̽��ֱ�� of Cambridge - liver

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.

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – as here, on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

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‘Mini liver tumours’ created in a dish for the first time

cjb250 — Thu, 16 Nov 2017 08:25:55 +0000

Primary liver cancer is the second most lethal cancer worldwide. To better understand the biology of the disease and develop potential treatments, researchers need models that can grow in the lab and accurately reflect how the tumours behave in patients. Previously, cultures of cells had been used but these are hard to maintain and fail to recreate the 3D structure and tissue architecture of human tumours.

̽��ֱ��researchers created the mini tumours (up to 0.5mm) – termed ‘tumouroids’ – to mimic the three most common forms of primary liver cancer. ̽��ֱ��tumour cells were surgically removed from eight patients and grown in a solution containing specific nutrients and substances which prevent healthy cells out-competing the tumour cells.

̽��ֱ��team, from the Wellcome/Cancer Research UK Gurdon Institute in Cambridge, used the tumouroids to test the efficacy of 29 different drugs, including those currently used in treatment and drugs in development. One compound, a type of protein inhibitor, was found to inhibit the activation of a protein called ERK in two of the three types of tumouroids, a crucial step in the development of liver cancer.

̽��ֱ��researchers then tested this compound in vivo, transplanting two types of tumouroids into mice and treating them with the drug. A marked reduction in tumour growth was seen in mice treated with the drug, identifying a potential novel treatment for some types of primary liver cancer.

̽��ֱ��tumouroids were able to preserve tissue structure as well as the gene expression patterns of the original human tumours from which they were derived. ̽��ֱ��individual subtypes of three different types of liver cancer, as well as the different tumour tissues which they came from, were all still distinguishable even after they had been grown in a dish for a long time. As the tumouroids retain the biological features of their parent tumour, they could play an important role in developing personalised medicine for patients.

̽��ֱ��creation of biologically accurate models of tumours will also reduce the number of animals needed in certain experiments. Animal studies will still be required to validate findings, but the tumouroids will allow scientists to explore key questions about the biology of liver cancer in cultures rather than mice.

Lead researcher Dr Meritxell Huch, a Wellcome Sir Henry Dale Fellow from the Gurdon Institute, said: “We had previously created organoids from healthy liver tissue, but the creation of liver tumouroids is a big step forward for cancer research. They will allow us to understand much more about the biology of liver cancer and, with further work, could be used to test drugs for individual patients to create personalised treatment plans.”

Dr Andrew Chisholm, Head of Cellular and Developmental Sciences at Wellcome said: “This work shows the power of organoid cultures to model human cancers. It is impressive to see just how well the organoids are able to mimic the biology of different liver tumour types, giving researchers a new way of investigating this disease. These models are vital for the next generation of cancer research, and should allow scientists to minimise the numbers of animals used in research.”

Dr Vicky Robinson, Chief Executive of the NC3Rs which partially funded the work, said: “We are pleased to see that the funds from our annual 3Rs prize, sponsored by GlaxoSmithKline, have furthered Dr Huch's research. Each year the prize recognises exceptional science which furthers the 3Rs, and the work being conducted by Meri and her team is continuing to make progress in this area. This new breakthrough involving liver cancer organoids has the potential to reduce the number of animals required in the early stages of liver cancer research, and provide more biologically accurate models of human tumours.”

This work was funded by a National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) research prize, Wellcome and Cancer Research UK Cambridge Centre.

Reference
Broutier, L et al. Human primary liver cancer–derived organoid cultures for disease modelling and drug screening. Nature Medicine; 13 Nov 2017; DOI: 10.1038/nm.4438

Press release from Wellcome.

Scientists have created mini biological models of human primary liver cancers, known as organoids, in the lab for the first time. In a paper published in Nature Medicine, the tiny laboratory models of tumours were used to identify a new drug that could potentially treat certain types of liver cancer.

Learning from the liver how to regenerate

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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

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Cambridge spin-out raises £7 million to develop treatments for lung disease

sc604 — Thu, 04 May 2017 15:57:10 +0000

̽��ֱ��company, Z Factor Limited, was founded by Professor Jim Huntington of the Cambridge Institute for Medical Research. ̽��ֱ��new funding has come from existing investor Medicxi, as well as Cambridge Innovation Capital and Cambridge Enterprise, the ̽��ֱ��’s commercialisation arm.

