Stem cell advance made by Cambridge scientists

By adminSeptember 13, 2014Stem Cell Medicine

Cambridge scientists have successfully reset human pluripotent stem cells to the earliest developmental state equivalent to cells found in an 7-9 day old embryo before it implants in the womb.

The researchers believe that these pristine stem cells, which have until now been impossible to replicate in the lab, could mark the true starting point for human development.

It is hoped that the discovery, published in Cell, will lead to a better understanding of human development and could in future allow the production of safe and more reproducible starting materials for a wide range of applications including cell therapies.

Researchers led by the Wellcome Trust-Medical Research Council (MRC) Cambridge Stem Cell Institute at the University of Cambridge, have managed to induce a ground state by rewiring the genetic circuitry in human embryonic and induced pluripotent stem cells. Their reset cells share many of the characteristics of authentic nave embryonic stem cells isolated from mice, suggesting that they represent the earliest stage of development.

Human pluripotent stem cells, which have the potential to become any of the cells and tissues in the body, can be made in the lab either from cells extracted from a very early stage embryo or from adult cells that have been induced into a pluripotent state.

To date, scientists have struggled to generate human pluripotent stem cells that are truly pristine researchers have only been able to derive cells which have advanced slightly further down the developmental pathway. These bear some of the early hallmarks of differentiation into distinct cell types theyre not a truly blank slate. This may explain why existing human pluripotent stem cell lines often exhibit a bias towards producing certain tissue types in the laboratory.

Capturing embryonic stem cells is like stopping the developmental clock at the precise moment before they begin to turn into distinct cells and tissues, explains Professor Austin Smith, Director of the Stem Cell Institute, who co-authored the paper.

Scientists have perfected a reliable way of doing this with mouse cells, but human cells have proved more difficult to arrest and show subtle differences between the individual cells. Its as if the developmental clock has not stopped at the same time and some cells are a few minutes ahead of others.

The process of generating stem cells in the lab is easier to control in mouse cells, which can be frozen in a state of nave pluripotency using a protein called LIF. Human cells are not as responsive to LIF, so they must be controlled in a different way that involves switching key genes on and off. For this reason scientists have been unable to generate human pluripotent cells that are as primitive or as consistent as mouse embryonic stem cells.

The researchers overcame this problem by introducing two genes NANOG and KLF2 causing the network of genes that control the cell to reboot and induce the nave pluripotent state. Importantly, the introduced genes only need to be present for a short time. Then, like other stem cells, reset cells can self-renew indefinitely to produce large numbers, are stable and can differentiate into other cell types, including nerve and heart cells.

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Stem cell advance made by Cambridge scientists

Stem cells help researchers understand how schizophrenic brains function

By adminSeptember 12, 2014Stem Cell Medicine

PUBLIC RELEASE DATE:

11-Sep-2014

Contact: Mary Beth O'Leary moleary@cell.com 617-397-2802 Cell Press @CellPressNews

Using human induced pluripotent stem cells (hiPSCs), researchers have gained new insight into what may cause schizophrenia by revealing the altered patterns of neuronal signaling associated with this disease. They did so by exposing neurons derived from the hiPSCs of healthy individuals and of patients with schizophrenia to potassium chloride, which triggered these stem cells to release neurotransmitters, such as dopamine, that are crucial for brain function and are linked to various disorders. By discovering a simple method for stimulating hiPSCs to release neurotransmitters, the findings in the International Society for Stem Cell Research's journal Stem Cell Reports, published by Cell Press, could provide new insights into how neurons communicate with each other and could lead to a better understanding of the neural mechanisms underlying a range of brain disorders.

