Monday, 24 October 2011

Cambridge Stem Cells United

Cohesion, collaboration and clinical impact are the watchwords of a new phase of stem cell research in Cambridge, UK
Monday, 24 October 2011

Few areas of research have been surrounded by such hope – and such hype – as stem cell biology. With their unique capacity to renew themselves and to give rise to the body’s many different cell types, stem cells have the potential to repair tissues damaged by disease or trauma: from a failing heart to lost nerve cells.
Rosettes of human, patient-specific
neural stem cells. Credit: Rick Livesey
and Yichen Shi.
But the route from the laboratory to the clinic is a long one. Before patients can be treated, many years of fundamental research and clinical testing have to take place.

“Rushing into the clinic without basic understanding may create some headlines but no real benefit for patients,” said Professor Austin Smith, Director of Cambridge’s Wellcome Trust (WT) Centre for Stem Cell Research.

“Cambridge is one of the few places in the world that has a critical mass in both basic stem cell science and medical translation.”

Since 2007, the University has invested over £38 million in laboratories and posts, and has prioritised stem cell biology as a Strategic Research Initiative. There are now 26 stem cell laboratories across the University, which have attracted some £95 million in funding. Many of the researchers are hosted by the WT Centre and the University’s Medical Research Council (MRC) Laboratory for Regenerative Medicine (established by Professor Roger Pedersen), which focus on fundamental and translational stem cell research, respectively.

Now, a major effort is under way to draw together stem cell research across the University into a new Stem Cell Institute (SCI). The SCI currently spans several sites but the intention is to bring all these groups together ultimately in a major new research institute on the Cambridge Biomedical Campus. Unification will create the ideal stage for the translation of fundamental research into clinical benefits – research such as the long-running programme led by Professor Robin Franklin in the Department of Veterinary Medicine, whose work on multiple sclerosis is about to move into clinical trials (see below).

“Collaboration has always happened in Cambridge,” explained Professor Smith, “but pulling people together will capitalise fully on the rich opportunities. SCI will provide a unified organisation and a strategic direction for stem cell research that starts from basic science but sets clinical delivery and interaction with bio industry firmly in its sights.”

A key component will be interdisciplinary research teams that link stem cell biology with molecular disease mechanisms through to clinical applications.

Alongside Professor Smith in spearheading the reshaping will be the newly established Chair of Stem Cell Medicine, to which Professor Oliver Brüstle has been elected. Professor Brüstle is currently Director of the Institute of Reconstructive Neurobiology at the University Of Bonn, Germany, and an expert in stem cells of the nervous system and their application in neurodegenerative disease.

Professor Brüstle – who notably fought for legalisation of research on human embryonic stem (ES) cells in Germany and finally became the first scientist to obtain a respective license – regards stem cell therapies as “just another way to treat disease”. He is at pains to emphasise that cell transplantation is not the only way that stem cells can bring clinical benefit.

“In fact, a much closer prospect is the use of stem cells to study specific diseases in the laboratory and to develop new drugs.”

Another important opportunity is the possibility of improving cancer treatment by identifying and targeting tumour stem cells.

“Of course there are challenges to overcome before stem-cell-based medicine is commonplace,” added Professor Brüstle.

“For example, we need to learn more about how human ES cells differ from mouse ES cells, and how their fate is controlled.”

In fact, a major discovery about the differences between human and mouse ES cells was made in Cambridge. Professor Pedersen and Dr Ludovic Vallier and colleagues showed that human ES cells represent a developmentally more mature stage than naive mouse ES cells. This can explain why some procedures for producing specific cell types from mouse ES cells do not work well with human cells.

“Human ES cells are less versatile. This research has changed the way stem cell researchers think about human ES cells,” explained Professor Smith.

The goal now is to understand this difference at a molecular level. Professor Azim Surani at the WT/Cancer Research UK Gurdon Institute in Cambridge has pioneered a deep-sequencing technique to do precisely this. His team can now analyse the entire transcriptome (all the gene products) in a single stem cell, opening the door not only to understanding the specific nature of human ES cells but perhaps also to how to make them more like mouse cells.

