Title: Targeting metabolic regulation of hepatocyte differentiation to develop therapeutic strategies for liver disease.
Funder: The Academy of Medical Sciences

Abstract: This project will identify how glycolytic activity drives hepatocyte differentiation and provide a pathway towards developing a therapeutic approach for liver disease using our liver organoid models. Liver disease is the third largest cause of premature deaths in the UK. Cell therapies would provide an abundant source for replacement treatments and overcome the current lack of organ donors; however improved in vitro differentiation strategies are required. To this end, this project has three aims: 1) Identify in vitro conditions to drive liver progenitors toward proliferative, functional hepatocytes. 2) Establish the causal relationship of targeted glycolytic perturbations on liver progenitor differentiation. 3) Develop technologies that enable these cells to be generated in a clinically compliant manner for use in patients. Our liver organoids will be used to assess the activity and effects of specific metabolic-signalling pathways promoting hepatocyte fate during developmental and regenerative processes. Chemical and genetic metabolic perturbations will be used to alter the levels of glycolytic substrates which influence cell fate decisions via their action as rate-limiting factors in epigenetic modifications, post-translational modifications and signalling cofactors. In order to determine how nutrient-driven post-translational modifications impact cell fate decisions in the liver we will use proteomic profiling. In addition to global proteomic profiling, we will perform proteomic analyses to quantify post-translation modifications including phosphorylation, acetylation, glycosylation and ligand binding profiles during cell fate transitions under specific metabolic conditions. In parallel we will develop a synthetic hydrogel to support the generation of functional hepatocytes in clinically compliant manner.

Lay abstract: The liver performs multiple functions vital to our health, therefore when compromised, either via damage (alcohol, adverse drug reactions, etc.) or through genetic and acquired diseases, this leads to high morbidity and ultimately mortality. Liver disease is one of the main causes of premature mortality in the UK, with mortality rates progressively increasing over the past 20 years. To date, there are few treatments available to treat the majority of liver diseases. The only effective cure is organ transplantation, however, this severely impeded by a limited number of donors. To address this issue, we will investigate the underlying principles of stem cell fate decisions in the liver, with the aim of enhancing endogenous liver repair mechanisms and to develop cell therapies. Liver research is hampered by the inaccessibility of human samples and differences between animal and human biology. Recently, we have described 3D cell systems (organoids) that can model many biological properties of the liver in the laboratory. Using our liver organoids we will determine how nutrient availability influences cells in the developing and regenerating liver and how these processes can be chemically targeted to produce a large number of mature liver cells for use as cell therapies. We will also work to optimise the culture methods to ensure the liver cells generated in the laboratory are safe for clinical use. With these liver organoids, we can investigate processes that were previously unachievable in human tissues and develop potential strategies to treat end-stage liver disease.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL