Coordinated development of the mouse extrahepatic bile duct: Implications for neonatal susceptibility to biliary injury.
Animals
Animals, Newborn
Bile Ducts, Extrahepatic
/ cytology
Biliary Atresia
Cell Survival
Cells, Cultured
Collagen Type I
/ metabolism
Collagen Type I, alpha 1 Chain
Disease Models, Animal
Elastin
/ metabolism
Epithelial Cells
/ metabolism
Female
Green Fluorescent Proteins
/ metabolism
Humans
Hyaluronic Acid
/ metabolism
Immunohistochemistry
Intercellular Junctions
/ metabolism
Male
Mice
Mice, Inbred BALB C
Microscopy, Electron, Transmission
Mucous Membrane
/ metabolism
Proteoglycans
/ metabolism
Biliary atresia
Fibrogenesis
Glycocalyx
Lectin
Submucosa
Journal
Journal of hepatology
ISSN: 1600-0641
Titre abrégé: J Hepatol
Pays: Netherlands
ID NLM: 8503886
Informations de publication
Date de publication:
01 2020
01 2020
Historique:
received:
13
03
2019
revised:
09
08
2019
accepted:
30
08
2019
pubmed:
29
9
2019
medline:
2
6
2021
entrez:
29
9
2019
Statut:
ppublish
Résumé
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. 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. 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 31562906
pii: S0168-8278(19)30550-1
doi: 10.1016/j.jhep.2019.08.036
pmc: PMC7079197
mid: NIHMS1544628
pii:
doi:
Substances chimiques
Collagen Type I
0
Collagen Type I, alpha 1 Chain
0
Proteoglycans
0
Green Fluorescent Proteins
147336-22-9
Hyaluronic Acid
9004-61-9
Elastin
9007-58-3
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
135-145Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK092111
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK050306
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK111866
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK119290
Pays : United States
Organisme : NIDDK NIH HHS
ID : T32 DK101371
Pays : United States
Organisme : NCATS NIH HHS
ID : TL1 TR001880
Pays : United States
Organisme : NIAAA NIH HHS
ID : U01 AA022614
Pays : United States
Organisme : NIH HHS
ID : S10 OD021633
Pays : United States
Informations de copyright
Copyright © 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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