Professor Smith foresees a time when stem cells will permeate all areas of biology.

“Stem cells are going to be instrumental in taking us to the next level of understanding about how cells make decisions about their fate. Increasingly, we’ll see them being used in laboratories as systems to look at basic biological questions that may have nothing directly to do with stem cell biology. Stem cells will soon become the research tool of choice in mammalian cell biology.”

Self-service brain repair in multiple sclerosis (MS)
Researchers led by Professor Robin Franklin at the MS Society Cambridge Centre for Myelin Repair recently discovered a molecule that is capable of activating the brain’s own stem cells to repair damage caused by MS. Now, preparations have begun for a small-scale trial to test whether this process can regenerate lost nerve function, for which there is currently no treatment available.

Nerve fibres are progressively damaged in MS because they lose a protective coating of myelin when the cells that make it (the oligodendrocytes) are destroyed by the body’s immune system. The aim of the new treatment will be to stimulate stem cells that occur naturally in the brain and which have the ability to regenerate lost oligodendrocytes.

In the course of over two decades of research, Professor Franklin and colleagues have found that one of the major problems in MS is that the patient’s stem cells lose the ability to become normal oligodendrocytes. When oligodendrocytes are destroyed during the MS disease process, they are not replenished from the brain’s pool of stem cells. But the ability can be regained when the patient’s stem cells are activated through the retinoid acid receptor RXR-γ, as shown in collaboration with colleagues in Edinburgh using animal models and published in Nature Neuroscience in January 2011.

The discovery was a landmark moment in the search for treatments for MS, as Professor Franklin explained.

“If we can encourage the patient’s own stem cells to develop into oligodendrocytes and replace the lost myelin, then this might restore the nerve functions lost in MS.”

The idea behind the proposed treatment is not only to repair the damage but also to arrest any further damage caused by the patient’s immune system. An effective treatment for halting the destruction of oligodendrocytes, alemtuzumab (Campath), was developed in Cambridge by Professor Alastair Compston and Dr Alasdair Coles at the Department of Clinical Neuroscience.

The prospective new trial, which is currently being designed by Dr Coles together with colleagues at University College London and the University of Edinburgh, and is not yet recruiting patients, plans to use a licensed drug, bexarotene, which activates RXR-γ.

Professor Franklin added: “Essentially, the philosophy of our approach is not to transplant stem cells from elsewhere but to encourage the patient’s own stem cells to do the work of repairing the damaged tissue.”


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Monday, 10 October 2011

Seeking Superior Stem Cells: New Technique Reprograms Human Cells into Stem Cells

100-fold increase in efficiency in reprogramming human cells to induced stem cells
Monday, 10 October 2011

Researchers from the Wellcome Trust Sanger Institute have today announced a new technique to reprogram human cells, such as skin cells, into stem cells. Their process increases the efficiency of cell reprogramming by one hundred-fold and generates cells of a higher quality at a faster rate.

Until now cells have been reprogrammed using four specific regulatory proteins. By adding two further regulatory factors, Liu and co-workers brought about a dramatic improvement in the efficiency of reprogramming and the robustness of stem cell development. The new streamlined process produces cells that can grow more easily.

"This research is a milestone in human stem cells," explains Wei Wang, first author on the research from the Wellcome Trust Sanger Institute.

"Our technique provides a foundation to unlock the full potential of stem cells."

Stem cells are unspecialized cells that are able to renew themselves through cell division and can be induced to become functional tissue- or organ-specific cells. It is hoped that stem cells will be used to replace dying or damaged cells with healthy, functional cells. This could have wide-ranging uses in medicine such as organ replacement, bone replacement and treatment of neurodegenerative diseases.

With more than 20 years of research, gold standard stem cells are derived from mice, largely because they are easy to work with and provide accurate and reproducible results. The team's aim was to develop human cells of equivalent quality to mouse stem cells.

