An experimental cystic fibrosis drug has been shown prevent the disease’s damage to the liver, thanks to a world-first where scientists grew mini bile ducts in the lab.
Images a and b show immunofluorescence (left) and light microscopy (right) images of organoids, demonstrating the formation of cystic and branching (arrows) tubular structures. Image c shows Transmitted electron microscopy images (right) and Immunofluorescence analyses (left) demonstrating the presence of cilia (arrow). [DOI: 10.1038/nbt.3275]
For the first time, researchers led by scientists from the Wellcome Trust-Medical Research Council Stem Cell Institute 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 dysfunctioning bile ducts are implicated in a third of adult and 70 per cent of children’s liver transplantations.
The researchers used their lab-grown 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 therapeutic agent to prevent the damage cystic fibrosis causes to the liver and bile duct.
Dr Fotios Sampaziotis, first author from the Wellcome Trust-Medical Research Council Stem Cell Institute and 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. We were delighted to identify a new experimental drug that could prevent patients with cystic fibrosis, one of the most common inherited disorders in Europe, from undergoing a liver transplantation, a major and life changing operation. But, this treatment will need to be tested in clinical trials before it can be recommended to patients.”
” 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. “
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 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 therapeutic agents.”
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 to also understand how diseased bile ducts behave and how they may respond to therapeutic treatment. This platform 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 the signature of these cells with those 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 lead to functioning spare liver parts being grown to replace damaged areas.”
Notes to Editors
Cholangiocytes derived from human induced pluripotent stem cells for disease modelling and drug validation.
Nature Biotechnology 2015
This work was funded by an ERC starting grant, Relieve IMDs, from the Cambridge Hospitals National Institute for Health Research Biomedical Research Centre; the Evelyn Trust and the EU Fp7 grant TissueGEN, an Addenbrooke’s Charitable Trust Clinical Research Training Fellowhsip and a joint MRC-Sparks Clinical Research Training Fellowship.
Wellcome Trust-Medical Research Council Stem Cell Institute, Wellcome Trust Sanger Institute, University of Cambridge and NIHR Cambridge Biomedical Research Centre, Oslo University Hospital, University of Oslo, Cambridge University Hospitals NHS Foundation Trust.
Medical Research Council
The Medical Research Council is at the forefront of scientific discovery to improve human health. Founded in 1913 to tackle tuberculosis, the MRC now invests taxpayers’ money in some of the best medical research in the world across every area of health. Thirty-one MRC-funded researchers have won Nobel prizes in a wide range of disciplines, and MRC scientists have been behind such diverse discoveries as vitamins, the structure of DNA and the link between smoking and cancer, as well as achievements such as pioneering the use of randomised controlled trials, the invention of MRI scanning, and the development of a group of antibodies used in the making of some of the most successful drugs ever developed. Today, MRC-funded scientists tackle some of the greatest health problems facing humanity in the 21st century, from the rising tide of chronic diseases associated with ageing to the threats posed by rapidly mutating micro-organisms.
Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute
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Addenbrooke’s Charitable Trust
Addenbrooke’s Charitable Trust (ACT) is the dedicated charity for Addenbrooke’s and the Rosie hospitals. ACT raises funds for cutting edge technology, additional specialist staff, environmental enhancements and extra comforts for patients that make all the difference. It also provides funding for Cambridge Clinical Research Fellowships that provide a springboard for clinical academics embarking on a research career and for early stage research projects.
The Wellcome Trust Sanger Institute
The Wellcome Trust Sanger Institute is one of the world’s leading genome centres. Through its ability to conduct research at scale, it is able to engage in bold and long-term exploratory projects that are designed to influence and empower medical science globally. Institute research findings, generated through its own research programmes and through its leading role in international consortia, are being used to develop new diagnostics and treatments for human disease.
The Wellcome Trust
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