Z Factor is developing new treatments for Alpha-1-Antitrypsin Deficiency (AATD). AATD, which is a significant cause of liver and lung disease, results from a defect in the gene encoding Alpha-1-antitrypsin, a type of protein. Individuals with two defective copies of the gene, making up around 1 in 2000 of the Western population, typically develop emphysema starting in their 30s. They are also at an increased risk of developing liver diseases such as cirrhosis and cancer. Around 2% of people have one defective copy of this gene, and are at five-fold increased risk of developing Chronic Obstructive Pulmonary Disease (COPD) as they age.

̽��ֱ��most common mutation causing AATD is called the Z mutation, which disrupts the normal folding of the protein. Professor Huntington and his team obtained the crystallographic structure of this mutant form of Alpha-1-antitrypsin, which allowed for the first time the rational design of drugs that could correct folding and prevent the development of associated diseases. These small-molecule drugs act like molecular ‘chaperones’ for the defective protein, accelerating folding to the correct state.

Cambridge Enterprise helped in Z Factor’s formation in 2015, licensing key intellectual property to the company. ̽��ֱ��company has already identified dozens of molecules that can correct the folding defect caused by the Z mutation, and shown that some of these drug candidates can increase Alpha-1-antitrypsin levels in an in vivo model of AATD.

Z Factor is now working to select the best molecules for use as a drug in human trials. ̽��ֱ��company expects to reach the clinic with its lead candidate in 2019.

“We are delighted to work once again with Cambridge Enterprise to ensure this exciting basic science is rapidly and efficiently translated into new medicines for a surprisingly common and debilitating cause of liver and lung disease,” said David Grainger, Partner at Medicxi and Executive Chairman at Z Factor.

Following closely on the announcement of investments in ApcinteX and SuperX earlier this year, the Z Factor Series A brings the total raised during 2017 by companies founded by Professor Huntington, one of Cambridge’s most successful serial entrepreneurs, to almost £30 million. “Jim is a leading academic innovator and Z Factor is dedicated to developing a therapy that will address a serious unmet medical need,” said Christine Martin from Cambridge Enterprise, and a Director at Z Factor.

A ̽��ֱ�� of Cambridge spin-out company has raised £7 million in new funding, which will help in the development of treatments for liver and lung disease.

Jim Huntington

̽��ֱ��crystal structure of a trimer of Z alpha-1-antitrypsin revealed the C-terminal domain-swap mechanism of polymerisation and the structural defect caused by the E342K mutation.

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Wash cycle: making organs fit for transplantation

cjb250 — Wed, 20 Jul 2016 08:25:59 +0000

In a room in the Department of Surgery, a kidney sits inside a chamber connected to tubes and monitors. Solutions and gases are pumping through it and urine is coming out.

In fact, the chamber in itself is not particularly special – it’s an off-the-shelf machine used for cardiac bypass surgery in children: it’s how it has been adapted and the new uses it has found that make it so significant. This machine is able to rejuvenate kidneys deemed not fit for transplant, making them fit and healthy again – and suitable for a recipient.

Professor Andrew Bradley, Head of the Department of Surgery, is quick to point out that it is his team at Addenbrooke’s Hospital, part of Cambridge ̽��ֱ�� Hospitals – particularly Professor Mike Nicholson and Dr Sarah Hosgood – who should take all the credit for this machine, which they refer to as an organ perfusion system.

There is a chronic shortage of suitable organs for transplant and something needs to be done. To help address the problem, in December 2015, Wales became the first country in the UK to make organ donation an ‘opt-out’ system – in other words, doctors would remove the organs from deceased individuals and provide them for use in sick patients unless the individual had explicitly refused consent before their death.

Unfortunately, not every donated organ is suitable for transplant – in the case of kidneys, for example, around 15% are deemed unsuitable. This can be for a variety of reasons, including the age of the donor, their disease history and the length of time the organ has been in cold storage.

“Grading organs is not an exact science – it’s a mixture of factors about the circumstance in which it became available, its storage and how it looks to a trained eye,” says Nicholson. “This isn’t good enough, particularly if it means we’re losing some potentially suitable organs.”

What if there was a way of taking these organs and assessing them systematically? And to take it a step further, could some of them even be rejuvenated? Before coming to Cambridge, Nicholson and Hosgood developed a system while at the ̽��ֱ�� of Leicester that effectively recirculates essential nutrients through the kidney, bringing it back to life.

“We use a combination of red blood cells, a priming solution, nutrients, protective agents and oxygen,” explains Hosgood. “We pump this through the kidney while maintaining a temperature close to our body temperature. It mimics being in the body.”

