Modelling Sex Dependent Differences in Human Liver Disease using Stem Cell-Derived Models and Organ on a Chip Devices

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Metabolism syndrome directly influences different conditions such asdiabetes, heart disease or fat accumulation in individuals around the waist causing liver disease,for example, liver steatosis. Liver steatosis can progress into non-alcoholic fatty liver disease(NAFLD). NAFLD usually progresses into non-alcoholic steatohepatitis (NASH) causing tissuefibrosis and in 20% of the cases, cirrhosis of the liver. The susceptibility to NAFLD is impactedby excessive body fat and insulin insensitivity. Epidemiological studies show sex and agedifferences are important factors in developing fatty liver disease and metabolic syndrome,suggesting that sex hormones play important roles. Hence studying the effect of different sexhormones in different systems would cause an early risk prediction and would help to create amodel in the highly understudied scientific field.The studies show that age is an important factor in developing the NAFLD as premenopausalwomen are less likely to develop NAFLD than post-menopausal women due to sex hormonedeficiency. Moreover, androgens and oestrogens regulate lipid, glucose and cholesterolhomeostasis differently in men and women. Whilst testosterone protects males from fataccumulation in the liver, in females it promotes it. Oestrogens have an impact on theinflammatory response. In summary, sex hormones have different roles in different sexes thatare age-sensitive. Modelling sex differences would help us understand the progression of theliver disease, followed by new therapeutic strategies such as the precise dosage of hormonaltreatment.The aim of this project is to define the molecular basis of sex dependent differences in thedevelopment of non-alcoholic fatty liver disease as the basis for developing novel therapies tocorrect the aberrant phenotype. By using the novel NAFLD model that employs pluripotent stemcell derived hepatocyte like cells (HLCs) and exposing them to physiologically relevant levels ofandrogen, oestrogen and growth hormones, different environmental conditions ('fatty' or normaldiet) will be imposed. The interaction of hormone signaling and the development of steatosis willbe studied in vitro using a semi-automated platform developed in prof. Hay's lab (Centre ofRegenerative Medicine, University of Edinburgh), with a focus on key changes in liver cellbiology, including hepatic metabolism and function, cell viability, gene transcription and factorsecretion. Following in-depth analysis using bioinformatics coupled with target identification, thesex specific models developed from these studies will be further sophisticated using organ on achip systems. The gene regulatory datasets derived in static and perfused culture will be usedas a basis to restore hepatocyte homeostasis by reversing steatosis and/or reducinginflammatory gene expression. Studies will benefit from a close collaboration with an industrialpartner and an opportunity to work in different laboratories to gain experience in a broad rangeof methods and different working environments.