探花直播 of Cambridge - Meritxell Huch

Regeneration mechanism discovered in mice could provide target for drugs to combat chronic liver disease

Anonymous — Mon, 04 Nov 2019 16:00:00 +0000

探花直播mechanism, identified in mice, was discovered by researchers at the 探花直播 of Cambridge鈥檚 Gurdon Institute.

It has long been known that the human liver is one of the organs that can regenerate its own tissue after short-term injury. But chronic damage in conditions such as alcohol abuse, fatty liver disease and certain viral infections, leads to impaired regeneration and cirrhosis (scarring), with eventual loss of liver function.聽

探花直播molecular mechanisms by which adult liver cells trigger the regenerative response, and how this fails in chronic liver disease, remain largely unknown. Around 30 million people across Europe suffer from chronic liver diseases, for which there is currently no cure, with liver transplants being the only treatment for liver failure. Scientists are therefore exploring how to trigger the intrinsic regenerative capacity of the liver, as an alternative means to restore function.

Researchers used mice and liver organoids ('mini-livers' generated in the lab from mouse liver cells) to study adult liver regeneration. They discovered that a molecule called TET1 is produced in healthy adult liver cells during the first steps of regeneration, and that this process is mimicked in liver organoids, where it has a role in stimulating organoid growth. 探花直播work is described in a paper published in the journal Nature Cell Biology.

Dr Luigi Aloia, first author of the paper and postdoctoral researcher at the Gurdon Institute, said: 鈥淲e now understand how adult liver cells respond to the changes caused by tissue injury. This paves the way for exciting future work to boost cell regeneration in chronic liver disease, or in other organs where regeneration is minimal such as the brain or pancreas."聽

TET1 and similar molecules are known to be essential in the developing embryo, where cells divide and differentiate to produce all the different organs of the body. But this study is the first to demonstrate that the activity of TET1 underpins regeneration in adult mouse liver tissue.

探花直播adult liver is formed by two main types of cells: hepatocytes, which perform many of the liver's functions, and ductal cells, which form the network of tiny ducts delivering bile to the intestine. After acute (short-term) damage hepatocytes are able to regenerate, but after more severe injury they are not. After severe or chronic injury, the ductal cells become capable of generating both new hepatocytes and new ductal cells to replenish the liver tissue, through induction of an identity-switching process known as plasticity.

探花直播researchers, in collaboration with colleagues in the UK and Germany, explored the molecular mechanism that provides ductal cells with this power to regenerate the liver tissue. They showed that TET1 activates a chemical switch - known as an epigenetic modification - on the ductal cell's DNA. This switch allows genes to 'turn on' so that the cell can respond to changes in the environment such as damage, and activate the regeneration program when needed.聽

Dr Meritxell Huch, who led the research, said: "Our finding pinpoints TET1 as the protein that enables plasticity of the ductal cells and their regenerative capacity in response to injury. Because the epigenetic switch activated by TET1 does not modify the genetic sequence of the cell, but the mechanism by which the genes are expressed, it represents a target that could be modified by drugs."聽

探花直播work was funded by the Wellcome Trust, Cancer Research UK and the Royal Society; Luigi Aloia holds a Horizon 2020 Marie Sklodowska-Curie Individual Fellowship.

聽
Reference
Aloia, L et al. 鈥�Epigenetic remodelling licences adult cholangiocytes for organoid formation and liver regeneration鈥� (2019) Nature Cell Biology. DOI: 10.1038/s41556-019-0402-6.
聽聽

A newly-discovered molecular mechanism that allows damaged adult liver cells to regenerate could pave the way for drugs to treat conditions such as cirrhosis or other chronic liver diseases where regeneration is impaired.聽

We now understand how adult liver cells respond to the changes caused by tissue injury. This paves the way for exciting future work to boost cell regeneration in chronic liver disease.

Luigi Aloia

Luigi Aloia and Ludovica Bastianini

Images show the TET1 epigenetic mark within the cells in an adult liver organoid

探花直播text in this work is licensed under a Creative Commons Attribution 4.0 International License. Images, including our videos, are Copyright 漏探花直播 of Cambridge and licensors/contributors as identified.聽 All rights reserved. We make our image and video content available in a number of ways 鈥� 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.

Yes

探花直播body in miniature

cjb250 — Tue, 20 Mar 2018 15:22:55 +0000

In Cambridge alone, there are groups growing mini-livers, mini-brains, mini-oesophaguses,mini-bile ducts,聽mini-lungs, mini-intestines,聽mini-wombs, mini-pancreases鈥� Almost the whole body in miniature, it seems.

