̽��ֱ�� of Cambridge - Roger Pedersen

Stem cells likely to be safe for use in regenerative medicine, study confirms

cjb250 — Fri, 18 Dec 2015 10:59:29 +0000

Human pluripotent stem cells for use in regenerative medicine or biomedical research come from two sources: embryonic stem cells, derived from fertilised egg cells discarded from IVF procedures; and induced pluripotent stem cells, where skin cells are ‘reset’ to their original, pluripotent form. They are seen as having promising therapeutic uses in regenerative medicine to treat devastating conditions that affect various organs and tissues, particularly those that have poor regenerative capacity, such as the heart, brain and pancreas.

However, some scientists have been concerned that the cells may not incorporate properly into the body and hence not proliferate or distribute themselves as intended, resulting in tumours. Today’s study suggests that this will not be the case and that stem cells, when transplanted appropriately, are likely to be safe for use in regenerative medicine.

Professor Roger Pedersen from the Anne McLaren Laboratory for Regenerative Medicine at the ̽��ֱ�� of Cambridge, commenting on co-author Victoria Mascetti’s research findings, says: “Our study provides strong evidence to suggest that human stem cells will develop in a normal – and importantly, safe – way. This could be the news that the field of regenerative medicine has been waiting for.”

̽��ֱ��best way to test how well stem cells would incorporate into the body is to transplant them into an early-stage embryo and see how they develop. As this cannot be done ethically in humans, scientists use mouse embryos. ̽��ֱ��gold standard test, developed in Cambridge in the 1980s, involves putting the stem cells into a mouse blastocyst, a very early stage embryo after fertilisation, then assessing stem cell contribution to the various tissues of the body.

Previous research has not succeeded in getting human pluripotent stem cells to incorporate into embryos. However, in research funded by the British Heart Foundation, Victoria Mascetti and Professor Pedersen have shown that it is possible to successfully transplant human pluripotent stem cells into the mouse embryo and that they then develop and grow normally.

Image: Mouse embryo with human pluripotent stem cells (red) incorporated into the brain region

“Stem cells hold great promise for treating serious conditions such as heart disease and Parkinson’s disease, but until now there has been a big question mark over how safe and effective they will be,” explains Professor Pedersen.

Mascetti’s research breakthrough in this new study was to demonstrate that human pluripotent stem cells are equivalent to an embryonic counterpart. Where attempts to incorporate human pluripotent stem cells had failed previously, it was because the stem cells had not been matched to the correct stage of embryo development: the cells needed to be transplanted into the mouse embryo at a later stage than was previously thought (a stage of embryo development known as gastrulation). Once transplanted at the correct stage, the stem cells went on to grow and proliferate normally, to integrate into the embryo and to distribute themselves correctly across relevant tissues.

Ms Mascetti adds: “Our finding that human stem cells integrate and develop normally in the mouse embryo will allow us to study aspects of human development during a window in time that would otherwise be inaccessible.”

Professor Jeremy Pearson, Associate Medical Director at the British Heart Foundation, which helped fund the study, said: “These results substantially strengthen the view that induced pluripotent stem cells from adult tissue are suitable for use in regenerative medicine – for example in attempts to repair damaged heart muscle after a heart attack.

“ ̽��ֱ��Cambridge team has shown definitively that when stem cells are introduced into early mouse embryos under the right conditions, they multiply and contribute in the correct way to all the cell types that are formed as the embryo develops.”

Reference
Victoria L Mascetti and Roger A Pedersen. Human-Mouse Chimerism Validates Human Stem Cell Pluripotency. Cell Stem Cell; 17 Dec 2015

Cambridge researchers have found the strongest evidence to date that human pluripotent stem cells – cells that can give rise to all tissues of the body – will develop normally once transplanted into an embryo. ̽��ֱ��findings, published today in the journal Cell Stem Cell, could have important implications for regenerative medicine.

Our study provides strong evidence to suggest that human stem cells will develop in a normal – and importantly, safe – way. This could be the news that the field of regenerative medicine has been waiting for

Roger Pedersen

Roger Pederson/Victoria Mascetti

Mouse embryo yolk sac with human pluripotent stem cells (green) incorporated

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

Yes

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

̽��ֱ��text in this work is licensed under a Creative Commons Licence. If you use this content on your site please link back to this page. For image rights, please see the credits associated with each individual image.

