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04.11.19 Regeneration mechanism uncovered in adult mouse liver tissue provides target for drug design

last modified Nov 04, 2019 05:14 PM
The Huch lab and collaborators have uncovered a novel molecular mechanism in mice that allows damaged adult liver cells to regenerate, paving the way for design of drugs to boost regeneration in conditions such as cirrhosis or other chronic liver diseases where regeneration is impaired.

Regeneration mechanism uncovered in adult mouse liver tissue provides potential target for drugs to combat chronic 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 design of drugs to boost regeneration in conditions such as cirrhosis or other chronic liver diseases where regeneration is impaired. The work is described in a paper published in the journal Nature Cell Biology

Liver organoid TRIPLE TET1 Huch Aloia

Images show a single adult liver organoid illuminated for fluroescent markers: left, to show the TET1 epigenetic mark (5-hydroxymethylcytosine) in red; centre, to show cell nuclei in blue; and right, merged to show TET1 in nuclei. From Luigi Aloia; graphic design Ludovica Bastianini.

 

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. Around 30 million people across Europe suffer from chronic liver diseases, for which there is currently no cure, with liver transplants being the only treatment for liver failure. Scientists are therefore exploring how to trigger the intrinsic regenerative capacity of the liver, as an alternative means to restore function. 

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. Aftersevere 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."

Acknowledgements

The work was funded by the Wellcome Trust, Cancer Research UK and the Royal Society; Luigi Aloia held a Horizon 2020 Marie Sklodowska-Curie Individual Fellowship.

Reference

Aloia, L et al. Epigenetic remodelling licences adult cholangiocytes for organoid formation and liver regeneration (2019) Nature Cell BiologyDOI:10.1038/s41556-019-0402-6

NOTE: Since 1st October 2019 Dr Meritxell Huch has been in post as Lise Meitner Research Group Leader at the Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG) in Dresden, Germany.

Text reproduced from press release issued by the University of Cambridge.

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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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