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6 November, 2019 - 17:11 By Kate Sweeney

Cambridge research could trigger new drugs for liver disease

Researchers at the University of Cambridge have uncovered a novel molecular mechanism that allows damaged adult liver cells to regenerate – paving the way for the design of drugs to boost regeneration in conditions such as cirrhosis or other chronic liver diseases.

The Huch lab and collaborators say the exciting discovery could help 30 million sufferers across Europe alone. At present there is no cure.

With transplants being the only treatment for liver failure, scientists are exploring how to trigger the intrinsic regenerative capacity of the organ as an alternative means to restore function. 

It has long been known that the human liver is one of the organs that can regenerate its own tissue after short-term injury. But chronic damage in conditions such as alcohol abuse, fatty liver disease and certain viral infections, leads to impaired regeneration and cirrhosis (scarring), with eventual loss of liver function. 

The molecular mechanisms by which adult liver cells trigger the regenerative response and how this fails in chronic liver disease remain largely unknown. 

Researchers at the University of Cambridge’s Gurdon Institute used mouse models and liver organoids (‘mini-livers’ generated in the lab from mouse liver cells) to study the biological principles of adult liver regeneration. 

They discovered that a molecule called TET1 is produced in healthy adult liver cells during the first steps of the regenerative response, and that this process is mimicked in liver organoids, where it has a role in stimulating organoid growth. 

Dr Luigi Aloia, first author of the paper and postdoctoral researcher at the Gurdon Institute, said: “We now understand how adult liver cells respond to the changes caused by tissue injury. This paves the way for exciting future work to target TET1 activity with drugs in an effort to boost cell regeneration in chronic liver disease, or in other organs where regeneration is minimal such as the brain or pancreas.”  

TET1 and similar molecules are known to be essential in the developing embryo, where cells are dividing and differentiating to produce all the different organs of the body. But this study is the first to demonstrate that the activity of TET1 underpins regeneration in adult mouse liver tissue. 

The adult liver is formed by two main types of cells: hepatocytes, which perform many of the liver’s functions, and ductal cells, which form the network of tiny ducts delivering bile to the intestine.

After acute (short-term) damage hepatocytes are able to regenerate, but after more severe injury they are not. After severe or chronic injury, the ductal cells become capable of generating both new hepatocytes and new ductal cells to replenish the liver tissue, through induction of an identity-switching process known as plasticity.

Researchers from Cambridge’s Gurdon Institute took part in the collaborative study along with colleagues in the UK and Germany, to explore the molecular mechanism that provides ductal cells with this power to regenerate the liver tissue. 

They showed that a chemical switch – known as an epigenetic modification – on the ductal cell’s DNA is activated by TET1. This switch allows genes to ‘turn on’ so that the cell can respond to changes in the environment such as damage, and activate the regeneration program when needed.  

Dr Meritxell Huch, who led the research, said: “Our finding pinpoints TET1 as the protein that enables plasticity of the ductal cells and their regenerative capacity in response to injury.

“Because the epigenetic switch activated by TET1 does not modify the genetic sequence of the cell, but the mechanism by which the genes are expressed, it represents a target that could be modified by drugs.”

The Gurdon Institute is funded by Wellcome and Cancer Research UK to study the biology of development and how normal growth and maintenance go wrong in cancer and other diseases.

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