"The reprogrammed cells developed by our team have proved to have the same capabilities as mouse stem cells," states Pentao Liu, senior author from the Sanger Institute.

"Our approach will enable researchers to easily engineer and reprogram human stem cells to generate cell types for cell replacement therapies in humans."

Retinoic acid receptor gamma (RAR-γ) and liver receptor homolog (Lrh-1), the additional regulatory factors used by Liu and co-workers, were introduced into the skin cells along with the four other regulatory proteins. The team's technology produced reprogrammed cells after just four days, compared to the seven days required for the four-protein approach. Key indicators of successfully reprogrammed cells, Oct4 and Rex-1 genes, were seen to be switched on much faster in a much higher number of cells, demonstrating increased efficiency in reprogramming.

"This is the most promising and exciting development in our attempt to develop human stem cells that lend themselves in practical applications. It bears comparison to other technologies as it is simple, robust and reliable," says Allan Bradley, Senior Group Leader and Director of Emeritus at Sanger Institute.

Contact: Don Powell, Media Manager

For more on stem cells and cloning, go to CellNEWS at

Friday, 7 October 2011

Expression of Pluripotency-associated Gene Marks Many Types of Adult Stem Cells

Mass. General/Harvard study shows Sox2 expression is a widespread marker of adult stem cells
Friday, 07 October 2011

Investigators at the Massachusetts General Hospital (MGH) Center for Regenerative Medicine and the Harvard Stem Cell Institute (HSCI) have found that Sox2 – one of the transcription factors used in the conversion of adult stem cells into induced pluripotent stem cells (iPSCs) – is expressed in many adult tissues where it had not been previously observed. They also confirmed that Sox2-expressing cells found in the stomach, testes, cervix and other structures are true adult stem cells that can give rise to all mature cell types in those tissues. The study appears in the October issue of Cell Stem Cell.

"We have known that Sox2 is essential for maintaining pluripotency in embryonic stem cells and neural stem cells and, with three other embryonic genes, is sufficient to convert adult cells into iPSCs," says Konrad Hochedlinger, PhD, of the MGH Center for Regenerative Medicine and HSCI, who led the study.

"Our study shows that Sox2 is a much more widespread marker of adult stem cells and suggests these cells may share common genetic programs to maintain stem cell fate, findings that could be exploited to amplify or modify these cells for applications in regenerative medicine."

Hochedlinger's team set out to investigate whether genes known to be important to pluripotent stem cells – cells that can give rise to several different types of tissue – also play a role in adult stem cells, which maintain populations of particular types of tissue. Sox2 is one of four embryonic genes that are required to be expressed for the generation of iPSCs – which have many of the characteristics of embryonic stem cells – but the other three genes are not expressed in adult stem cells. Sox2 is known to be expressed at the very earliest stages of embryonic development and to play a role in development of several types of fetal tissue. But prior to this study, its expression had been observed in only a few types of adult tissues.

In a series of experiments with mice, the researchers first showed that Sox2 continues to be expressed in specific populations of adult cells of the stomach, esophagus, testes, cervix, anus and the lens of the eye. These Sox2-expressing cells were proven to be able both to replenish their population and to give rise to the fully differentiated cells found within the particular tissue, confirming their status as adult stem cells.

Additional findings revealed that fetal tissues expressing Sox2, which are at a stage before the appearance of true stem cells, will develop into tissues that include Sox2-expressing adult stem cells and that Sox2 appears to be the only transcription factor expressed in stem cells at all stages of development – embryonic, fetal and adult. However, Sox2 expression has never been found in muscle or connective tissue, blood cells, or in organs such as the heart or kidney, indicating that other factors must play a similar role in those tissues.

"Adult stem cells are difficult to isolate and manipulate, so the fact that Sox2 appears to be a marker for many adult stem cells may allow researchers to isolate them more easily and study them in more detail," Hochedlinger explains.