As the perfusion solution is being circulated, the kidney will begin to function and produce urine. By analysing the contents of this urine and monitoring blood flow, doctors can see how the kidney is performing and whether it might make a viable transplant organ. After just a 60-minute perfusion, the kidneys are resuscitated and are potentially ready for transplantation.

This is no longer just an experiment: since moving to Cambridge, with funding from Kidney Research UK and the National Institute for Health Research, the team has been able to take kidneys rejected from other transplant centres, resuscitate and assess them, then transplant them. In December last year, two individuals on the organ transplant waiting list received the perfect Christmas present courtesy of the Cambridge team: a new kidney.

So far, the team has taken five discarded kidneys and managed to rescue three. “We’re hoping to process another hundred over the next four years,” says Hosgood, who is also working with centres in Newcastle, Edinburgh and at Guy’s Hospital in London, in the hope of replicating their success.

̽��ֱ��current kit, which was not purpose-built for organ perfusion, is bulkier and clumsier than ideal, so the team is currently fundraising to help design a dedicated machine, in collaboration with colleagues from the Department of Engineering. “It’s not very mobile, so we couldn’t use it to help resuscitate organs in transit to other centres.”

Nicholson and Hosgood’s success has spurred on other colleagues. Professor Chris Watson describes himself as “piggybacking” on their work to develop a technique for perfusing livers. ̽��ֱ��situation for liver transplants is even more serious than it is for kidneys: as many as one in five patients on the waiting list will die before a liver becomes available.

So far, his team has taken 12 livers, all but one of which had been rejected by other centres, and successfully resuscitated and transplanted them using a system that builds on the pioneering work of his two colleagues.

“There’s a scene in the Woody Allen film Sleeper where Allen’s character stumbles across a 200-year-old Volkswagen Beetle and manages to start it first time,” he says. “ ̽��ֱ��liver is like that. You take it out of cold storage and expect it to start first time. By first assessing it on our machine, we can be more confident it will work first time.”

In some ways, this has proved more of a challenge than it did for kidneys, he adds. “With kidneys, you can put them in the machine for an hour, resuscitate them and then transplant them. If it doesn’t work immediately, the patient stays on dialysis until it picks up. With a liver, it takes longer to analyse and resuscitate the organ, and if it doesn’t work it’s a disaster for the patient.”

Now that the team has successfully revived and transplanted kidneys and livers, this is by no means the end of the story. There is still much work to be done to further improve the organ – and hence improve the function and prolong survival, says Hosgood.

Once transplanted, organs face a battle with the body’s immune system, which recognises its new occupant as a foreign body. This is one reason why the perfusion system uses only red blood cells, not white – to do so would risk an inflammatory response that could damage the organ.

“Of course, as soon as you transplant the kidney, it will face a similar inflammatory response, but by then it should be in an improved state and able to cope better with what the body throws at it,” she explains. ̽��ֱ��Department is in the process of recruiting 400 patients for a randomised controlled trial to test this technology.

̽��ֱ��perfusion system also enables therapies to be given directly to the kidney. This ensures optimal delivery of the treatment to the targeted organ and avoids any side effects in the patient. One promising avenue of research, in collaboration with Professor Jordan Pober at Yale ̽��ֱ�� (USA), is the use of nanoparticles that target the endothelial cells in the lining of the kidney. These cells play an important role in the inflammatory response after transplantation. “ ̽��ֱ��delivery of nanoparticles in this way may reduce damage to the organ after transplantation,” she adds.

̽��ֱ��shortage of suitable organs is not going away. Not even a UK-wide ‘opt-out’ system is likely to completely eradicate the problem. If anything, the crisis is likely to get worse – the flipside of good news stories such as fewer road traffic fatalities and better medicines that reduce the number of young people dying early. ̽��ֱ��team recognises that the system alone is not the answer, but it brings a new relevance to the old adage “waste not, want not”.

There’s a nationwide shortage of suitable organs for transplanting – but what if some of those organs deemed ‘unsuitable’ could be rejuvenated? Researchers at Addenbrooke’s Hospital have managed just that – and last year gave two patients an unexpected Christmas present.

Grading organs is not an exact science – it’s a mixture of factors about the circumstance in which it became available, its storage and how it looks to a trained eye. This isn’t good enough, particularly if it means we’re losing some potentially suitable organs.