"This study is novel because it shows that stem cell neurons derived from patients can provide new insight into neurotransmitter mechanisms occurring in brain disorders such as schizophrenia," says senior study author Vivian Hook of the University of California, San Diego. "The approach of this study has broad opportunities for uncovering the neurochemistry of brain cell communication in numerous brain disorders, via these studies of human disease in a dish. Findings from these studies will lead to new therapeutic strategies for brain disorders, especially those mental and neurological diseases for which no drug treatments exist today."

hiPSCS are cells that are taken from adults, genetically reprogrammed to an embryonic stem cell-like state, and then converted into specialized cells such as neurons. Patient-derived hiPSCs offer the possibility of modeling an individual's disease in a dish and assessing which drugs will most effectively treat the disease. Because dysfunction in neural communication is linked to brain disorders such as schizophrenia, Hook and Fred Gage of The Salk Institute and Kristen Brennand of the Icahn School of Medicine at Mount Sinai set out to determine whether hiPSC-derived neurons can be induced to release important brain signaling chemicals, allowing disease mechanisms to be studied in a dish.

To address this question, the researchers exposed hiPSC-derived neurons from healthy individuals and patients with schizophrenia to a chemical known to stimulate the release of neurotransmitters. They found that these cells contained neurotransmitter-producing enzymes and were capable of secreting dopamine, norepinephrine, and epinephrineneurotransmitters that are crucial for brain function and that are linked to various disorders. Moreover, secretion of the three neurotransmitters was enhanced in hiPSC-derived neurons from schizophrenia patients compared with those from healthy individuals.

"The significance of this study is that patient-derived stem cell neurons can uncover previously unknown neurotransmitter brain mechanisms occurring in schizophrenia," Hook says. "Because in vivo human brain research is limited, hiPSC neurons derived from patients create new opportunities to understand changes occurring in brain cells occurring in nervous system disorders. These approaches can potentially define new drug targets for the development of therapeutic agents to improve the lives of schizophrenia patients."

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Stem Cell Reports, Hook et al.: "Human iPSC Neurons Display Activity-Dependent Neurotransmitter Secretion: Aberrant Catecholamine Levels in Schizophrenia Neurons."

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Stem cells help researchers understand how schizophrenic brains function

In directing stem cells, study shows context matters

By adminSeptember 9, 2014Stem Cell Medicine

20 hours ago by Terry Devitt When blank slate stem cells are exposed to a soft as opposed to a hard surface on which to grow, they begin to transform themselves into neurons, the large, complex cells of the central nervous system. Absent any soluble factors to direct cell differentiation, surface matters, according to new research from the lab of University of Wisconsin-Madison chemist and biochemist Laura Kiessling. Credit: Kiessling Lab/UW-Madison

Figuring out how blank slate stem cells decide which kind of cell they want to be when they grow upa muscle cell, a bone cell, a neuronhas been no small task for science.

Human pluripotent stem cells, the undifferentiated cells that have the potential to become any of the 220 types of cells in the body, are influenced in the lab dish by the cocktail of chemical factors and proteins upon which they are grown and nurtured. Depending on the combination of factors used in a culture, the cells can be coaxed to become specific types of cells.

Now, in a new study published today, Sept. 8, in the Proceedings of the National Academy of Sciences, a team of researchers from the University of Wisconsin-Madison has added a new wrinkle to the cell differentiation equation, showing that the stiffness of the surfaces on which stem cells are grown can exert a profound influence on cell fate.

"To derive lineages, people use soluble growth factors to get the cells to differentiate," explains Laura Kiessling, a UW-Madison professor of chemistry and biochemistry and stem cell expert.

Past work, she notes, hinted that the qualities of the surface on which a cell lands could exert an influence on cell fate, but the idea was never fully explored in the context of human pluripotent stem cell differentiation.

In the lab, stem cells are grown in plastic dishes coated with a gel that contains as many as 1,800 different proteins. Different factors can be introduced to obtain certain types of cells. But even in the absence of introduced chemical or protein cues, the cells are always working to differentiatebut in seemingly random, undirected ways.

The Wisconsin group, directed by Kiessling and led by chemistry graduate student Samira Musah, decided to test the idea that the hardness of a surface can make a difference. After all, in a living body, cells seek different niches with different qualities and transform themselves accordingly.

