Coordinated development of the mouse extrahepatic bile duct: Implications for neonatal susceptibility to biliary injury

JOURNAL OF HEPATOLOGY

卷:72

Article

Khandekar, Gauri¹  Llewellyn, Jessica¹  Kriegermeier, Alyssa²  Waisbourd-Zinman, Orith^2,3  Johnson, Nicolette⁴  Du, Yu¹  Giwa, Roquibat¹  Liu, Xiao⁵  Kisseleva, Tatiana⁵  Russo, Pierre A.⁶  Theise, Neil D.⁷  Wells, Rebecca G.^1,8,9,10 

[1] Univ Penn, Dept Med, Perelman Sch Med, Div Gastroenterol, Philadelphia, PA 19104 USA

[2] Childrens Hosp Philadelphia, Dept Pediat, Div Gastroenterol Hepatol & Nutr, Philadelphia, PA 19104 USA

[3] Tel Aviv Univ, Schneider Childrens Hosp, Sackler Fac Med, Tel Aviv, Israel

[4] Univ Penn, Cell & Mol Biol Grad Grp, Perelman Sch Med, Philadelphia, PA 19104 USA

[5] Univ Calif San Diego, Dept Surg, La Jolla, CA 92093 USA

[6] Childrens Hosp Philadelphia, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA

[7] NYU, Sch Med, Dept Pathol, New York, NY USA

[8] Univ Penn, Sch Engn & Appl Sci, Dept Bioengn, Philadelphia, PA 19104 USA

[9] Univ Penn, Dept Pathol & Lab Med, Perelman Sch Med, Philadelphia, PA 19104 USA

[10] Univ Penn, Ctr Engn MechanoBiol, Philadelphia, PA 19104 USA

关键词: Glycocalyx;    Biliary atresia;    Submucosa;    Fibrogenesis;    Lectin;   

DOI  :  10.1016/j.jhep.2019.08.036

来源: Elsevier

【 摘 要 】

Background & Aims: The 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. Methods: We 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. Results: The 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. Conclusion: We 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 summary: Biliary 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. (C) 2019 European Association for the Study of the Liver. Published by Elsevier B.V.

【 授权许可】

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