Apical bulkheads accumulate as adaptive response to impaired bile flow in liver disease

Abstract

Hepatocytes form bile canaliculi that dynamically respond to the signalling activity of bile acids and bile flow. Little is known about their responses to intraluminal pressure. During embryonic development, hepatocytes assemble apical bulkheads that increase the canalicular resistance to intraluminal pressure. Here, we investigate whether they also protect bile canaliculi against elevated pressure upon impaired bile flow in adult liver. Apical bulkheads accumulate upon bile flow obstruction in mouse models and patients with primary sclerosing cholangitis (PSC). Their loss under these conditions leads to abnormally dilated canaliculi, resembling liver cell rosettes described in other hepatic diseases. 3D reconstruction reveals that these structures are sections of cysts and tubes formed by hepatocytes. Mathematical modelling establishes that they positively correlate with canalicular pressure and occur in early PSC stages. Using primary hepatocytes and 3D organoids, we demonstrate that excessive canalicular pressure causes the loss of apical bulkheads and formation of rosettes. Our results suggest that apical bulkheads are a protective mechanism of hepatocytes against impaired bile flow, highlighting the role of canalicular pressure in liver diseases.

Hepatoblast iterative apicobasal polarization is regulated by extracellular matrix remodeling

“…The analysis of bile canaliculi morphology and bile canaliculi network properties was performed using a previously published script (Mayer, 2023 71 ) running on Fiji Fiji (Schindelin, 2012 72 ). Briefly, Images were imported using Bioformats (Linkert, 2010 73 ) and the aspecific staining (appearing as extracellular puncta of saturated pixels) was segmented using a simple threshold combined with an inflation and then removed from the images.…”

Shaping epithelial lumina under pressure

“…While these bulkheads are known to be mechanical elements that increase the pressure that a bile canaliculus can hold [ 21 ], the biological and physical mechanisms of their formation remain a mystery. Understanding more about how bile canaliculi transition to a tubular shape and how apical bulkheads form, therefore, promises key insights into the formation of bile canaliculi in development and into the response of bile canaliculi to bile pressure changes in normal physiology and in disease [ 38 ].…”