"Many cell types grow on a surface. If a cell is near bone, the environment has certain features," says Kiessling, whose groupcollaborating with UW-Madison colleagues Sean Palecek, Qiang Chang and William Murphyhas been working to produce precise, chemically defined surfaces on which to grow stem cells. "A cell will react differently if it lands near soft tissue like the brain."

To fully explore the idea that surface matters to a stem cell, Kiessling's group created gels of different hardness to mimic muscle, liver and brain tissues. The study sought to test whether the surface alone, absent any added soluble factors to influence cell fate decisions, can have an effect on differentiation.

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In directing stem cells, study shows context matters

Why age reduces our stem cells' ability to repair muscle

By adminSeptember 8, 2014Stem Cell Medicine

PUBLIC RELEASE DATE:

7-Sep-2014

Contact: Paddy Moore padmoore@ohri.ca 613-737-8899 x73687 Ottawa Hospital Research Institute

Ottawa, Canada (September 7, 2014) As we age, stem cells throughout our bodies gradually lose their capacity to repair damage, even from normal wear and tear. Researchers from the Ottawa Hospital Research Institute and University of Ottawa have discovered the reason why this decline occurs in our skeletal muscle. Their findings were published online today in the influential journal Nature Medicine.

A team led by Dr. Michael Rudnicki, senior scientist at the Ottawa Hospital Research Institute and professor of medicine at the University of Ottawa, found that as muscle stem cells age, their reduced function is a result of a progressive increase in the activation of a specific signalling pathway. Such pathways transmit information to a cell from the surrounding tissue. The particular culprit identified by Dr. Rudnicki and his team is called the JAK/STAT signalling pathway.

"What's really exciting to our team is that when we used specific drugs to inhibit the JAK/STAT pathway, the muscle stem cells in old animals behaved the same as those found in young animals," said Dr. Michael Rudnicki, a world leader in muscle stem cell research. "These inhibitors increased the older animals' ability to repair injured muscle and to build new tissue."

What's happening is that our skeletal muscle stem cells are not being instructed to maintain their population. As we get older, the activity of the JAK/STAT pathway shoots up and this changes how muscle stem cells divide. To maintain a population of these stem cells, which are called satellite cells, some have to stay as stem cells when they divide. With increased activity of the JAK/STAT pathway, fewer divide to produce two satellite cells (symmetric division) and more commit to cells that eventually become muscle fibre. This reduces the population of these regenerating satellite cells, which results in a reduced capacity to repair and rebuild muscle tissue.

While this discovery is still at early stages, Dr. Rudnicki's team is exploring the therapeutic possibilities of drugs to treat muscle-wasting diseases such as muscular dystrophy. The drugs used in this study are commonly used for chemotherapy, so Dr. Rudnicki is now looking for less toxic molecules that would have the same effect.

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The full article titled "Inhibition of JAK/STAT signaling stimulates adult satellite cell function" was published online September 7, 2014, by Nature Medicine.

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Why age reduces our stem cells' ability to repair muscle

How to tell good stem cells from the bad

By adminSeptember 6, 2014Stem Cell Medicine

Sep 05, 2014 by Bill Hathaway Separating the good stem cells from the bad. Credit: Matthew Chock, NYC

The promise of embryonic stem cell research has been thwarted by an inability to answer a simple question: How do you know a good stem cell from a bad one?

Yale researchers report in the Sept. 4 issue of the journal Cell Stem Cell that they have found a marker that predicts which batch of personalized stem cells will develop into a variety of tissue types and which will develop into unusable placental or tumor-like tissues.

Scientists have been unable to capitalize on revolutionary findings in 2006 that adult cells could be made young again with the simple introduction of four factors. Hopes were raised that doctors would soon have access to unlimited supplies of a patient's own iPSCsinduced pluripotent stem cellsthat could be used to repair many types of tissue damage. However, efforts to direct these cells to therapeutic goals have proved difficult. Many attempts to use cells clinically have failed because they form tumors instead of the desired tissue.

