‘Mini Bile Ducts’ used to Discover New Drugs that could Prevent Liver Damage
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For the first time, researchers led by scientists from the Wellcome Trust-Medical Research Council Stem Cell Institute at the University of Cambridge and the Wellcome Trust Sanger Institute in Cambridge, used stem cells to grow fully functional three-dimensional bile ducts in the lab. Bile ducts act as the liver’s waste disposal system, and malfunctioning bile ducts are behind a third of adult and 70 per cent of children’s liver transplantations.
The researchers used their ‘miniature bile ducts’ to test new drugs for biliary disease, leading to the discovery that VX809 – an experimental compound originally designed to treat the effects of cystic fibrosis in the lungs – could be the first treatment to prevent the damage cystic fibrosis causes to the liver and bile duct.
Dr Fotios Sampaziotis, lead author and an MRC-Sparks clinical research fellow in hepatology, said: “Treating liver complications caused by bile duct disorders constitutes a major challenge – with the only treatment option often being liver transplantation. Identifying a new experimental drug that could prevent patients with cystic fibrosis from undergoing a liver transplantation, a major and life changing operation, could have huge implications for our patients. But, this treatment will need to be tested in clinical trials before it can be recommended to patients.”
Until now there has been no way of generating large numbers of fully functional bile ducts that mimic disease in the lab, which has limited our understanding of biliary disorders and restricted the development of new drugs.
Using their ‘bile duct replicas’ the researchers reproduced key features of two more bile duct diseases – polycystic liver disease and Alagille syndrome – and tested the effects of additional drugs, such as octreotide.
Professor Ludovic Vallier, Principal Investigator and corresponding author from the Wellcome Trust-Medical Research Council Stem Cell Institute and the Wellcome Trust Sanger Institute, said: “The pharmaceutical applications of our system are particularly important as we don’t have many human samples of this type of tissue to work on. This system could provide a unique resource for identifying new treatments.”
Dr Nicholas Hannan, a senior author from the Wellcome Trust-Medical Research Council Stem Cell Institute, said: “The bile duct cells we have generated represent an invaluable tool to understand not only how healthy bile ducts develop and function, but also how diseased bile ducts behave and how they may respond to treatment. This opens up the possibility of modelling complex liver diseases and will certainly progress our understanding of biliary disease in the future.”
To demonstrate that the cells they had grown were in fact forming bile ducts the researchers looked for characteristic markers and functions of the cells. They then compared these with samples from human donors and found that they were almost identical.
Dr Paul Colville-Nash, programme manager for stem cell, developmental biology and regenerative medicine at the MRC, said: “The approach developed in this work will enable a vast range of work, from understanding how organs grow and develop to a greater understanding of disease and testing new drugs. This work could also one day open the way to researchers building new bile ducts that will replace damaged segments of the liver.”
