Windows bug-testing software cracks stem cell programs

SOFTWARE used to keep bugs out of Microsoft Windows programs has begun shedding light on one of the big questions in modern science: how stem cells decide what type of tissue to become.

Not only do the results reveal that cellular decision-making is nowhere near as complicated as expected, they also raise hopes that the software could become a key tool in regenerative medicine.

"It is a sign of the convergence between carbon and silicon-based life," says Chris Mason, a regenerative medicine specialist at University College London. "World-class stem cell scientists and a world-class computer company have found common ground. It is work at such interfaces that brings the big breakthroughs."

Stem cells are the putty from which all tissues of the body are made. That means they have the potential to repair damaged tissue and even grow into new organs.

Embryonic stem cells hold particular promise as they can either renew themselves indefinitely or differentiate into any kind of cell in the body a property known as pluripotency.

The process that sets a stem cell on the path to either self-renewal or differentiation was thought to be a highly complex web of genetic and environmental interactions. That web is known as the interactome.

Embryonic stem cells are currently being trialled as a way to restore vision and treat spinal injury. But these trials, and others in the pipeline, are hampered by the fact that no one really knows what determines the fate of any particular stem cell. Today's techniques for making a stem cell differentiate into a certain tissues are hit-and-miss, says Mason.

What's needed is a more deterministic, reliable method, says Sara-Jane Dunn, a computational biologist at Microsoft Research in Cambridge. One approach is to frame the problem in the language of computation. The genetic and environmental cues that determine the cell's fate can be thought of as inputs, with the cell itself as the processor, Dunn says.

Stem cells' capacity to renew themselves is the simplest of the two possible paths out of the pluripotent state. To find the program behind this, Dunn, along with stem cell scientists Graziano Martello at the University of Padua in Italy, and Austin Smith at the University of Cambridge, tried to isolate the genetic and environmental processes at work in mouse embryonic stem cells.

They used a technique pioneered at Smith's lab that uses cultures of various inhibitory proteins to keep embryonic stem cells continually renewing themselves rather than differentiating into other cells. The team immersed the stem cells in four different types of these cultures and analysed which genes they expressed in which environment, and to what extent.

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Windows bug-testing software cracks stem cell programs

Researchers use human stem cells to create light-sensitive retina in a dish

PUBLIC RELEASE DATE:

10-Jun-2014

Contact: Lauren Nelson lnelso35@jhmi.edu 410-955-8725 Johns Hopkins Medicine

Using a type of human stem cell, Johns Hopkins researchers say they have created a three-dimensional complement of human retinal tissue in the laboratory, which notably includes functioning photoreceptor cells capable of responding to light, the first step in the process of converting it into visual images.

"We have basically created a miniature human retina in a dish that not only has the architectural organization of the retina but also has the ability to sense light," says study leader M. Valeria Canto-Soler, Ph.D., an assistant professor of ophthalmology at the Johns Hopkins University School of Medicine. She says the work, reported online June 10 in the journal Nature Communications, "advances opportunities for vision-saving research and may ultimately lead to technologies that restore vision in people with retinal diseases."

Like many processes in the body, vision depends on many different types of cells working in concert, in this case to turn light into something that can be recognized by the brain as an image. Canto-Soler cautions that photoreceptors are only part of the story in the complex eye-brain process of vision, and her lab hasn't yet recreated all of the functions of the human eye and its links to the visual cortex of the brain. "Is our lab retina capable of producing a visual signal that the brain can interpret into an image? Probably not, but this is a good start," she says.

The achievement emerged from experiments with human induced pluripotent stem cells (iPS) and could, eventually, enable genetically engineered retinal cell transplants that halt or even reverse a patient's march toward blindness, the researchers say.

The iPS cells are adult cells that have been genetically reprogrammed to their most primitive state. Under the right circumstances, they can develop into most or all of the 200 cell types in the human body. In this case, the Johns Hopkins team turned them into retinal progenitor cells destined to form light-sensitive retinal tissue that lines the back of the eye.

Using a simple, straightforward technique they developed to foster the growth of the retinal progenitors, Canto-Soler and her team saw retinal cells and then tissue grow in their petri dishes, says Xiufeng Zhong, Ph.D., a postdoctoral researcher in Canto-Soler's lab. The growth, she says, corresponded in timing and duration to retinal development in a human fetus in the womb. Moreover, the photoreceptors were mature enough to develop outer segments, a structure essential for photoreceptors to function.

Retinal tissue is complex, comprising seven major cell types, including six kinds of neurons, which are all organized into specific cell layers that absorb and process light, "see," and transmit those visual signals to the brain for interpretation. The lab-grown retinas recreate the three-dimensional architecture of the human retina. "We knew that a 3-D cellular structure was necessary if we wanted to reproduce functional characteristics of the retina," says Canto-Soler, "but when we began this work, we didn't think stem cells would be able to build up a retina almost on their own. In our system, somehow the cells knew what to do."

