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

Metabolism syndrome directly influences different conditions such as
diabetes, 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 tissue
fibrosis and in 20% of the cases, cirrhosis of the liver. The susceptibility to NAFLD is impacted
by excessive body fat and insulin insensitivity. Epidemiological studies show sex and age
differences are important factors in developing fatty liver disease and metabolic syndrome,
suggesting that sex hormones play important roles. Hence studying the effect of different sex
hormones in different systems would cause an early risk prediction and would help to create a
model in the highly understudied scientific field.
The studies show that age is an important factor in developing the NAFLD as premenopausal
women are less likely to develop NAFLD than post-menopausal women due to sex hormone
deficiency. Moreover, androgens and oestrogens regulate lipid, glucose and cholesterol
homeostasis differently in men and women. Whilst testosterone protects males from fat
accumulation in the liver, in females it promotes it. Oestrogens have an impact on the
inflammatory response. In summary, sex hormones have different roles in different sexes that
are age-sensitive. Modelling sex differences would help us understand the progression of the
liver disease, followed by new therapeutic strategies such as the precise dosage of hormonal
treatment.
The aim of this project is to define the molecular basis of sex dependent differences in the
development of non-alcoholic fatty liver disease as the basis for developing novel therapies to
correct the aberrant phenotype. By using the novel NAFLD model that employs pluripotent stem
cell derived hepatocyte like cells (HLCs) and exposing them to physiologically relevant levels of
androgen, oestrogen and growth hormones, different environmental conditions ('fatty' or normal
diet) will be imposed. The interaction of hormone signaling and the development of steatosis will
be studied in vitro using a semi-automated platform developed in prof. Hay's lab (Centre of
Regenerative Medicine, University of Edinburgh), with a focus on key changes in liver cell
biology, including hepatic metabolism and function, cell viability, gene transcription and factor
secretion. Following in-depth analysis using bioinformatics coupled with target identification, the
sex specific models developed from these studies will be further sophisticated using organ on a
chip systems. The gene regulatory datasets derived in static and perfused culture will be used
as a basis to restore hepatocyte homeostasis by reversing steatosis and/or reducing
inflammatory gene expression. Studies will benefit from a close collaboration with an industrial
partner and an opportunity to work in different laboratories to gain experience in a broad range
of methods and different working environments.