Modelling of the bile canalicular network during liver regeneration and fibrosis after carbon tetrachloride intoxication

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HammadSeddik_2012_06_15.pdf (3.94 MB)

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2012

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DOI:
http://dx.doi.org/10.22029/jlupub-11806

Abstract

The liver contains two networks: 1) the microvessels network also named liver sinusoids and 2) the bile canalicular network. The disruption of the bile canalicular network leads to improper bile flow, cholestasis and toxicity of the liver cells. Relatively little is known about the organization of the bile canalicular network in healthy livers and it is not completely described after liver intoxication, regeneration and fibrosis processes. Therefore, the goals of the present study are to: i) establish a mouse model of acute hepatoxicity by carbon tetrachloride injection; ii) determine the maintenance and establishment of hepatocellular polarity during the intoxication and regeneration processes; and iii) reconstruct the bile canalicular network of the normal, intoxicated and regenerated as well as fibrotic mouse livers. In the present study, I used carbon tetrachloride as a well accepted model for liver cell destruction, intoxication and fibrosis induction. The obtained results describing the liver intoxication and regeneration process were in agreement with published data. Therefore, the liver tissue after acute and chronic administration of carbon tetrachloride could be used to analyze the bile canalicular network under conditions of acute liver damage and fibrosis. The steps of the normal hepatic micro-architecture restoration after liver intoxication could be summarized as follows: i) the proliferating hepatocytes maintained their polarity; ii) the daughter hepatocytes are aligned in the direction of the closest microvessels; and iii) the existing bile canaliculus is invaginated between the daughter hepatocytes to establish a novel branch. Currently, there is no technique available to quantify the bile canalicular network. Therefore, to understand the architecture of the bile canalicular network and to bridge this gap, a method for analyzing three dimensional organization of the bile canaliculi and hepatic sinusoids was established using confocal microscopy and image analysis. Based on the reconstructed data sets of the healthy mice, I could detect some basic structures of the bile canalicular network including: 1) the bile canaliculi form three half-hexagonal belts around the hepatocytes. Two halves are connected to form a belt and third half sometimes is connected to the belt or formed an unconnected branch; 2) two classes of bile canaliculi could be differentiated. Whereby canaliculi of first class are oriented in parallel to the closest sinusoid and the second class of bile canaliculi are perpendicular to the sinusoid; 3) three hepatocytes surrounding one sinusoid form a frequently observed basic building block; 4) hepatic sinusoids are surrounded by a hexagonal belt of bile canaliculi; 5) unconnected branches of the bile canalicular network dead ends were observed; and 6) bile canaliculi are located mainly at the center of the lateral surface or very rarely at the edges of the hepatocyte surface. The disruption of the bile canalicular network was recorded in injured livers. This disruption includes disappearance of the network in damaged areas (necrotic and fibrotic) and an increase in the number of the unconnected branches in the surviving tissue. A fish bone appearance was also frequently recorded in the tissue with the surviving hepatocytes. The current study demonstrates that the architecture of the bile canalicular network clearly differs from the way it is presented in textbooks. It represents a low order network but some basic features and building principles are maintained all over the tissue. Liver damage induces a tightly controlled sequence of events by which the bile canalicular network is reconstructed.

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