Developing disease-state liver models to determine the effects on brain function in vitro

Abstract

The liver is responsible for filtering and detoxifying harmful chemicals from the body. Because of its role as the barrier between the gut and the circulatory system, and due to the brain’s high perfusion rate, the liver’s function as a regulator for blood composition is highly important for the brain. Although the blood brain barrier blocks certain large molecules from entering into the organ, small molecules, such as ammonia, can freely pass through the fenestrations in the barrier or are naturally transported by the endothelial cells. When damage occurs to the liver and there are alterations in behavior or cognition, the condition is termed hepatic encephalopathy. Therefore, the health of the liver is important for regulating the function of the brain. However, the methods for creating in vitro hepatoid models with varying levels of dysfunction are not well developed. With this in mind, my doctoral research examines the role of using tunable collagen-polyethylene glycol hydrogels to modulate the response of hepatoids and hepatocarcinoma to exogenous factors. Chapter 2 investigates how the morphology and functionality of the zebrafish liver is degraded by endocrine disrupting chemicals, such as estrogen and bisphenol-A. Chapter 3 explores methods for developing a hepatocarcinoma model which can depict varying levels of matrix invasion and functionality. Finally, Chapter 4 investigates how collagen-hyaluronic acid hydrogels affect cortical neuron cluster morphology and the resulting change in neurotransmitter production when exposed to the hyperammonemia conditions present during hepatic encephalopathy.