̽��ֱ�� of Cambridge - Ludovic Vallier

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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̽��ֱ��Academy of Medical Sciences announces new Fellows for 2020

sc604 — Wed, 13 May 2020 01:00:00 +0000

̽��ֱ��new Fellows have been chosen for their exceptional contributions to advancing biomedical science via world-leading research discoveries, running national science communication and engagement programmes and translating scientific advances into benefits for patients and the public.

̽��ֱ��value of medical science has never been more apparent than during the current coronavirus global health crisis. From testing and vaccine development, to public health and behavioural science, to addressing the impacts of lockdown measures on mental health, biomedical and health scientists are helping to guide the UK through unprecedented challenges.

Several new Fellows have redirected their research efforts to tackle the effects of the pandemic, such as Professor Ludovic Vallier FMedSci, a stem cell expert from the ̽��ֱ�� of Cambridge, who has refocussed part of his team to study the effects of coronavirus on the liver. Professor Tamsin Ford CBE FMedSci, a Professor of Psychiatry at Cambridge, has channelled her expertise into looking at mental health impacts of the pandemic on children and young people.

Professor Sir Robert Lechler PMedSci, President of the Academy of Medical Sciences said: “This year our new Fellows announcement happens amidst a global health crisis. Never has there been a more important time to recognise and celebrate the people behind ground-breaking biomedical and health research, working harder than ever to further knowledge and protect patients and the public.

“It brings me great pleasure to congratulate the new Fellows, and see our Fellowship grow to even greater heights of evidence-based advice, leadership and expertise.”

̽��ֱ�� ̽��ֱ�� of Cambridge Fellows elected in 2020 are:

Professor Menna Clatworthy FLSW, NIHR Research Professor and Professor of Translational Immunology, ̽��ֱ�� of Cambridge and Associate Faculty, Wellcome Sanger Institute, Fellow, Pembroke College

Dr Helen Firth, Consultant Clinical Geneticist, Cambridge ̽��ֱ�� Hospitals, Honorary Faculty Member, Wellcome Sanger Institute, Bye-Fellow, Newnham College

Professor Tamsin Ford CBE, Professor of Child and Adolescent Psychiatry, ̽��ֱ�� of Cambridge, Fellow, Hughes Hall

Professor Ziad Mallat, Professor of Cardiovascular Medicine, ̽��ֱ�� of Cambridge

Dr Nitzan Rosenfeld, Senior Group Leader, Cancer Research UK Cambridge Institute, ̽��ֱ�� of Cambridge

Professor Ludovic Vallier, Professor of Regenerative Medicine, Wellcome - MRC Cambridge Stem Cell Institute, ̽��ֱ�� of Cambridge, Fellow, St Edmund’s College

̽��ֱ��new Fellows will be formally admitted to the Academy on 25 June 2020.

Six affiliates of the ̽��ֱ�� of Cambridge are among 50 world-leading UK researchers who have been elected to the prestigious Fellowship of the Academy of Medical Sciences.

Big T Images for Academy of Medical Sciences

Academy of Medical Sciences

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New innovation hub aims to take a 'moon shot' at cystic fibrosis

cjb250 — Wed, 18 Apr 2018 14:01:05 +0000

John Winn’s office at Microsoft Research looks like that of any typical academic: on one wall is a whiteboard graffitied with impenetrable equations and mathematical scribblings, on the opposite wall books and files line shelves, and on his desk are photos of his family.

His desk, however, is somewhat different: it can rise or fall, depending on whether he wants to work standing or sitting – and underneath is a treadmill for walking and working at the same time. “There have been times when I’ve been deep in thought and almost fallen off it,” he jokes.

Winn has cystic fibrosis (CF) and keeping fit is an important part of managing his condition: the stronger his lung function, the better equipped he is to fight the potentially life-threatening infections that plague people living with the condition.

CF occurs when an individual inherits two copies of a single genetic variant, one from each parent. ̽��ֱ��disease causes a build-up of thick, sticky mucous in the lungs, intestines and organs, and those affected by the condition are particularly susceptible to lung infections leading to progressive inflammatory lung damage. Although life expectancy for people with CF has almost doubled in recent decades, it is still significantly below average.

Winn is a machine learning specialist and is using his expertise to fight the condition that affects his everyday life. Together with Professor Andres Floto from the Department of Medicine at Cambridge, he is turning data from the daily lives of people with cystic fibrosis into potentially life-saving information.