Mike Nicholson

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'Tip Top Stomerij en Wasserette' Linnaeusstraat Amsterdam

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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

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Testing time for stem cells

lw355 — Thu, 23 Oct 2014 09:27:30 +0000

Much has been written about the promise of stem cells for modern medicine, and cell-based therapies to treat diseases are now being developed by commercial companies in Europe and across the world. But it is their use both to screen medicinal drugs for toxicity and to identify potential new therapies which is increasingly being viewed as one that could have an immediate and far-reaching impact.

Cambridge-based company DefiniGEN supplies the pharmaceutical industry with liver and pancreatic cells that have been reprogrammed from human skin cells. These cells, known as induced pluripotent stem (IPS) cells, are used to test potential new drugs, and can also be used as in vitro models for disease.

̽��ֱ��company spun out of the ̽��ֱ�� in 2012 and is one of the first commercial opportunities to arise from Cambridge’s expertise in stem cell research. Its portfolio of products is based on the research of Dr Ludovic Vallier, Professor Roger Pedersen, Dr Tamir Rashid, Dr Nick Hannan and Dr Candy Cho at the Anne McLaren Laboratory for Regenerative Medicine (LRM) in Cambridge.

“Drug failure in the late phase of clinical development is a major challenge to finding new therapeutics which are urgently needed by a broad number of patients with major health-care problems such as diabetes,” said Vallier. “A great deal of time and money are often lost following these false leads, and this limits the capacity of pharmaceutical companies to explore novel therapies. So, identifying toxic drugs as early as possible is vital to the efficiency and safety of the drug discovery process.

“Because we use human cells, our lab has a specific philosophy that all the data we generate is used not only for fundamental research, but also relates back to the clinic,” added Vallier, who holds a joint appointment at the LRM and the Wellcome Trust Sanger Institute, and is also Chief Scientific Officer at DefiniGEN. “We are interested in how stem cells work but we also always ask how the research we’re doing might have a clinical or translational interest.”

IPS cells can be grown outside the body indefinitely, but can also develop into almost any other cell type, providing the opportunity to have a ready source of human cells for testing new drugs. Vallier’s lab is combining basic knowledge in developmental biology and stem cells to develop methods for differentiating IPS cells into liver and pancreatic cells. Despite being generated in a dish, these cells show many of the same characteristics as those generated through natural development.

In particular, the group uses a mix of IPS cells and human embryonic stem (ES) cells to understand the molecular mechanisms that could govern the onset of various metabolic diseases such as those that affect the liver and pancreas.

̽��ֱ��liver is a large and complex organ and plays a number of important roles in the body, including digestion and the secretion and production of proteins. It is also the key organ for metabolising drugs and removing toxic substances from the body. For this reason, demonstrating that a drug candidate is not toxic to the liver is a crucial stage in the development of new drugs. It is also a test that most new drug candidates fail – increasing the cost and decreasing the efficiency of the drug development process.

A lack of high-quality human liver cells, or primary hepatocytes, means that inferior models are often used for testing potential new drugs. ̽��ֱ��cells generated in Vallier’s lab, however, show many of the same functional characteristics as primary hepatocytes, both for toxicology testing and as models of liver disease, including the most commonly inherited metabolic conditions such as familial hypercholesterolaemia and alpha 1-antitrypsin disorder.

Vallier’s team is also able to use these cells to model a diverse range of inherited liver diseases, offering the potential to accelerate the development of new therapies for these conditions. “There is no cure for end-stage liver disease apart from transplantation,” said Vallier. “Due to an acute shortage of donors, many research groups have been looking at alternative means of treating liver failure, including stem-cell-based therapy.”

Understanding the basic mechanisms behind the genesis and development of liver disease is helping his team develop new ways to generate functional liver cells that could be used to treat these conditions in future.

̽��ֱ��researchers are taking a similar approach to the pancreas, with a particular focus on diabetes. According to Diabetes UK, 3.2 million people in the UK have been diagnosed with diabetes, and an estimated 630,000 people have the condition, but don’t know it.

A promising therapy to treat type 1 diabetes is transplanting the insulin-producing islet cells of the pancreas, but there are only enough donated islets to treat fewer than 1% of diabetic patients who might benefit from this form of treatment.

Vallier’s group is working to generate large numbers of pancreatic islet cells from stem cells, which could be used for transplantation-based therapy. In addition, they are building in vitro models to study the molecular mechanisms that control pancreatic specification in the embryo. Vallier’s group has identified several genes that could be important for pancreatic development and in determining an individual’s resistance to diabetes.