The team of Yale Stem Cell Center researchers led by senior author Andrew Xiao identified a variant histonea protein that helps package DNAwhich can predict the developmental path of iPSC cells in mice. An accompanying paper in the same journal by researchers at the Whitehead Institute at MIT and Hebrew University in Israel also identifies at different marker that also appears to predict stem cell fate.

"The trend is to raise the standards and quality very high, so we can think about using these cells in clinic," Xiao said. "With our assay, we have a reliable molecular marker that can tell what is a good cell and what is a bad one."

Explore further: New reprogramming factor cocktail produces therapy-grade induced pluripotent stem cells

Journal reference: Cell Stem Cell

Provided by Yale University

Induced pluripotent stem cells (iPSCs)adult cells reprogrammed back to an embryonic stem cell-like statemay hold the potential to cure damaged nerves, regrow limbs and organs, and perfectly model a ...

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How to tell good stem cells from the bad

Disease in a dish approach could aid Huntington's disease discovery

By adminSeptember 6, 2014Stem Cell Medicine

PUBLIC RELEASE DATE:

5-Sep-2014

Contact: Lisa Newbern lisa.newbern@emory.edu 404-727-7709 Emory Health Sciences

Creating induced pluripotent stem cells or iPS cells allows researchers to establish "disease in a dish" models of conditions ranging from Alzheimer's disease to diabetes. Scientists at Yerkes National Primate Research Center have now applied the technology to a model of Huntington's disease (HD) in transgenic nonhuman primates, allowing them to conveniently assess the efficacy of potential therapies on neuronal cells in the laboratory.

The results were published in Stem Cell Reports.

"A highlight of our model is that our progenitor cells and neurons developed cellular features of HD such as intranuclear inclusions of mutant Huntingtin protein, which most of the currently available cell models do not present," says senior author Anthony Chan, PhD, DVM, associate professor of human genetics at Emory University School of Medicine and Yerkes National Primate Research Center. "We could use these features as a readout for therapy using drugs or a genetic manipulation."

Chan and his colleagues were the first in the world to establish a transgenic nonhuman primate model of HD. HD is an inherited neurodegenerative disorder that leads to the appearance of uncontrolled movements and cognitive impairments, usually in adulthood. It is caused by a mutation that introduces an expanded region where one amino acid (glutamine) is repeated dozens of times in the huntingtin protein.

The non-human primate model has extra copies of the huntingtin gene that contains the expanded glutamine repeats. In the non-human primate model, motor and cognitive deficits appear more quickly than in most cases of Huntington's disease in humans, becoming noticeable within the first two years of the monkeys' development.

First author Richard Carter, PhD, a graduate of Emory's Genetics and Molecular Biology doctoral program, and his colleagues created iPS cells from the transgenic monkeys by reprogramming cells derived from the skin or dental pulp. This technique uses retroviruses to introduce reprogramming factors into somatic cells and induces a fraction of them to become pluripotent stem cells. Pluripotent stem cells are able to differentiate into any type of cell in the body, under the right conditions.

Carter and colleagues induced the iPS cells to become neural progenitor cells and then differentiated neurons. The iPS-derived neural cells developed intracellular and intranuclear aggregates of the mutant huntingtin protein, a classic sign of Huntington's pathology, as well as an increased sensitivity to oxidative stress.

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Disease in a dish approach could aid Huntington's disease discovery

Japan's Riken Reboots After Stem-Cell Scandal

By adminAugust 28, 2014Stem Cell Medicine

By Dow Jones Business News, August 27, 2014, 12:55:00 AM EDT

TOKYO--A scandal that started with a few suspicious images has led Japan's most prestigious research institute to slash its stem-cell unit by half and acknowledge deeper flaws in its ethics.