As part of this study, funded by the Cystic Fibrosis Trust and Royal Papworth Hospital, participants have been submitting data – everything from heart rate and lung function through to self-reported wellbeing – via an app that also monitors their activity levels. Machine learning then sifts through the data, looking for patterns and – it’s hoped – building a model that can predict when a patient’s health is about to deteriorate and advise them to seek medical help.

“ ̽��ֱ��overarching principle is about giving people control over their own health data and making it work for them,” says Winn. “There’s some informal feedback that just participating in the study and taking these readings has already improved health outcomes for some individuals: for example, it’s helped with adherence with taking their medications as they noticed that if they missed taking certain medicines, their readings got worse.”

̽��ֱ��project is just one strand of a major new Cystic Fibrosis Innovation Hub based on the Cambridge Biomedical Campus and run by Floto. ̽��ֱ��Hub is supported through a £5 million commitment from the Cystic Fibrosis Trust and matching funds from the ̽��ֱ�� of Cambridge. It will strengthen existing collaborations across the ̽��ֱ�� and with the Wellcome Trust Sanger Institute, as well as build new collaborative research networks with CF centres around the UK. ̽��ֱ��Trust’s Chief Executive, David Ramsden, said it will “provide in CF research across the country”.

Floto agrees with this sentiment: “We have an opportunity to uplift UK CF research in general by providing knowhow, training and reagents in a number of areas including genomics, bioinformatics, stem cells and clinical trials technology.”

A major part of the Hub’s activities will be around developing new drugs that target chronic inflammation in CF, in collaboration with the pharmaceutical company GSK as part of the GSK/Cambridge Strategic Partnership, as well as new antibiotic therapy for the main causes of lung infection in the condition.

Finding new drugs against these bacteria is becoming increasingly urgent – Floto and Professor Julian Parkhill at Sanger recently showed that Mycobacterium abscessus, the pathogen behind one of the most serious infections, is becoming increasingly multi-drug resistant and spreading globally. This is one reason why people with CF are advised not to meet each other.

“Clearly the techniques that we develop – and the drug-like molecules that come out of it – will have more general applicability to patients with other multi-drug resistant infections,” Floto says. This will be welcome news to England’s Chief Medical Officer, Professor Dame Sally Davies, who has warned of a future where “any one of us could go into hospital in 20 years for minor surgery and die because of an ordinary infection that can’t be treated by antibiotics.”

̽��ֱ��timing of all this is particularly good: Papworth Hospital, whose Adult Cystic Fibrosis Centre has gained a national and international reputation for its treatment of patients and its contribution to research, is due to move to the Biomedical Campus later in 2018. ̽��ֱ��CF wards will feature state-of-the-art air flow systems, designed with Floto’s work on the spread of multi-drug resistant CF pathogens in mind.

This close proximity between the patients and the researchers will help Floto test the new treatments he is pioneering. He is particularly excited about the potential for new cellular therapies he’s developing with Professor Ludovic Vallier at the Department of Surgery. Floto describes these as their “moon shot”. These would involve taking cells from a CF patient, re-programming them – correcting the genetic defect along the way – and then re-injecting them into patients. “This could provide a way to regenerate damaged lungs,” he says.

Floto knows his plans for the Hub are ambitious, but given that it’s almost 30 years since the gene that causes CF was discovered and there is still no cure for the disease, believes it’s time to take this shot at the moon.

Floto’s collaborators in the CF Innovation Hub include Chris Abell (Chemistry), Sir Tom Blundell (Biochemistry), Julian Parkhill and Ludovic Vallier.

Almost 30 years on from the discovery of the genetic defect that causes cystic fibrosis, treatment options are still limited and growing antibiotic resistance presents a grave threat. Now, a team of researchers from across Cambridge, in a major new centre supported by the Cystic Fibrosis Trust, hopes to turn fortunes around.

We have an opportunity to uplift UK cystic fibrosis research in general by providing knowhow, training and reagents in a number of areas including genomics, bioinformatics, stem cells and clinical trials technology

Andres Floto

Cambridge Biomedical Campus

A no-strings-attached scientific relationship

Professor Claire Bryant, like Floto, works on an inflammatory lung disease as part of the GSK/Cambridge Strategic Partnership. In her case, she’s looking at chronic obstructive pulmonary disease (COPD).

COPD is a condition caused by smoking, pollution and severe asthma. Bryant is looking in particular at how COPD makes the lungs ‘stickier’ to bacteria, increasing the risk of infections.

