Abstract
Biliary ducts collect bile from liver lobules, the smallest functional and anatomical units of liver, and carry it to the gallbladder. Disruptions in this process caused by defective embryonic development, or through ductal reaction in liver disease have a major impact on life quality and survival of patients. A deep understanding of the processes underlying bile duct lumen formation is crucial to identify intervention points to avoid or treat the appearance of defective bile ducts. Several hypotheses have been proposed to characterize the biophysical mechanisms driving initial bile duct lumen formation during embryogenesis. Here, guided by the quantification of morphological features and expression of genes in bile ducts from embryonic mouse liver, we sharpened these hypotheses and collected data to develop a high resolution individual cell-based computational model that enables to test alternative hypotheses in silico. This model permits realistic simulations of tissue and cell mechanics at sub-cellular scale. Our simulations suggest that successful bile duct lumen formation requires a simultaneous contribution of directed cell division of cholangiocytes, local osmotic effects generated by salt excretion in the lumen, and temporally-controlled differentiation of hepatoblasts to cholangiocytes, with apical constriction of cholangiocytes only moderately affecting luminal size.
Highlights
The liver is composed of multiple repetitive anatomical and physiological units, the liver lobules
At the onset of biliary lumen formation, cholangiocytes are located adjacent to the periportal mesenchyme, which separates the cholangiocytes from the endothelial cells lining the portal vein
Lumen formation was shown to be initiated at single cholangiocytes expressing Na+/H+ exchanger regulatory factor 1 (NHERF1) and Moesin at their apical pole [8]
Summary
The liver is composed of multiple repetitive anatomical and physiological units, the liver lobules. A liver lobule is approximately hexagonal in shape and is fed by oxygen rich blood from the hepatic artery, and oxygen-poor blood from the portal vein. Inside the lobule the blood flows through complex network of capillaries with a design that promotes a maximal exchange of molecules between blood and hepatocytes until it drains into the central vein. Defects in the biliary duct system resulting from defective development or from disease, e.g. by ductal reaction [1] can significantly impact life quality and survival of a patient. A deep understanding of the processes underlying lumen formation during bile duct development is crucial to intervene in such defective cases, and can be used to engineer functional liver tissue in vitro
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