“Using IPS cells, we’re trying to understand how individual genetics can influence development, insulin production capacity and disease onset,” said Vallier. “Essentially, human IPS cells can be used to model human genetics in a dish, which hasn’t been possible until now.

“Thanks to IPS cells, we’re now able to discover things that are not possible to do using animal models or any in vitro system. Not only will this help us understand more about the mechanisms behind human development, such as how cells in the human embryo develop into organs, but it will also help with drug screening and with making more-precise drugs, which is what’s really needed for the liver and pancreas. These types of in vitro applications are possible now, while cell-based treatments are more in the longer term. But you have to walk before you can run.”

DefiniGEN is one of the first commercial opportunities to arise from Cambridge’s expertise in stem cell research. Here, we look at some of the fundamental research that enables it to supply liver and pancreatic cells for drug screening.

Thanks to IPS cells, we’re now able to discover things that are not possible to do using animal models or any in vitro system

Ludovic Vallier

̽��ֱ��District

Testing time for stem cells

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Mini-livers show promise to reduce animal use in science

sjr81 — Wed, 26 Feb 2014 10:18:48 +0000

Dr Meritxell Huch from the Gurdon Institute, who tonight receives the National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) 3Rs Prize, has developed a method that enables adult mouse stem cells to grow and expand into fully functioning three-dimensional liver tissue.

Using this method, cells from one mouse could be used to test 1000 drug compounds to treat liver disease, and reduce animal use by up to 50,000.

Growing hepatocytes (liver cells) in the laboratory has been attempted by liver biologists for many years, since it would reduce their reliance on using mice to study liver disease and would open up new opportunities in medical research and drug safety testing. Until now no laboratory has been successful in deciphering how to isolate and grow these cells.

Liver stem cells are typically found in a dormant state in the liver, only becoming active following injury to produce new liver cells and bile ducts. Dr Huch and colleagues at the Netherlands’ Hubrecht Institute located the specific type of stem cells responsible for this regeneration, which are recognised by a key surface protein (Lgr5+) that they share with similar stem cells in the intestine, stomach and hair follicles.

By isolating these cells and placing them in a culture medium with the right conditions, the researchers were able to grow small liver organoids, which survive and expand for over a year in a laboratory environment. When implanted back into mice with liver disease they continued to grow, ameliorating the disease and extending the survival of the mice.

Having further refined the process using cells from rats and dogs, Dr Huch is now moving onto testing it with human cells, which could potentially translate to the development of a patient’s own liver tissue for transplantation.

Commenting on the new method’s potential to reduce animal use in liver research, Dr Huch said: “Typically a study to investigate one potential drug compound to treat one form of liver disease would require up to 50 live animals per experiment, so testing 1000 compounds would need 50,000 mice. By using the liver culture system I developed, we can test 1000 compounds using cells that come from only one mouse, resulting in a significant reduction in animal use.

“If other laboratories adopt this method then the impact on animal use in the liver research field would be immediate. A vast library of potential drug compounds could be narrowed down to just one or two very quickly and cheaply, which can then be tested further in an animal study.”

Dr Vicky Robinson, Chief Executive of the NC3Rs said: “Growing functioning liver cells in culture has been the Holy Grail for liver biologists for many years, so a limitless supply of hepatocytes could have a huge 3Rs impact both on basic research to understand liver disease and for the screening and safety testing of pharmaceuticals. Researchers need to utilise this alternative technology as soon as possible to ensure the benefits to animals and human health are fully realised.”

Professor Kevin Shakesheff, Director of the UK Regenerative Medicine Hub in Acellular Materials, said: “ ̽��ֱ��work of Dr Huch and team demonstrates how three-dimensional culture and molecular biology combine to open new possibilities in the regeneration of complex tissues. ̽��ֱ��liver is an excellent target for this work as the human body has an ability to regenerate liver tissue that is very hard to replicate in the lab. Unlocking new mechanisms to generate functional liver creates therapeutic approaches for patients with liver disease or injury and could offer a route to high quality human liver models that enhance drug development.”

Cambridge research that has for the first time successfully grown “mini-livers” from adult mouse stem cells has won the UK’s international prize for the scientific and technological advance with the most potential to replace, reduce or refine the use of animals in science (the 3Rs).

If other laboratories adopt this method then the impact on animal use in the liver research field would be immediate.

Meritxell Huch

Mini-liver research to reduce animal use in science

NC3Rs

Meritxell Huch

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