She holds two grants under the GSK/Cambridge Strategic Partnership, which aims to develop the next wave of ‘game-changing’ medicines by bringing academic and industrial expertise together to tackle often intractable disease. Based at Cambridge’s Department of Veterinary Medicine, Bryant currently has a three-day-a-week sabbatical at GSK’s headquarters in Stevenage. As such, it’s arguable whether anyone embodies the partnership more than she does.

̽��ֱ��three-year sabbatical provides Bryant with three postdocs, two PhD students and budget, with access to GSK resources, but with “no strings attached”. ̽��ֱ��only proviso is that if she works with a GSK reagent, they have first rights on what she does with this. Crucially, she says, it gives her “the space to think”.

Bryant is embedded in GSK’s Respiratory Drug Discovery Unit and attends its lab meeting every week. “I’ve met really smart, clever scientists at GSK, with different skills to those of us in academia,” she says. “I get to see all aspects of what happens at GSK, everything from how a target is identified to how drugs are developed to target it, through to taking these drugs to clinical trials. I see the whole spectrum.”

It is, though, a mutually beneficial programme, she stresses. Bryant brings her knowledge of innate immunity and her experience of multi-disciplinary collaborations, particularly in imaging. “It’s effectively like being a consultant,” she says. “I want them to get as much out of me as I do out of them.”

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̽��ֱ��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, mini-lungs, mini-intestines, mini-wombs, mini-pancreases… 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.

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

David Turner

Confocal microscope image of gastruloid

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Genome editing reveals role of gene important for human embryo development

sc604 — Wed, 20 Sep 2017 17:00:00 +0000

̽��ֱ��team used genome editing techniques to stop a key gene from producing a protein called OCT4, which normally becomes active in the first few days of human embryo development. After the egg is fertilised, it divides until at about 7 days it forms a ball of around 200 cells called the ‘blastocyst’. ̽��ֱ��study found that human embryos need OCT4 to correctly form a blastocyst.

“We were surprised to see just how crucial this gene is for human embryo development, but we need to continue our work to confirm its role” says Dr Norah Fogarty from the Francis Crick Institute, first author of the study. “Other research methods, including studies in mice, suggested a later and more focussed role for OCT4, so our results highlight the need for human embryo research.”

Dr Kathy Niakan from the Francis Crick Institute, who led the research adds, “One way to find out what a gene does in the developing embryo is to see what happens when it isn’t working. Now we have demonstrated an efficient way of doing this, we hope that other scientists will use it to find out the roles of other genes. If we knew the key genes that embryos need to develop successfully, we could improve IVF treatments and understand some causes of pregnancy failure. It will take many years to achieve such an understanding, our study is just the first step.”

̽��ֱ��research was published in Nature and led by scientists at the Francis Crick Institute, in collaboration with colleagues at Cambridge ̽��ֱ��, Oxford ̽��ֱ��, the Wellcome Trust Sanger Institute, Seoul National ̽��ֱ�� and Bourn Hall Clinic. It was chiefly funded by the UK Medical Research Council, Wellcome and Cancer Research.

̽��ֱ��team spent over a year optimising their techniques using mouse embryos and human embryonic stem cells before starting work on human embryos. To inactivate OCT4, they used an editing technique called CRISPR/Cas9 to change the DNA of 41 human embryos. After seven days, embryo development was stopped and the embryos were analysed.

̽��ֱ��embryos used in the study were donated by couples who had undergone IVF treatment, with frozen embryos remaining in storage; the majority were donated by couples who had completed their family, and wanted their surplus embryos to be used for research. ̽��ֱ��study was done under a research licence and strict regulatory oversight from the Human Fertilisation and Embryology Authority (HFEA), the UK Government's independent regulator overseeing infertility treatment and research.

As well as human embryo development, OCT4 is thought to be important in stem cell biology. ‘Pluripotent’ stem cells can become any other type of cell, and they can be derived from embryos or created from adult cells such as skin cells. Human embryonic stem cells are taken from a part of the developing embryo that has high levels of OCT4.

“We have the technology to create and use pluripotent stem cells, which is undoubtedly a fantastic achievement, but we still don’t understand exactly how these cells work,” explains Dr James Turner, co-author of the study from the Francis Crick Institute. “Learning more about how different genes cause cells to become and remain pluripotent will help us to produce and use stem cells more reliably.”