Yes

̽��ֱ��role of stem cells in developing new drugs

Anonymous — Tue, 30 Oct 2012 13:00:42 +0000

̽��ֱ��potential therapeutic applications of stem cells – such as regenerating damaged tissues or organs – have generated a great deal of interest over the past decade. While these types of applications are exciting, it is a long journey from lab to clinic. ̽��ֱ��most immediate impact of stem cells on human health will most likely come from their use in the development of new drugs.

̽��ֱ��ability to generate stem cells by reprogramming cells from patients’ skin has revolutionised human stem cell research. These cells, known as human induced pluripotent stem cells (hIPSC), can be differentiated into almost any cell type, allowing the opportunity to have a ready source of human cells for testing new therapies.

DefiniGEN, a new spin-out company from the ̽��ֱ�� of Cambridge, has been formed to supply hIPSC-derived cells to the drug discovery and regenerative medicine sectors. ̽��ֱ��company is based on the research of Dr Ludovic Vallier, Dr Tamir Rashid and Professor Roger Pedersen of the Anne McLaren Laboratory of Regenerative Medicine.

Dr Vallier led a team, including Dr Rashid, Dr Nick Hannan and Candy Cho, that developed the technology to generate human liver cells (hepatocytes) in a highly reproducible and scalable manner for commercial use. This represents a major breakthrough in the costly and time-consuming process of developing new therapies. ̽��ֱ��technology has also been used to effectively model a diverse range of inherited liver diseases and has the potential to accelerate the development of new therapies for these conditions.

̽��ֱ��liver is the key organ for metabolising drugs and removing toxins from the body. Consequently, it is often affected by toxic compounds. Demonstrating that a new drug candidate is free from liver toxicity is a key test in the development process, and it is a test that most drug candidates fail.

“If a drug’s failure occurs in the clinical phase of development, a great deal of time and money will have been lost,” said Dr Vallier. “Therefore, identifying toxic drugs as early as possible is vital to the safety and efficiency of the drug discovery process.”

Currently, either primary human hepatocytes or immortalised cell lines are used for toxicity testing. Primary hepatocytes have a high degree of batch-to-batch variation, are expensive and difficult to obtain in suitable quantities, while immortalised cell lines are an inferior model for toxicity testing.

̽��ֱ��hIPSC-derived cells produced by DefiniGEN, however, show many of the functional characteristics of primary cells, are highly reproducible and can be made in large quantities, making them ideal for toxicity testing.

In addition, the company’s OptiDIFF platform has produced libraries of disease-modelled cells for a range of diseases, including the most common inherited metabolic conditions such as Familial hypercholesterolemia and Alpha 1 anti-trypsin disorder. ̽��ֱ��cells effectively demonstrate key pathologies of diseases and can be used to improve lead optimisation studies, assisting the development of new therapies for these conditions.

̽��ֱ��company will also develop pancreatic beta cell products which, in combination with hepatocyte products, will enable the optimised development of new therapeutics for diabetes.

“This is a technology whose time has come,” said Dr Marcus Yeo, DefiniGEN’s CEO. “Cambridge has more expertise in the area of stem cells than perhaps anywhere else on earth, and now we are starting to see promising commercial opportunities which build on that expertise.”

DefiniGEN is based in Cambridge, and has been funded by a group led by Cambridge Enterprise, the ̽��ֱ��’s commercialisation arm, along with members of Cambridge Angels and Cambridge Capital Group.

Cambridge team which developed method to generate liver cells from skin cells has formed a new company to supply stem cell products to the drug discovery and regenerative medicine sectors.

Cambridge has more expertise in the area of stem cells than perhaps anywhere else on earth, and now we are starting to see promising commercial opportunities which build on that expertise.

Dr Marcus Yeo

Ludovic Vallier

Differentiation of human Induced Pluripotent Stem Cells (hIPSC) to functional liver hepatocyte cells

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

Yes