̽��ֱ�� of Cambridge - Fotios Sampaziotis

̽��ֱ��off-patent drug that could protect us from future COVID-19 variants

cjb250 — Mon, 05 Dec 2022 16:00:00 +0000

Cambridge scientists have identified a drug that can be repurposed to prevent COVID-19 in research involving a unique mix of ‘mini-organs’, donor organs, animal studies and patients.

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

cjb250 — Thu, 18 Feb 2021 19:00:42 +0000

̽��ֱ��research 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 in Science, scientists at the ̽��ֱ�� of Cambridge 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,” said Dr Fotios Sampaziotis from the Wellcome-MRC Cambridge Stem Cell Institute. “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.”

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.

̽��ֱ��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 ̽��ֱ�� 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 confirmed that their cell-based therapy could be used to repair damaged livers.

Professor Ludovic Vallier from the Wellcome-MRC Cambridge Stem Cell Institute, joint senior author, said: “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.”

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.

Mr Kourosh Saeb-Parsy from the Department of Surgery at the ̽��ֱ�� of Cambridge and Cambridge ̽��ֱ�� Hospitals NHS Foundation Trust, joint senior author, added: “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.”

̽��ֱ��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; 18 Feb 2021

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.

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

Fotios Sampaziotis

Can we regenerate damaged organs in the lab?

Dr Fotios Sampaziotis and Dr Teresa Brevini, ̽��ֱ�� of Cambridge

Cholangiocyte organoids reconstruct human bile duct

Cambridge Festival: How organoids help us understand ourselves and treat diseases

13:00-14:00 on Monday 29 March 2021

What are organoids? Where do they come from? And how can organoids be used to help us understand and treat human diseases? Kourosh Saeb-Parsy will be taking part in an event as part of the Cambridge Festival, chaired by Richard Westcott, BBC Science Correspondent.

Booking for the Cambridge Festival opens on Monday 22 February. For details visit the Cambridge Festival website.

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Artificial bile ducts grown in lab and transplanted into mice could help treat liver disease in children

cjb250 — Mon, 03 Jul 2017 15:11:08 +0000

In research published in the journal Nature Medicine, the researchers grew 3D cellular structure which, once transplanted into mice, developed into normal, functioning bile ducts.

Bile ducts are long, tube-like structures that carry bile, which is secreted by the liver and is essential for helping us digest food. If the ducts do not work correctly, for example in the childhood disease biliary atresia, this can lead to damaging build of bile in the liver.

̽��ֱ��study suggests that it will be feasible to generate and transplant artificial human bile ducts using a combination of cell transplantation and tissue engineering technology. This approach provides hope for the future treatment of diseases of the bile duct; at present, the only option is a liver transplant.

̽��ֱ�� ̽��ֱ�� of Cambridge research team, led by Professor Ludovic Vallier and Dr Fotios Sampaziotis from the Wellcome-MRC Cambridge Stem Cell Institute and Dr Kourosh Saeb-Parsy from the Department of Surgery, extracted healthy cells (cholangiocytes) from bile ducts and grew these into functioning 3D duct structures known as biliary organoids. When transplanted into mice, the biliary organoids assembled into intricate tubular structures, resembling bile ducts.

̽��ֱ��researchers, in collaboration with Mr Alex Justin and Dr Athina Markaki from the Department of Engineering, then investigated whether the biliary organoids could be grown on a ‘biodegradable collagen scaffold’, which could be shaped into a tube and used to repair damaged bile ducts in the body. After four weeks, the cells had fully covered the miniature scaffolding resulting in artificial tubes which exhibited key features of a normal, functioning bile duct. These artificial ducts were then used to replace damaged bile ducts in mice. ̽��ֱ��artificial duct transplants were successful, with the animals surviving without further complications.

“Our work has the potential to transform the treatment of bile duct disorders,” explains Professor Vallier. “At the moment, our only option is liver transplantation, so we are limited by the availability of healthy organs for transplantation. In future, we believe it will be possible to generate large quantities of bioengineered tissue that could replace diseased bile ducts and provide a powerful new therapeutic option without this reliance on organ transplants.”

“This demonstrates the power of tissue engineering and regenerative medicine,” adds Dr Sampaziotis. “These artificial bile ducts will not only be useful for transplanting, but could also be used to model other diseases of the bile duct and potentially develop and test new drug treatments.”

Professor Vallier is part of the Department of Surgery at the ̽��ֱ�� of Cambridge and his team are jointly based at the Wellcome Trust-MRC Cambridge Stem Cell Institute and the Wellcome Trust Sanger Institute.

̽��ֱ��work was supported by the Medical Research Council, Sparks children’s medical research charity and the European Research Council.

Reference
Sampaziotis, F et al. Reconstruction of the murine extrahepatic biliary tree using primary extrahepatic cholangiocyte organoids. Nature Medicine; 3 July 2017; DOI: 10.1038/nm.4360

Cambridge scientists have developed a new method for growing and transplanting artificial bile ducts that could in future be used to help treat liver disease in children, reducing the need for liver transplantation.

Our work has the potential to transform the treatment of bile duct disorders

Ludovic Vallier

Fotis Sampaziotis

mage of a mouse gallbladder following repair with a bioengineered patch of tissue incorporating human 'bile duct' cells, shown in green. ̽��ֱ��human bile duct cells have fully repaired and replaced the damaged mouse epithelium

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

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'Mini bile ducts' help identify new drugs that could prevent the need for liver transplantation

cjb250 — Thu, 16 Jul 2015 10:44:30 +0000

For the first time, researchers from the Wellcome Trust-Medical Research Council Stem Cell Institute at the ̽��ֱ�� 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.

̽��ֱ��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 at the Department of Surgery, 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 from the Wellcome Trust-Medical Research Council Stem Cell Institute and the Wellcome Trust Sanger Institute, said: “ ̽��ֱ��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: “ ̽��ֱ��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: “ ̽��ֱ��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.”

̽��ֱ��study was funded by a joint MRC-Sparks clinical research training fellowship, the European Research Council and the European fp7 grant TissuGEN, the Cambridge ̽��ֱ�� Hospitals National Institute for Health Research Biomedical Research Centre, Addenbrooke’s Charitable Trust and the Wellcome Trust

Reference
Sampaziotis, F et al. Cholangiocytes derived from human induced pluripotent stem cells for disease modeling and drug validation. Nature Bioetch; 13 July 2015

Adapted from a press release from the Medical Research Council.

An experimental cystic fibrosis drug has been shown to prevent the disease’s damage to the liver, thanks to a world-first where scientists grew mini bile ducts in the lab.

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

Fotios Sampaziotis

Nature Biotechnology/ ̽��ֱ�� of Cambridge

‘Mini-bile ducts’ at day 25, stained with fluorescent dyes

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

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