Sir Paul Nurse, Director of the Francis Crick Institute, says: “This is exciting and important research. ̽��ֱ��study has been carried out with full regulatory oversight and offers new knowledge of the biological processes at work in the first five or six days of a human embryo’s healthy development. Kathy Niakan and colleagues are providing new understanding of the genes responsible for a crucial change when groups of cells in the very early embryo first become organised and set on different paths of development. ̽��ֱ��processes at work in these embryonic cells will be of interest in many areas of stem cell biology and medicine.”

Dr. Kay Elder, study co-author from the Bourn Hall Clinic, says: "Successful IVF treatment is crucially dependent on culture systems that provide an optimal environment for healthy embryo development. Many embryos arrest in culture, or fail to continue developing after implantation; this research will significantly help treatment for infertile couples, by helping us to identify the factors that are essential for ensuring that human embryos can develop into healthy babies.”

Dr Ludovic Vallier, co-author on the study from the Wellcome Trust Sanger Institute and the Wellcome - MRC Cambridge Stem Cell Institute, said: “This study represents an important step in understanding human embryonic development. ̽��ֱ��acquisition of this knowledge will be essential to develop new treatments against developmental disorders and could also help understand adult diseases such as diabetes that may originate during the early stage of life. Thus, this research will open new fields of opportunity for basic and translational applications.”

Reference:
Norah M.E. Fogarty et al. 'Genome editing of OCT4 reveals distinct mechanisms of lineage specification in human and mouse embryos.' Nature (2017). DOI: 10.1038/nature24033.

Adapted from a Francis Crick Institute press release.

Researchers have used genome editing technology to reveal the role of a key gene in human embryos in the first few days of development. This is the first time that genome editing has been used to study gene function in human embryos, which could help scientists to better understand the biology of our early development.

This knowledge will be essential to develop new treatments against developmental disorders and could also help understand adult diseases such as diabetes that may originate during the early stage of life.

Ludovic Vallier

Dr Kathy Niakan/Nature

Day 2 embryo

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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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New stem cell method produces millions of human brain and muscle cells in days

cjb250 — Thu, 23 Mar 2017 16:50:39 +0000

Human pluripotent stem cells are ‘master cells’ that have the ability to develop into almost any type of tissue, including brain cells. They hold huge potential for studying human development and the impact of diseases, including cancer, Alzheimer’s, multiple sclerosis, and heart disease.

In a human, it takes nine to twelve months for a single brain cell to develop fully. It can take between three and 20 weeks using current methods to create human brain cells, including grey matter (neurons) and white matter (oligodendrocytes) from an induced pluripotent stem cell – that is, a stem cell generated by reprogramming a skin cell to its ‘master’ stage. However, these methods are complex and time-consuming, often producing a mixed population of cells.

̽��ֱ��new platform technology, OPTi-OX, optimises the way of switching on genes in human stem cells. Scientists applied OPTi-OX to the production of millions of nearly identical cells in a matter of days. In addition to the neurons, oligodendrocytes, and muscle cells the scientists created in the study, OPTi-OX holds the possibility of generating any cell type at unprecedented purities, in this short timeframe.

To produce the neurons, oligodendrocytes, and muscle cells, the team altered the DNA in the stem cells. By switching on carefully selected genes, they reprogrammed the stem cells and created a large and nearly pure population of identical cells. ̽��ֱ��ability to produce as many cells as desired combined with the speed of the development gives an advantage over other methods. ̽��ֱ��new method opens the door to drug discovery, and potentially therapeutic applications in which large amounts of cells are needed.

Study author Professor Ludovic Vallier from the Wellcome Trust-Medical Research Centre Stem Cell Institute at the ̽��ֱ�� of Cambridge says: “What is really exciting is we only needed to change a few ingredients – transcription factors – to produce the exact cells we wanted in less than a week. We over-expressed factors that make stem cells directly convert into the desired cells, thereby bypassing development and shortening the process to just a few days.”

OPTi-OX has applications in various projects, including the possibility to generate new cell types which may be uncovered by the Human Cell Atlas. ̽��ֱ��ability to produce human cells so quickly means the new method will facilitate more research.

Joint first author, Daniel Ortmann from the ̽��ֱ�� of Cambridge, adds: “When we receive a wealth of new information on the discovery of new cells from large scale projects, like the Human Cell Atlas, it means we’ll be able to apply this method to produce any cell type in the body, but in a dish.”

Dr Mark Kotter, lead author and clinician, also from Cambridge, says: “Neurons produced in this study are already being used to understand brain development and function. This method opens the doors to producing all sorts of hard-to-access cells and tissues so we can better our understanding of diseases and the response of these tissues to newly developed therapeutics.”

