Dr Fotios Sampaziotis, Dr Teresa Brevini, University of Cambridge

Lab-grown ‘mini-bile ducts’ used to repair human livers in regenerative medicine first

For the first time, this new study has successfully created ‘mini-organs’ in the lab, that could help patients with liver damage

Scientists have used a technique to grow bile duct organoids – often referred to as ‘mini-organs’ – in the lab and shown that these can be used to repair damaged human livers. This is the first time that the technique has been used on human organs.

The research, from the University of Cambridge, Wellcome-MRC Cambridge Stem Cell Institute and the Wellcome Sanger Institute, paves the way for cell therapies to treat liver disease. In other words, growing ‘mini-bile ducts’ in the lab as replacement parts that can be used to restore a patient’s own liver to health – or to repair damaged organ donor livers, so that they can still be used for transplantation.

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, with no alternative treatments. There is currently a shortage of liver donors – according to the NHS, the average waiting time for a liver transplant in the UK is 135 days for adults and 73 days for children. This means that only a limited number of patients can benefit from this therapy.

Approaches to increase organ availability or provide an alternative to whole organ transplantation are urgently needed. Cell-based therapies could provide an advantageous alternative. However, the development of these new therapies is often impaired and delayed by the lack of an appropriate model to test their safety and efficacy in humans before embarking in clinical trials.

Now, in a study published today (18 February) in Science, scientists at the University of Cambridge, Wellcome-MRC Cambridge Stem Cell Institute and the Wellcome Sanger Institute have developed a new approach that takes advantage of a recent ‘perfusion system’ that can be used to maintain donated organs outside the body. Using this technology, they demonstrated for the first time that it is possible to transplant biliary cells grown in the lab known as cholangiocytes into damaged human livers to repair them. As proof-of-principle for their method, they repaired livers deemed unsuitable for transplantation due to bile duct damage. This approach could be applied to a diversity of organs and diseases to accelerate the clinical application of cell-based therapy.

“Given the chronic shortage of donor organs, it’s important to look at ways of repairing damaged organs, or even provide alternatives to organ transplantation. We’ve been using organoids for several years now to understand biology and disease or their regeneration capacity in small animals, but we have always hoped to be able to use them to repair human damaged tissue. Ours is the first study to show, in principle, that this should be possible.”

Dr Fotios Sampaziotis from the Wellcome-MRC Cambridge Stem Cell Institute

Bile duct diseases affect only certain ducts while sparing others. This is important because in disease, the ducts in need of repair are often fully destroyed and cholangiocytes may be harvested successfully only from spared ducts.

Using the techniques of single-cell RNA sequencing and organoid culture, the researchers discovered that, although duct cells differ, biliary cells from the gallbladder, which is usually spared by the disease, could be converted to the cells of the bile ducts usually destroyed in disease (intrahepatic ducts) and vice versa using a component of bile known as bile acid. This means that the patient’s own cells from disease-spared areas could be used to repair destroyed ducts.

To test this hypothesis, the researchers grew gallbladder cells as organoids in the lab. Organoids are clusters of cells that can grow and proliferate in culture, taking on a 3D structure that has the same tissue architecture, function and gene expression and genetic functions as the part of the organ being studied. They then grafted these gallbladder organoids into mice and found that they were indeed able to repair damaged ducts, opening up avenues for regenerative medicine applications in the context of diseases affecting the biliary system.

The team used the technique on human donor livers taking advantage of the perfusion system used by researchers based at Addenbrooke’s Hospital, part of Cambridge University Hospitals NHS Foundation. They injected the gallbladder organoids into the human liver and showed for the first time that the transplanted organoids repaired the organ’s ducts and restored their function. This study therefore that their cell-based therapy could be used to repair damaged livers.

“This is the first time that we’ve been able to show that a human liver can be enhanced or repaired using cells grown in the lab. We have further work to do to test the safety and viability of this approach, but hope we will be able to transfer this into the clinic in the coming years.”

