes, providing an endogenous back-up system. Functional studies on BECs often rely on isolations of an BEC cell population from healthy and/or injured livers. However, a consensus on the characterization of these cells has not yet been reached. The aim of this study was to compare the publicly available transcriptome profiles of human and mouse BECs and to establish gene signatures that can identify quiescent and activated human and mouse BECs. Methods: We used publicly available transcriptome data sets of human and mouse BECs, compared their profiles and analyzed co-expressed genes and pathways. By merging both human and mouse BEC-enriched genes, we obtained a quiescent and activation gene signature and tested them on BEC-like cells and different liver diseases using gene set enrichment analysis. In addition, we identified several genes from both gene signatures to identify BECs in a scRNA sequencing data set. Results: Comparison of mouse BEC transcriptome data sets showed that the isolation method and array platform strongly influences their general profile, still most populations are highly enriched in most genes currently associated with BECs. Pathway analysis on human and mouse BECs revealed the KRAS signaling as a new potential pathway in BEC activation. We established a quiescent and activated BEC gene signature that can be used to identify BEC-like cells and detect BEC enrichment in alcoholic hepatitis, non-alcoholic steatohepatitis (NASH) and peribiliary sclerotic livers. Finally, we identified a gene set that can distinguish BECs from other liver cells in mouse and human scRNAseq data. Conclusions: Through a meta-analysis of human and mouse BEC gene profiles we identified new potential pathways in BEC activation and created unique gene signatures for quiescent and activated BECs. These signatures and pathways will help in the further characterization of this progenitor cell type in mouse and human liver development and disease. Full article

Primary biliary cirrhosis (PBC) is a chronic progressive autoimmune cholestatic liver disease characterized by highly specific antimitochondrial antibodies (AMAs) and the specific immune-mediated injury of small intrahepatic bile ducts. Unique apoptotic feature of biliary epithelial cells (BECs) may contribute to apotope presentation to the immune system, causing unique tissue damage in PBC. Perpetuation of inflammation may result in senescence of BECs, contributing to irreversible loss of bile duct. In addition to the classic liver manifestations, focal inflammation and tissue damage are also seen in salivary glands and urinary tract in a significant proportion of PBC patients. These findings provide potent support to the idea that molecular mimicry may be involved in the breakdown of autoimmune tolerance and mucosal immunity may lead to a systematic epithelitis in PBC patients. Thus, PBC is considered a generalized epithelitis in clinical practice. Full article