̽��ֱ�� of Cambridge - Sparks

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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Low cost, safe and accurate test could help diagnose rare childhood cancers

cjb250 — Wed, 16 Dec 2015 00:00:11 +0000

Reported today in the British Journal of Cancer, the test could enable doctors to monitor the effectiveness of treatments without exposing patients to repeated doses of radiation.

̽��ֱ��target of the test is a type of cancer known as germ cell cancer. Germ cells are those cells in the body that go on to develop into sperm and egg cells. Germ cells can develop into tumours – both benign and malignant – particularly in the testes or ovaries, where the cells are normally found. However, occasionally germ cells can get trapped in the wrong part of the body during development and may later turn into brain tumours, for example.

̽��ֱ��five year disease-free and overall survival rates for patients with high-risk malignant germ cell tumours remains less than 50%, and so accurate diagnosis and monitoring is crucial to improving outcomes for patients. All of the current tests are expensive, and none are ideal.

̽��ֱ��most reliable diagnostic method currently in use is biopsy, where a section of the suspected tumour is extracted surgically and analysed by a pathologist. However, biopsies are prone to sampling errors and so may not be representative of the tumour as a whole. Computerised tomography (CT) scans and magnetic resonance imaging (MRI) also provide useful information but are not diagnostic and do not discriminate between benign and malignant tumours.

̽��ֱ��ideal tool for diagnosis would be a non-invasive blood test; however, currently available tests only identify around three in five malignant germ cell tumours, potentially delaying diagnosis and the ability to prioritise patients for surgery. Accurate disease monitoring with routine blood testing is not possible for two in five patients, requiring follow up CT scans with exposure to harmful radiation and an associated increased secondary cancer risk.

“Although relatively rare, childhood germ cell tumours need to be diagnosed accurately and followed up carefully to give us the best chances of treating them,” says Professor Nick Coleman from the Department of Pathology, ̽��ֱ�� of Cambridge. “At the moment, we are not good enough at diagnosing these tumours and monitoring their treatment: we need better, safer and more cost-effective tests.”

In research funded by Sparks charity, Great Ormond Street Hospital Children’s Charity and Cancer Research UK, researchers at the ̽��ֱ�� of Cambridge have developed a test for blood and cerebrospinal fluid samples that looks for a specific panel of four pieces of short genetic code known as microRNAs, which are found in greater quantities in malignant germ cell tumours. ̽��ֱ��test can distinguish malignant germ cell tumours from benign germ cell tumours and other cancers. ̽��ֱ��test can be used for diagnosis of malignant germ cell tumours in any part of the body, including the brain.

̽��ֱ��test can also be used to check the effectiveness of treatments and, as it is safe and cost-effective, allows for frequent testing to monitor for the recurrence of malignant germ cell tumours.

Dr Matthew Murray from the Department of Paediatric Haematology and Oncology, Cambridge ̽��ֱ�� Hospitals NHS Foundation Trust, says: “This test, developed with Dr Emma Bell, a postdoctoral scientist in our laboratory, could be exactly what we need: it could help us diagnose malignant germ cell tumours cheaply, safely and above all, more accurately than current methods. Our next step is to confirm our findings in a large clinical trial and, if this is successful, we hope to see the test in routine use in hospitals in the near future.”

Reference
Murray, MJ, Bell E, et al. A pipeline to quantify serum and cerebrospinal fluid microRNAs for diagnosis and detection of relapse in paediatric malignant germ-cell tumours. British Journal of Cancer; 15 Dec 2015

A non-invasive, low cost blood test that could help doctors diagnose some types of malignant childhood tumour has been developed by researchers at the ̽��ֱ�� of Cambridge and Addenbrooke’s Hospital, Cambridge ̽��ֱ�� Health NHS Foundation Trust.

At the moment, we are not good enough at diagnosing these tumours and monitoring their treatment: we need better, safer and more cost-effective tests

Nick Coleman

̽��ֱ�� of Cambridge

Addenbrooke's Hospital

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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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