A human Liver-on-a-Chip model for studying alcohol-associated liver disease

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Project Summary Alcohol-associated liver disease (ALD) is still a serious health concern as 47% of liver-related death is due to excessive alcohol consumption. Despite of extensive research efforts, no effective therapy has been developed for ALD. One of the reasons suspending the development of effective therapy for ALD could be the lack of model systems suitable to study human relevant molecular mechanism of ALD. The current available cell culture systems and rodent ALD models do not recapitulate an ALD condition relevant in humans. To investigate more physiological experimental conditions in vitro, we established a Liver-on-a-chip model, which is a 3D in vitro hepatic micro-physiological system designed to simulate the in vivo functional conditions of liver tissues by co-culturing human-originated cells. We recently engineered a human liver-on-a-chip model suitable for investigating the underlying molecular mechanism of ALD in vitro based on the fact that human primary hepatocytes on liver-on-a-chip express higher levels of alcohol-metabolizing enzymes, such as alcohol dehydrogenase 1 (ADH1), aldehyde dehydrogenase 2 (ALDH2), and CYP2E1, compared with monolayer cultured hepatocytes. In this proposal, based on our new preliminary data using a liver-on-a-chip model, we hypothesis that, in addition to hepatocytes, liver sinusoidal endothelial cells (LSECs) and aldehyde metabolism in LSECs play important roles in regulating ethanol-induced liver damage. We will investigate whether ALDH2 in LSECs contributes to the protection for the development of ALD through acetaldehyde metabolism using a Liver-on-a-chip system (Aim 1). Because fibrosis is a risk factor for high-mortality of alcoholic hepatitis (AH), we further hypothesize that fibrotic changes in hepatic stellate cells (HSCs) and senescent changes in LSECs contribute to the increased susceptibility of ethanol-induced liver damage. We will investigate whether senescent LSECs and fibrotic HSCs contribute to the development of the microenvironment of severe ALD in cirrhotic livers as the mechanism of the development of severe AH in cirrhosis using a Liver-on-a-chip system (Aim 2). The proposed study will provide new insight into the role of ALDH2 expression and acetaldehyde metabolism in various liver cells in the progression of ethanol-induced liver damage, and provide the basis for the use of a liver-on-a-chip model as a new in vitro experimental tool to study ALD with human relevant conditions.