Read more about how these remarkable 'organoids' are helping transform biomedical research - including helping reduce the number of animals used in research.

探花直播past few years has seen an explosion in the number of studies using聽organoids聽鈥� so-called 鈥榤ini organs鈥�. While they can help scientists understand human biology and disease, some in the field have questioned their usefulness.聽But as the field matures, we could see their increasing use in聽personalised聽and regenerative medicine.

David Turner

Confocal microscope image of gastruloid

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

Yes

鈥楳ini liver tumours鈥� 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.聽

探花直播researchers created the mini tumours (up to 0.5mm) 鈥� termed 鈥榯umouroids鈥� 鈥� to mimic the three most common forms of primary liver cancer. 探花直播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.聽

探花直播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.

探花直播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.

探花直播tumouroids were able to preserve tissue structure as well as the gene expression patterns of the original human tumours from which they were derived. 探花直播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.

探花直播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.聽

Lead researcher Dr Meritxell Huch, a Wellcome Sir Henry Dale Fellow from the Gurdon Institute, said: 鈥淲e 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.鈥�

Dr Andrew Chisholm, Head of Cellular and Developmental Sciences at Wellcome said: 鈥淭his 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.聽 These models are vital for the next generation of cancer research, and should allow scientists to minimise the numbers of animals used in research.鈥�

Dr Vicky Robinson, Chief Executive of the NC3Rs which partially funded the work, said: 鈥淲e 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.鈥�

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鈥揹erived 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聽organoids, in the lab for the first time. In a paper published in Nature Medicine, the tiny laboratory models of聽tumours聽were used to identify a new drug that could potentially treat certain types of liver cancer.

Learning from the liver how to regenerate

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

Yes

Fighting cancer: Animal research at Cambridge

cjb250 — Fri, 24 Apr 2015 08:27:24 +0000

Animal research plays an essential role in our understanding of health and disease and in the development of modern medicines and surgical techniques. Without the use of animals, we would not have many of the modern medicines, antibiotics, vaccines and surgical techniques that we take for granted in both human and veterinary medicine.

Some of the important and pioneering work for which Cambridge is best known and which has led to major improvements in people鈥檚 lives was only possible using animals, from the development of IVF techniques through to human monoclonal antibodies.

We place good welfare at the centre of all our animal research and aim to meet the highest standards: good animal welfare and good science go hand-in-hand. As part of our commitment to openness, in our new film, we look inside one of our facilities, where mice are helping our scientists understand how cancers develop and how they can best be treated.

Our mice are housed in state-of-the-art facilities. Each animal is checked daily to ensure it has enough food and water and to look for signs that the animal is in pain, no matter how mild. We use some of the same imaging techniques used on humans, such as ultrasound 鈥� the non-invasive technique that allows doctors to monitor the health of a baby in the womb 鈥� to monitor tumour development in the mice.

Although animals will play a role in biomedical research for the foreseeable future, we strive to use the minimum number possible. Our researchers are actively looking at techniques to help us reduce 鈥� and ultimately replace 鈥� their use. In the film, we explore a new technique to develop 鈥榤ini-livers鈥� that will allow us to screen potential new drugs without the use of animals.

We welcome comments about this article. However, as with discussions on all of our news and feature pages, comments will be moderated so please do not post contributions that are offensive or contain profanities, and please stay on topic. We do not moderate comments in real-time so do bear with us if there is a delay before they appear.

A new film from the 探花直播 of Cambridge looks at how mice are helping the fight against cancer and the facilities in which they are housed, and explores issues of animal welfare and the search for replacements.

As part of our commitment to openness, in our new film, we look inside one of our facilities, where mice are helping our scientists understand how cancers develop

Fighting cancer: Animal research at Cambridge

探花直播 of Cambridge

Mouse

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

Yes

Licence type:

Attribution

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鈥� 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鈥檚 own liver tissue for transplantation.

Commenting on the new method鈥檚 potential to reduce animal use in liver research, Dr Huch said: 鈥淭ypically 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.

鈥淚f 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.鈥�

Dr Vicky Robinson, Chief Executive of the NC3Rs said:聽鈥淕rowing 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.鈥�

Professor Kevin Shakesheff, Director of the UK Regenerative Medicine Hub in Acellular Materials, said:聽鈥� 探花直播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. 探花直播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.鈥�

Cambridge research that has for the first time successfully grown 鈥渕ini-livers鈥� from adult mouse stem cells has won the UK鈥檚 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

This work is licensed under a Creative Commons Licence. If you use this content on your site please link back to this page.

Yes