"Manipulation of Sox2 expression could help us push embryonic stem cells into particular types of adult stem cells and, when combined with certain growth factors, induce differentiation into desired types of tissue. All of these possibilities need to be investigated."

Hochedlinger is an associate professor of Medicine at Harvard Medical School and a Howard Hughes Medical Institute Early Career Scientist.

Contact: Sue McGreevey

Sox2+ Adult Stem and Progenitor Cells Are Important for Tissue Regeneration and Survival of Mice
Katrin Arnold, Abby Sarkar, Mary Anna Yram, Jose M. Polo, Rod Bronson, Sumitra Sengupta, Marco Seandel, Niels Geijsen, Konrad Hochedlinger
Cell Stem Cell, Volume 9, Issue 4, 317-329, 4 October 2011, 10.1016/j.stem.2011.09.001


For more on stem cells and cloning, go to CellNEWS at

Stem Cell Reprogramming Technique is Safer than Previously Thought

Stem Cell Reprogramming Technique is Safer than Previously Thought
Friday, 07 October 2011

Stem cells made by reprogramming patients' own cells might one day be used as therapies for a host of diseases, but scientists have feared that dangerous mutations within these cells might be caused by current reprogramming techniques. A sophisticated new analysis of stem cells' DNA finds that such fears may be unwarranted.

Kristin Baldwin, Ph.D., is an associate
professor in the Scripps Research
Institute's Dorris Neuroscience
Center. Credit: photo courtesy of
The Scripps Research Institute.
"We've shown that the standard reprogramming method can generate induced pluripotent stem cells that have very few DNA structural mutations, which are often linked to dangerous cell changes such as tumorigenesis," said Kristin Baldwin, associate professor at The Scripps Research Institute's Dorris Neuroscience Center and a senior author of the report, which appears in the October 7, 2011 issue of the journal Cell Stem Cell. For this study the Baldwin lab collaborated with a genomics and bioinformatics expert, Ira M. Hall, an assistant professor of biochemistry and molecular genetics at the University of Virginia who is co-senior author.

The induced pluripotent stem cell (iPSC) technique was first described in 2006. It requires the insertion into an ordinary non-stem cell of four special genes, whose activities cause the cell to revert to a state like that of embryonic stem cell. In principle, iPSCs may be used to repair diseased or damaged tissues, and because they are made from a patient's own cells, they shouldn't provoke an immune reaction. But recent studies have found unacceptably high levels of mutations in iPSCs derived from adult human cells. That has led to widespread suspicion that the reprogramming process is largely to blame.

In the new study, the Scripps Research and University of Virginia researchers set out to investigate this issue using the latest chromosomal error-mapping methods.

"The techniques that our University of Virginia colleagues brought to this study are much more sensitive than anything else that's available right now," said Michael J. Boland, a research associate in the Scripps Research Baldwin lab and co-first author of the paper with Aaron R. Quinlan, a postdoctoral researcher in Hall's lab. The new methods included a high-resolution version of a DNA-error-finding technique known as paired-end mapping, and an advanced algorithm, "HYDRA," for handling the voluminous mapping data.

To generate the iPSCs, the Scripps Research team followed the standard, four-gene reprogramming procedure, but sought to minimize other potential sources of DNA mutations that might have influenced some previously reported results. The donor cells they selected were not decades-old human skin cells, but relatively error-free fibroblast cells from fetal mice. The researchers also kept these fibroblast cells only briefly in lab dishes before reprogramming them.

When the team members analyzed these iPSCs they used two strategies to distinguish which mutations were present in rare donor fibroblast cells and which were newly acquired during reprogramming. Their advanced techniques also allowed them to find more kinds of mutations, across a wider range of the genome, than ever before. Yet instead of finding more mutations, they found almost none.

"We sequenced three iPSC lines at very high resolution, and were surprised to find that very few changes to the chromosomal sequence had appeared during reprogramming," said Boland.