̽��ֱ��research was supported by Wellcome, the Medical Research Council, the German Research Foundation, the British Heart Foundation, ̽��ֱ��National Institute for Health Research UK and the Qatar Foundation.

Reference
Matthias Pawlowski et al. Inducible and deterministic forward programming of human pluripotent stem cells. Stem Cell Reports; 23 Mar 2017; DOI: 10.1016/j.stemcr.2017.02.016

Adapted from a press release by the Wellcome Trust Sanger Institute.

Scientists at the ̽��ֱ�� of Cambridge and the Wellcome Trust Sanger Institute have created a new technique that simplifies the production of human brain and muscle cells - allowing millions of functional cells to be generated in just a few days. ̽��ֱ��results published today in Stem Cell Reports open the door to producing a diversity of new cell types that could not be made before in order to study disease.

This method opens the doors to producing all sorts of hard-to-access cells and tissues so we can better our understanding of diseases and the response of these tissues to newly developed therapeutics

Mark Kotter

Sanger Institute - Grow Muscle and Brain in a dish: OPTi-OX in action

Wikimedia

Oligodendrocyte

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Enhanced CRISPR lets scientists explore all steps of health and disease in every cell type

cjb250 — Tue, 29 Nov 2016 17:15:06 +0000

Two complementary methods were developed: sOPiTKO is a knock-out system that turns off genes by disrupting the DNA, while sOPTiKD is a knock-down system that silences the action of genes by disrupting the RNA. Using these two methods, scientists can turn off or silence genes in any cell type, at any stage of a cell’s development from stem cell to fully differentiated adult cell. These systems will allow researchers world-wide to rapidly and accurately explore the changing role of genes as the cells develop into tissues such as liver, skin or heart, and discover how this contributes to health and disease.

̽��ֱ��body contains approximately 37 trillion cells, yet the human genome only contains around 20,000 genes. So, to produce every tissue and cell type in the body, different combinations of genes must operate at different moments in the development of an organ or tissue. Being able to turn off genes at specific moments in a cell’s development allows their changing roles to be investigated.

Professor Ludovic Vallier, one of the senior authors of the study from the Wellcome Trust–Medical Research Council Cambridge Stem Cell Institute at the ̽��ֱ�� of Cambridge and the Sanger Institute said: “As a cell develops from being stem cell to being a fully differentiated adult cell, the genes within it take on different roles. Before, if we knocked out a gene, we could only see what effect this had at the very first step. By allowing the gene to operate during the cell’s development and then knocking it out with sOPTiKO at a later developmental step, we can investigate exactly what it is doing at that stage.”

̽��ֱ��sOPTiKO and sOPTiKD methods allow scientists to silence the activity of more than one gene at a time, so researchers are now able to investigate the role of whole families of related genes by knocking down the activity of all of them at once.

Dr Alessandro Bertero, one of the first authors of the study from the Cambridge Stem Cell Institute, said: “In the past we have been hampered by the fact we could study a gene’s function only in a specific tissue. Now you can knock out the same gene in parallel in a diversity of cell types with different functions.”

In addition, the freely available system allows experiments to be carried out far more rapidly and cheaply. sOPTiKO is highly flexible so that it can be used in every tissue in the body without needing to create a new system each time. sOPiTKD allows vast improvements in efficiency: it can be used to knock down more than one gene at a time. Before, to silence the activity of three genes, researchers had to knock down one gene, grow the cell line, and repeat for the next gene, and again for the next. Now it can do it all in one step, cutting a nine-month process down to just one to two months.

Reference
Bertero A et al. (2016) Optimized inducible shRNA and CRISPR/Cas9 platforms for in vitro studies of human development using hPSCs. Development 143: 4405-4418. doi:10.1242/dev.138081

Adapted from a press release by the Wellcome Trust Sanger Institute.

Researchers from the Wellcome Trust Sanger Institute and the ̽��ֱ�� of Cambridge have created sOPTiKO, a more efficient and enhanced inducible CRISPR genome editing platform. Today, in the journal Development, they describe how the freely available single-step system works in every cell in the body and at every stage of development. This new approach will aid researchers in developmental biology, tissue regeneration and cancer.

In the past we have been hampered by the fact we could study a gene’s function only in a specific tissue. Now you can knock out the same gene in parallel in a diversity of cell types with different functions

Alessandro Bertero

Rob Walker

Light Switch (cropped)

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