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Molecular profiling of liver cells could lead to new treatments for liver disease

Published: 04 November 2019

Research supported by the NIHR Bristol Biomedical Research Centre (BRC) and the NIHR Birmingham BRC has led to the discovery of new subtypes of cells linked to liver disease.

Experts hope that increasing understanding of how these cells behave could accelerate the development of new treatments for long-term liver damage, which is currently irreversible.

Liver disease is the biggest cause of death in people aged between 35-49 years old, and is linked to a number of conditions such as obesity, alcohol excess, genetic disorders, and viral infection. Repeated and continued damage to the liver leads to the formation of scar tissue, which interrupts the internal structure of the liver and impairs normal function.

There are currently no treatments available to prevent deterioration in liver growth and function, with deaths related to liver disease increasing by 400% since 1970.

Despite considerable progress in the understanding of liver disease in rodent models, there is a significant ‘translational gap’ in the transition of conceptual molecular targets into effective patient therapies. This is in part due to limited knowledge of the different cell types throughout the liver and of the complex interactions between cells that lead to liver damage and scarring.

Mapping these interactions may notably enhance current understanding of liver disease and promote the development of new drugs.

In this study, scientists at the University of Edinburgh, in collaboration with the universities of Birmingham, Bristol, Cambridge, Charité University Medical Center, NIHR Bristol BRC and NIHR Birmingham BRC, used a new technology called single cell RNA sequencing (scRNA-seq) to study individual cell populations at unprecedented definition.

By comparing the fingerprint of 100,000 cell types found in healthy and diseased human liver, the researchers discovered subtypes of three key cells: white blood cells called macrophages, endothelial cells – which line blood vessels – and scar-forming cells known as myofibroblasts.

Subsequent modelling of these three subtypes meant the researchers could identify some of the complex molecular and chemical markers that occur with liver scarring and disease. These pathological markers could be used as drug targets for liver scarring pathways, aiding the discovery of novel therapeutics for treating patients with a broad range of fibrotic diseases.

Lead author Dr Prakash Ramachandran, an MRC clinician scientist at the University of Edinburgh’s Centre for Inflammation Research and Consultant Liver Specialist at the Royal Infirmary of Edinburgh, said: “Identifying new treatments for liver scarring is critical to tackling the epidemic of liver disease that we are currently facing. For the first time, we now have an in-depth understanding of how cells behave and talk to each other in diseased livers and, importantly, how we might block their activity as a treatment for liver scarring.”

Senior author Professor Neil Henderson, a Wellcome Trust Senior Research Fellow at the Centre for Inflammation Research and Consultant Liver Specialist at the Royal Infirmary of Edinburgh, added: “Using this new technology has allowed us to study human liver scarring in high definition for the first time. We hope that this new cutting-edge approach will rapidly accelerate the discovery of much-needed new treatments for patients with liver disease”.

The study, published in Nature, was funded by the Wellcome Trust, Medical Research Council, Guts UK, Children’s Liver Disease Foundation, AbbVie pharmaceuticals, Tenovus Scotland, British Heart Foundation, and the NIHR.

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