Each of the iPSC lines contained only a single mutation that probably originated from the reprogramming process; two affected genes while the other appeared not to. Mutations inherited from the donor fibroblast cell were present in one pair of lines, while a second line "inherited" none. The researchers were particularly cheered by the complete absence of new "retro-element transpositions" — mutations caused by retrovirus-like sequences that burrowed into the mammalian genome long ago that can become active again in certain cell types. All cells have ways to suppress these retro-elements, but the suppression mechanisms in normal cells are different from those in stem cells, so the researchers had worried that retro-elements would be allowed to escape suppression during the transition to a stem cell state. While no previous surveys of iPSCs could detect these mutations, this study showed that despite very sensitive detection of controls, no retro-elements had become active during reprogramming.

"That was is very encouraging, because retro-element mutations can be very damaging to the genome," Boland said.

Some of the mutations seen in human iPSCs in previous studies might have been due to incomplete reprogramming that impaired the cells' DNA-maintenance mechanisms. In this study using mouse iPSCs, however, there was no doubt that a complete reprogramming to an embryonic state had occurred: all three iPSC lines were used to produce live, fertile mice, in work that Boland, Baldwin, and their colleagues described in Nature in 2009.

"The mice generated from these cells have survived to a normal lab-mouse lifespan without obvious diseases that might arise from new DNA mutations," said Baldwin.

Her lab now is trying to determine whether a reprogramming method similar to the one used with mouse iPSCs in this study could also yield relatively error-free human iPSCs.

"If our results with these mouse cells are applicable to human cells, then selecting better donor cells and using more sensitive genome-survey techniques should allow us to identify reprogramming methods that can produce human iPSCs that will be safer or more useful for therapies than current lines," she said.

Contact: Mika Ono

Genome Sequencing of Mouse Induced Pluripotent Stem Cells Reveals Retroelement Stability and Infrequent DNA Rearrangement during Reprogramming
Aaron R. Quinlan, Michael J. Boland, Mitchell L. Leibowitz, Svetlana Shumilina, Sidney M. Pehrson, Kristin K. Baldwin, Ira M. Hall
Cell Stem Cell, Volume 9, Issue 4, 366-373, 4 October 2011, 10.1016/j.stem.2011.07.018

For more on stem cells and cloning, go to CellNEWS at

Wednesday, 5 October 2011

Cloning: Human Oocytes Reprogram Somatic Cells to a Pluripotent State

A technique called somatic-cell nuclear transfer (cloning) has been applied to human oocytes, resulting in the generation of personalized stem cells, albeit genetically abnormal ones. Wednesday, 05 October 2011

A team of scientists led by Dieter Egli and Scott Noggle at The New York Stem Cell Foundation (NYSCF) Laboratory in New York City have made an important advance in the development of patient-specific stem cells that could impact the study and treatment of diseases such as diabetes, Parkinson’s, and Alzheimer’s. As reported in today’s Nature, for the first time the scientists have derived embryonic stem cells from individual patients by adding the nuclei of adult skin cells from patients with type-1 diabetes to unfertilized donor oocytes. However, this technique creates triploid human pluripotent stem-cell lines.

The achievement is significant because such patient-specific cells potentially can be transplanted to replace damaged or diseased cells in persons with diabetes and other diseases without rejection by the patient’s immune system. The scientists report further work is necessary before such cells can be used in cell-replacement medicine.

The research was conducted in The NYSCF Laboratory in Manhattan in collaboration with clinicians and researchers at Columbia University Medical Center. DNA analysis was provided by scientists at the University of California, San Diego.

“The specialized cells of the adult human body have an insufficient ability to regenerate missing or damaged cells caused by many diseases and injuries,” said Dr. Egli, NYSCF senior scientist in the study.

“But if we can reprogram cells to a pluripotent state, they can give rise to the very cell types affected by disease, providing great potential to effectively treat and even cure these diseases. In this three-year study, we successfully reprogrammed skin cells to the pluripotent state. Our hope is that we can eventually overcome the remaining hurdles and use patient-specific stem cells to treat and cure people who have diabetes and other diseases.”

