Structure-function properties of the gastrodigestive and hepatic systems of zebrafish (Danio rerio)

Abstract

While they lack mammal-specific organs, zebrafish provide a high degree of resemblance in their genetic profile, molecular mechanisms and organ physiology to humans and have been established as an excellent complementary platform to rodents. However, their use in gastroenterology and hepatology is under-utilised, conceivably due to a lack of digestive system ultrastructural details as most anatomical studies were performed by light and fluorescence imaging. This thesis provides detailed insights into the structure and function of the zebrafish digestive system, particularly the liver. Multimodal bio-imaging approaches were developed in order to investigate the hepatic ultrastructure and function. Using a protocol that renders samples compatible with multiple imaging platforms, we produce a detailed map of the zebrafish gastrodigestive system from organ to subcellular levels. Findings were compared with the rodent/human counterparts and while some differences exist between the zebrafish and the rodent/human hepatic parenchymal cells and biliary system organisations, many similarities, at the sub/cellular levels, were also demonstrated. Using advances in genetics and a protocol that retains endogenous fluorescence within zebrafish at the same time as ultrastructure for electron microscopy, we further investigated key hepatic functional properties (e.g. macromolecular transport routes) by performing albumin injections and studying the liver macrophages. While we demonstrated similarities in the albumin uptake pathway and in the morphology of liver macrophages in zebrafish, we reveal that zebrafish liver macrophages lack of phagocytic function (a key aspect in rodents and human), which may limit their use in hepatic-immune diseases studies. Altogether, our studies provide new insights and novel protocols for the analysis of the zebrafish liver and lay a foundation to further evaluate uptake routes for gastro-digestive research and drug delivery in various diseases.