The move by the Riken institute came seven months after the publication of papers that it initially hailed as equal in importance to the Copernican revolution in astronomy. Since then, the papers have been retracted, and one of the co- authors committed suicide.

On Wednesday, Riken said it would scale down to half its size the Center for Developmental Biology, rename the center and choose a new director with input from non-Japanese scientists, an indication of how the scandal has damaged the reputation of Japanese science.

"We believe it is important to move forward with the restructuring to improve the quality and promote honest research," said Ryoji Noyori, the Nobel Prize winner who leads Riken.

Riken's overhaul could also sway the field of stem-cell science, which has received billions of dollars in research funds in the hopes of cures for ailments such as diabetes and heart disease.

Some details of the overhaul, including whether anyone beside the director would indeed lose their job, remained murky. Nevertheless, science writer Shinya Midori said, "This could trigger scaling down in the field of regenerative medicine."

The scandal at Riken has deeply shaken the country's science establishment and the wider stem-cell world and sparked a debate about research ethics in Japan amid "results-first" pressure.

The drama has focused on the institute's 14-year-old developmental-biology center and erupted after one of its scientists, Haruko Obokata, was found guilty of manipulating data in a pair of papers published in the journal Nature. The studies, which claimed to show a groundbreaking method of making stem cells by dipping cells in a mild acid solution, were quickly challenged and Nature retracted the papers in July, saying they contained inaccurate data.

Riken initially stood by the 31-year-old Dr. Obokata, who had been hailed as a national hero after her research was first published, but later distanced itself from what it called her "sloppy data management" and poor research ethics.

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Pfizer buys into Cambridge life science innovation

By adminAugust 28, 2014Stem Cell Medicine

Stem cell technology pioneer,DefiniGEN Ltdhas joined the Pfizer-inspired European Bank for induced pluripotent stem cells (EBiSC) consortium.

The consortium comprises 26 partners, and has been newly-formed with support from the Innovative Medicines Initiative (IMI) and the European Federation of Pharmaceutical Industries and Associations (EFPIA).

DefiniGen, a Cambridge University spin-out that has raised millions, represents one of the first commercial opportunities to arise from the universitys expertise in stem cells and is based on the research of Dr Ludovic Vallier, Dr Tamir Rashid and Professor Roger Pedersen of the universitys Anne McLaren Laboratory of Regenerative Medicine.

The EBiSC iPS cell bank will act as a central storage and distribution facility for human iPS cells, to be used by researchers across academia and industry in the study of disease and the development of new therapeutics. DefiniGENs role will be to validate EBiSC iPS cell lines by generating liver hepatocyte cells for toxicology, disease modelling, and regenerative medicine applications.

Dr Marcus Yeo, CEO of DefiniGEN, said: We are delighted to be a part of this ground-breaking consortium which will provide a crucial platform resource to enable the realisation of the full potential of iPS technology.

Conceptualised and coordinated by Pfizer Ltd in Cambridge, UK and managed by Roslin Cells Ltd in Edinburgh, the EBiSC bank aims to become the European go to resource for high quality research grade human iPS cells.

Today, iPS cells are being created in an increasing number of research programmes underway in Europe, but are not being systematically catalogued and distributed at the necessary scale to keep pace with their generation, nor to meet future demand.

The 35 million project will support the initial build of a robust, reliable supply chain from the generation of customised cell lines, the specification to internationally accepted quality criteria and their distribution to any global qualified user, ensuring accessibility to consistent, high quality tools for new medicines development.

Ruth McKernan, CSO of Pfizers Neusentis research unit in Cambridge, said: We are excited to be a part of this precompetitive collaboration to build a sustainable repository of high quality human iPS cell lines.

For many areas of research in academia and in industry, understanding the biological basis of disease heterogeneity is the next horizon. A bank of well-characterised iPS lines with strong relevance to the entire research community will help us all in our mission to bring therapies to patients.