Professor Ludovic Vallier, joint senior author from the Wellcome-MRC Cambridge Stem Cell Institute, and Honorary Faculty member at Wellcome Sanger Institute

Although the researchers anticipate this approach being used to repair a patient’s own liver, they believe it may also offer a potential way of repairing damaged donor livers, making them suitable for transplant.

“This is an important step towards allowing us to use organs previously deemed unsuitable for transplantation. In future, it could help reduce the pressure on the transplant waiting list.”

Mr Kourosh Saeb-Parsy from the Department of Surgery at the University of Cambridge, joint senior author

Press Contacts

If you need help or have any queries, please contact us.

Emily Mobley
Media Manager
Tel +44 (0)1223 496 851
Email: emily.mobley@sanger.ac.uk

 

Dr Matthew Midgley
Media Officer
Tel +44 (0)1223 494 856
Email: matthew.midgley@sanger.ac.uk

 

Rachael Smith
Press Officer
Email: rachael.smith@sanger.ac.uk

 

Press office
Wellcome Sanger Institute, Hinxton,
Cambridgeshire, CB10 1SA, UK
Tel +44 (0) 7748 379849
Email: press.office@sanger.ac.uk

 

Notes to Editors

Funding

The research was supported by the European Research Council, the National Institute for Health Research and the Academy of Medical Sciences.

Reference

Sampaziotis, F et al. Cholangiocyte organoids can repair bile ducts after transplantation in human liver. Science 2021; 371: 839-846. DOI: 10.1126/science.aaz6964

https://science.sciencemag.org/content/371/6531/839

Selected websites

  • About the University of Cambridge

    The mission of the University of Cambridge is to contribute to society through the pursuit of education, learning and research at the highest international levels of excellence. To date, 110 affiliates of the University have won the Nobel Prize.

    Founded in 1209, the University comprises 31 autonomous Colleges and 150 departments, faculties and institutions. Cambridge is a global university. Its 19,000 student body includes 3,700 international students from 120 countries. Cambridge researchers collaborate with colleagues worldwide, and the University has established larger-scale partnerships in Asia, Africa and America.

    The University sits at the heart of the ‘Cambridge cluster’, which employs more than 61,000 people and has in excess of £15 billion in turnover generated annually by the 5,000 knowledge-intensive firms in and around the city. The city publishes 316 patents per 100,000 residents.

    www.cam.ac.uk

  • About the NIHR

    The National Institute for Health Research (NIHR) is the nation’s largest funder of health and care research. The NIHR:

    • Funds, supports and delivers high quality research that benefits the NHS, public health and social care
    • Engages and involves patients, carers and the public in order to improve the reach, quality and impact of research
    • Attracts, trains and supports the best researchers to tackle the complex health and care challenges of the future
    • Invests in world-class infrastructure and a skilled delivery workforce to translate discoveries into improved treatments and services
    • Partners with other public funders, charities and industry to maximise the value of research to patients and the economy
    • Funds applied global health research and training to meet the needs of the poorest people in low and middle-income countries

    The NIHR was established in 2006 to improve the health and wealth of the nation through research, and is funded by the Department of Health and Social Care. In addition to its national role, the NIHR supports applied health research for the direct and primary benefit of people in low- and middle-income countries, using UK aid from the UK government.

    For further information, visit the NIHR website (www.nihr.ac.uk).

  • The Wellcome Sanger Institute

    The Wellcome Sanger Institute is a world leading genomics research centre. We undertake large-scale research that forms the foundations of knowledge in biology and medicine. We are open and collaborative; our data, results, tools and technologies are shared across the globe to advance science. Our ambition is vast – we take on projects that are not possible anywhere else. We use the power of genome sequencing to understand and harness the information in DNA. Funded by Wellcome, we have the freedom and support to push the boundaries of genomics. Our findings are used to improve health and to understand life on Earth. Find out more at www.sanger.ac.uk or follow us on Twitter, Facebook, LinkedIn and on our Blog.

  • About Wellcome

    Wellcome exists to improve health by helping great ideas to thrive. We support researchers, we take on big health challenges, we campaign for better science, and we help everyone get involved with science and health research. We are a politically and financially independent foundation. https://wellcome.org/