Gurdon Institute unlocks secret of liver regeneration, giving fresh hope of treatment for cirrhosis
Scientists are hopeful that they have found the key to unlocking the liver’s regenerative powers, offering renewed hope of treatments for chronic liver conditions such as cirrhosis.
Researchers at the University of Cambridge’s Gurdon Institute used mice and liver organoids - mini livers generated in the laboratory from mouse liver cells - to study the organ’s function.
They found that a molecule called TET1 is produced in healthy adult liver cells during the first steps of regeneration, which opens up a possible new target for drug discovery.
This process was mimicked in the liver organoids, where it helped stimulate growth.
The human liver has remarkable regenerative power after acute, or short-term injury, but when chronic damage occurs in conditions such as alcohol abuse, fatty liver disease and some viral infections, this ability is impaired. The result is scarring, or cirrhosis, which leads to a loss of liver function.
About 30 million people across Europe have chronic liver diseases for which there is currently no cure, leaving transplants as the only option.
This has prompted scientists to explore the liver’s intrinsic regenerative power, to see if it could be switched back on.
Dr Luigi Aloia, first author of the paper and a 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 boost cell regeneration in chronic liver disease, or in other organs where regeneration is minimal such as the brain or pancreas.”
While it was known that TET1 and similar molecules are key in the developing embryo, where cells differentiate and form all of the different organs in the body, this study - published in the journal Nature Cell Biology - is the first to demonstrate that TET1 activity underpins regeneration in adult mouse liver tissue.
Inside the adult liver are two main cell types. Hepatocytes perform many of the liver's functions, while ductal cells form the network of tiny ducts delivering bile to the intestine.
Hepatocytes are able to regenerate after short-term injury but not after more severe damage.
Ductal cells, however, are capable of regenerating both new hepatocytes and new ductal cells to replenish liver tissue following severe or chronic injury by using an identity-switching process known as plasticity.
Collaborating with researchers in the UK and Germany, the researchers studied the molecular mechanism behind this ability and found TET1 is responsible for activating an epigenetic modification - a chemical switch - on the ductal cell's DNA.
This enables the genes to turn on so that the cell can respond to damage and activate the regeneration program as required.
Dr Meritxell Huch, who led the research, was highly commended in the Researcher of the Year category at last year’s Cambridge Independent Science and Technology Awards.
She 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 work was funded by the Wellcome Trust, Cancer Research UK and the Royal Society.