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Human biliary epithelial cells from discarded donor livers rescue bile duct structure and function in a mouse model of biliary disease.

ABSTRACT: Biliary diseases can cause inflammation, fibrosis, bile duct destruction, and eventually liver failure. There are no curative treatments for biliary disease except for liver transplantation. New therapies are urgently required. We have therefore purified human biliary epithelial cells (hBECs) from human livers that were not used for liver transplantation. hBECs were tested as a cell therapy in a mouse model of biliary disease in which the conditional deletion of Mdm2 in cholangiocytes causes senescence, biliary strictures, and fibrosis. hBECs are expandable and phenotypically stable and help restore biliary structure and function, highlighting their regenerative capacity and a potential alternative to liver transplantation for biliary disease.

SUBMITTER: Hallett JM

PROVIDER: S-EPMC8900617 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Human biliary epithelial cells from discarded donor livers rescue bile duct structure and function in a mouse model of biliary disease.

Hallett John M JM Ferreira-Gonzalez Sofia S Man Tak Yung TY Kilpatrick Alastair M AM Esser Hannah H Thirlwell Kayleigh K Macmillan Mark T MT Rodrigo-Torres Daniel D Dwyer Benjamin J BJ Gadd Victoria L VL Ashmore-Harris Candice C Lu Wei-Yu WY Thomson John P JP Jansen Maurits A MA O'Duibhir Eoghan E Starkey Lewis Philip J PJ Campana Lara L Aird Rhona E RE Bate Thomas S R TSR Fraser Alasdair R AR Campbell John D M JDM Oniscu Gabriel C GC Hay David C DC Callanan Anthony A Forbes Stuart J SJ

Cell stem cell 20220301 3

Biliary diseases can cause inflammation, fibrosis, bile duct destruction, and eventually liver failure. There are no curative treatments for biliary disease except for liver transplantation. New therapies are urgently required. We have therefore purified human biliary epithelial cells (hBECs) from human livers that were not used for liver transplantation. hBECs were tested as a cell therapy in a mouse model of biliary disease in which the conditional deletion of Mdm2 in cholangiocytes causes sen ...[more]

PMID: 35245467

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Project description:Background & aimsThe extrahepatic bile duct is the primary tissue initially affected by biliary atresia. Biliary atresia is a cholangiopathy which exclusively affects neonates. Current animal models suggest that the developing bile duct is uniquely susceptible to damage. In this study, we aimed to define the anatomical and functional differences between the neonatal and adult mouse extrahepatic bile ducts.MethodsWe studied mouse passaged cholangiocytes, mouse BALB/c neonatal and adult primary cholangiocytes, as well as isolated extrahepatic bile ducts, and a collagen reporter mouse. The methods used included transmission electron microscopy, lectin staining, immunostaining, rhodamine uptake assays, bile acid toxicity assays, and in vitro modeling of the matrix.ResultsThe cholangiocyte monolayer of the neonatal extrahepatic bile duct was immature, lacking the uniform apical glycocalyx and mature cell-cell junctions typical of adult cholangiocytes. Functional studies showed that the glycocalyx protected against bile acid injury and that neonatal cholangiocyte monolayers were more permeable than adult monolayers. In adult ducts, the submucosal space was filled with collagen I, elastin, hyaluronic acid, and proteoglycans. In contrast, the neonatal submucosa had little collagen I and elastin, although both increased rapidly after birth. In vitro modeling of the matrix suggested that the composition of the neonatal submucosa relative to the adult submucosa led to increased diffusion of bile. A Col-GFP reporter mouse showed that cells in the neonatal but not adult submucosa were actively producing collagen.ConclusionWe identified 4 key differences between the neonatal and adult extrahepatic bile duct. We showed that these features may have functional implications, suggesting the neonatal extrahepatic bile ducts are particularly susceptible to injury and fibrosis.Lay summaryBiliary atresia is a disease that affects newborns and is characterized by extrahepatic bile duct injury and obstruction, resulting in liver injury. We identify 4 key differences between the epithelial and submucosal layers of the neonatal and adult extrahepatic bile duct and show that these may render the neonatal duct particularly susceptible to injury.

Project description:Background & aimsBiliary atresia (BA) results from a neonatal inflammatory and fibrosing obstruction of bile ducts of unknown etiology. Although the innate immune system has been linked to the virally induced mechanism of disease, the role of inflammasome-mediated epithelial injury remains largely undefined. Here, we hypothesized that disruption of the inflammasome suppresses the neonatal proinflammatory response and prevents experimental BA.MethodsWe determined the expression of key inflammasome-related genes in livers from infants at diagnosis of BA and in extrahepatic bile ducts (EHBDs) of neonatal mice after infection with rotavirus (RRV) immediately after birth. Then, we determined the impact of the wholesale inactivation of the genes encoding IL-1R1 (Il1r1-/-), NLRP3 (Nlrp3-/-) or caspase-1 (Casp1-/-) on epithelial injury and bile duct obstruction.ResultsIL1R1, NLRP3 and CASP1 mRNA increased significantly in human livers at the time of diagnosis, and in EHBDs of RRV-infected mice. In Il1r1-/- mice, the epithelial injury of EHBDs induced by RRV was suppressed, with dendritic cells unable to activate natural killer cells. A similar protection was observed in Nlrp3-/- mice, with decreased injury and inflammation of livers and EHBDs. Long-term survival was also improved. In contrast, the inactivation of the Casp1 gene had no impact on tissue injury, and all mice died. Tissue analyses in Il1r1-/- and Nlrp3-/- mice showed decreased populations of dendritic cells and natural killer cells and suppressed expression of type-1 cytokines and chemokines.ConclusionsGenes of the inflammasome are overexpressed at diagnosis of BA in humans and in the BA mouse model. In the experimental model, the targeted loss of IL-1R1 or NLRP3, but not of caspase-1, protected neonatal mice against RRV-induced bile duct obstruction.Lay summaryBiliary atresia is a severe inflammatory and obstructive disease of bile ducts occurring in infancy. Although the cause is unknown, activation of the innate and adaptive immune systems injures the bile duct epithelium. In this study we found that patients' livers had increased expression of inflammasome genes. Using mice engineered to inactivate individual inflammasome genes, the epithelial injury and bile duct obstruction were prevented by the loss of Il1r1 or Nlrp3, with a decreased activation of natural killer cells and expression of cytokines and chemokines. In contrast, the loss of Casp1 did not change the disease phenotype. Combined, the findings point to a differential role of inflammasome gene products in the pathogenic mechanisms of biliary atresia.

Dataset Information

Human biliary epithelial cells from discarded donor livers rescue bile duct structure and function in a mouse model of biliary disease.

Publications

Human biliary epithelial cells from discarded donor livers rescue bile duct structure and function in a mouse model of biliary disease.

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