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Pfizer buys into Cambridge life science innovation

Can stem cells help mobility after stroke?

By adminAugust 28, 2014Stem Cell Medicine

MIAMI - When Bruce Daily woke up after having lumbar surgery a year ago, he realized he couldn't move the right side of his body.

"It took me a long while to figure out I wasn't gonna walk again," he said. "I knew I was down."

Daily, 69, had gone in for lumbar surgery at the University of Miami hospital and had an ischemic stroke while under anesthesia. An ischemic stroke results from an obstruction in a blood vessel that blocks the blood from getting to the brain.

Because he was unconscious, he missed the four-to-five hour-window to apply the tissue plasminogen activator, or tPA, the only medication available to treat ischemic strokes. The medication dissolves the clot, restoring blood flow to the brain.

But while he missed that chance, he was right on time to meet Dr. Dileep Yavagal, a neurosurgeon who practices at the University of Miami and Jackson Memorial hospitals. Yavagal was enrolling patients in RECOVER-stroke, a clinical trial treating recent stroke patients with stem cells from their bone marrow and applying them directly into the carotid artery, one of two arteries that supply the neck and head with blood. Daily was one of 47 patients nationwide who qualified for the study.

The study is funded by Cytomedix, the company that developed the technology to extract stem cells from bone marrow. The firm chose Yavagal to lead a national blind study at the end of 2012.

Yavagal enrolled 13 patients at the University of Miami/Jackson Memorial Hospital, between the end of 2012 and January of 2014. So far, the initial three-month results have revealed that the marrow cells are not doing any damage, and there was no clear difference between those who received the cells and those who didn't. The study's one-year final results will be revealed in January.

"There is severe need for developing treatment for ischemic stroke, and stem cells are the most promising," said Yavagal, whose own research is still in its initial phase, focusing on using a healthy donor's bone marrow stem cells versus the patient's own marrow.

Stroke, the leading cause of adult disability in the United States, and the No. 4 cause of death in the country, causes 130,000 deaths a year in the U.S., according to the Centers for Disease Control and Prevention.

Yavagal, associate professor of clinical neurology and neurosurgery and the director of interventional neurology at the University of Miami's Miller School of Medicine, said that restricted mobility or loss of speech resulting from a moderate to severe stroke can be devastating because patients often become dependent on someone else for daily activities.

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Can stem cells help mobility after stroke?

Method developed to print replacement tissues using stem cells

By adminAugust 26, 2014Stem Cell Medicine

Prof Frank Barry, scientific director of the Regenerative Medicine Institute at NUI Galway, with PhD student Babu Rajendra Prasad. Photograph: Joe OShaughnessy

By using tiny cartridges dispensing one stem cell at a time, Galway-based researchers may soon be able to literally print the scaffold of a healthy human tissue, and let it grow to become a therapeutic transplant.

When the Regenerative Medicine Institute at NUI Galway and Irish start-up company Poly-Pico Ltd recently joined forces for a trial proof-of-concept experiment, the results were spectacular.

They were able to dispense tiny drops from a cartridge filled with a stem cell mixture, each drop containing no more than a single stem cell.

Now imagine that we have five dispensing cartridges, each containing a different type of programmed stem cell, said Frank Barry, professor of cellular therapy and scientific director of the institute.

In principle we could essentially print them on to a surface and, by repeating the process a few thousands of times, obtain a mixture of growing cells and eventually a healthy pancreatic islet.

The islets produced by the printing process would then be transplanted into the pancreas of a Type 1 diabetic patient. The hope is that they will develop there and eventually help with the regulation of blood sugar levels.

It is a futuristic prospect, but it is not science fiction, Prof Barry said.

We are talking five years down the line for potential clinical trials.

In the experiment, the drops containing a single stem cell were easily identified and isolated. The cells were then allowed to replicate themselves into exact copies. Finally the researchers checked that they had remained viable and unaffected by the process.

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Method developed to print replacement tissues using stem cells