“The ultimate goal of this study is to save and enhance lives by finding better treatments and eventually cures for diabetes, Alzheimer’s, Parkinson’s and other debilitating diseases and injuries affecting millions of people across the US and the globe,” said NYSCF CEO Susan L. Solomon.

“This research brings us an important step closer to creating new healthy cells for patients to replace their cells that are damaged or lost through injury.”

The scientists demonstrate for the first time that the transfer of the nucleus from an adult skin cell of a patient into an oocyte without removing the oocyte nucleus results in reprogramming of the adult nucleus to the pluripotent state. Embryonic stem cell lines were then derived from the oocyte containing the patient’s genetic material.

Since these pluripotent stem cells also have a copy of the chromosome from the oocyte, resulting in an abnormal number of chromosomes, these cells are not ready for therapeutic use. Future work will focus on understanding the role of the oocyte chromosome so that patient specific stem cells can be made that contain only the patient’s DNA.

In the study, skin cells from patients with type-1 diabetes and healthy patients (control group) were reprogrammed, allowing the derivation of pluripotent stem cells, cells that have the capacity for universal tissue production. Such cells potentially could be used to create beta cells that produce insulin.

Patients with type 1 diabetes lack insulin-producing beta cells, resulting in insulin deficiency and high blood sugar levels. Producing beta cells from stem cells for transplantation holds promise for the treatment and potential cure of type-1 diabetes.

“This is an important step toward generating stem cells for disease modeling and drug discovery, as well as for ultimately creating patient-specific cell-replacement therapies for people with diabetes or other degenerative diseases or injuries,” said Rudolph L. Leibel, MD, co-director of Columbia’s Naomi Berrie Diabetes Center and a collaborator in the study.

The study raises the possibility of using somatic cell reprogramming to create banks of stem cells that could be used for a wide range of patients, noted another collaborator, Robin Goland, MD, co-director of the Naomi Berrie Diabetes Center.

“In theory, stem cell lines could be matched to a particular patient, much as we do now when we screen an individual for compatibility with a kidney transplant,” she said.

“This project is a great example of how enormous strides can be achieved when investigators in basic science and clinical medicine collaborate,” said Mark V. Sauer, MD, a coauthor of the paper and Vice Chairman of the Department of Obstetrics and Gynecology and chief of reproductive endocrinology at Columbia University Medical Center. Dr. Sauer is also program director of assisted reproduction at the Center for Women’s Reproductive Care.

“I feel fortunate to have been able to participate in this important project.”

Zach W. Hall, PhD, former Director of the NIH’s National Institute of Neurological Disorders and Stroke and former President of the California Institute for Regenerative Medicine said:

“This work represents a major advance toward the production of patient-specific stem cells for therapeutic use by demonstrating that the nucleated oocyte has the ability to completely reprogram the nucleus of an adult human cell.”

The study was funded solely with private funding and adhered to ethical guidelines adopted by the American Society for Reproductive Medicine and the International Society for Stem Cell Research, as well as protocols reviewed and approved by the institutional review board and stem cell committees of Columbia University.

The New York Stem Cell Foundation (NYSCF) conducts advanced stem cell research in its own laboratory and supports research by stem cell scientists at other institutions around the world. More information is available at

Columbia University Medical Center (CUMC) provides international leadership in basic, pre-clinical and clinical research, in medical and health sciences education, and in patient care. More information is available at

Contact: Diane Mathis Marr

Human oocytes reprogram somatic cells to a pluripotent state
Scott Noggle, Ho-Lim Fung, Athurva Gore, Hector Martinez, Kathleen Crumm Satriani, Robert Prosser, Kiboong Oum, Daniel Paull, Sarah Druckenmiller, Matthew Freeby, Ellen Greenberg, Kun Zhang, Robin Goland, Mark V. Sauer, Rudolph L. Leibel & Dieter Egli
Nature 478, 70–75 (06 October 2011), doi:10.1038/nature10397


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