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Researchers use human stem cells to create light-sensitive retina in a dish

Team applies new theory to learn how and why cells differentiate

Jun 16, 2014 An overview of the stem cell gene network gives a sense of the complex process involved in cell differentiation, as transcription factors and protein complexes influence and loop back upon each other. Rice University researchers found that stem cell differentiation can be defined as a many-body problem as they developed a theoretical system to analyze large gene networks. Credit: Bin Zhang/Rice University

How does a stem cell decide what path to take? In a way, it's up to the wisdom of the crowd.

The DNA in a pluripotent stem cell is bombarded with waves of proteins whose ebb and flow nudge the cell toward becoming blood, bone, skin or organs. A new theory by scientists at Rice University shows the cell's journey is neither a simple step-by-step process nor all random.

Theoretical biologist Peter Wolynes and postdoctoral fellow Bin Zhang set out to create a mathematical tool to analyze large, realistic gene networks. As a bonus, their open-access study to be published this week by the Proceedings of the National Academy of Sciences helped them understand that the process by which stem cells differentiate is a many-body problem.

"Many-body" refers to physical systems that involve interactions between large numbers of particles. Scientists assume these many bodies conspire to have a function in every system, but the "problem" is figuring out just what that function is. In the new work, these bodies consist not only of the thousands of proteins expressed by embryonic stem cells but also DNA binding sites that lead to feedback loops and other "attractors" that prompt the cell to move from one steady state to the next until it reaches a final configuration.

To test their tool, the researchers looked at the roles of eight key proteins and how they rise and fall in number, bind and unbind to DNA and degrade during stem cell differentiation. Though the interactions may not always follow a precise path, their general pattern inevitably leads to the desired result for the same reason a strand of amino acids will inevitably fold into the proper protein: because the landscape dictates that it be so.

Wolynes called the new work a "stylized," simplified model meant to give a general but accurate overview of how cell networks function. It's based on a theory he formed in 2003 with Masaki Sasai of Nagoya University but now takes into account the fact that not one but many genes can be responsible for even a single decision in a cellular process.

"This is what Bin figured out, that one could generalize our 2003 model to be much more realistic about how several different proteins bind to DNA in order to turn it on or off," Wolynes said.

A rigorous theoretical approach to determine the transition pathways and rates between steady states was also important, Zhang said. "This is crucial for understanding the mechanism of how stem cell differentiation occurs," he said.

Wolynes said that because the stem cell is stochasticthat is, its fate is not pre-determined"we had to ask why a gene doesn't constantly flip randomly from one state to another state. This paper for the first time describes how we can, for a pretty complicated circuit, figure out there are only certain periods during which the flipping can occur, following a well-defined transition pathway."

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Team applies new theory to learn how and why cells differentiate

Scientists create an 'eye-in-a-dish' using human stem cells

Scientists copied processes that occur in the womb to create eye tissue Study used adult stem cells that have been genetically reprogrammed Lab-grown tissue responded to light the same way as it does in the eye The study represents a first step towards restoring sight in the blind

By Ellie Zolfagharifard

Published: 12:14 EST, 10 June 2014 | Updated: 14:02 EST, 10 June 2014

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A light-sensitive 'eye-in-a-dish' has been created by scientists using a type of human stem cell.

The three dimensional structure represents a first step towards restoring sight to the blind, say the researchers.

Processes that occur in the womb were copied to create complex retinal tissue in a laboratory petri dish.

A light-sensitive 'eye-in-a-dish' has been created by scientists in Maryland. The three dimensional structure represents a first step towards restoring sight to the blind, say the researchers. Pictured are the photoreceptors (in green) within a 'mini retina' structure (blue) that was created using human stem cells

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Scientists create an 'eye-in-a-dish' using human stem cells

Mount Sinai Researchers Identify Protein That Keeps Blood Stem Cells Healthy as They Age

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Newswise (New York June 9, 2014) -- A protein may be the key to maintaining the health of aging blood stem cells, according to work by researchers at the Icahn School of Medicine at Mount Sinai recently published online in Stem Cell Reports. Human adults keep stem cell pools on hand in key tissues, including the blood. These stem cells can become replacement cells for those lost to wear and tear. But as the blood stem cells age, their ability to regenerate blood declines, potentially contributing to anemia and the risk of cancers like acute myeloid leukemia and immune deficiency. Whether this age-related decline in stem cell health is at the root of overall aging is unclear.

The new Mount Sinai study reveals how loss of a protein called Sirtuin1 (SIRT1) affects the ability of blood stem cells to regenerate normally, at least in mouse models of human disease. This study has shown that young blood stem cells that lack SIRT1 behave like old ones. With use of advanced mouse models, she and her team found that blood stem cells without adequate SIRT1 resembled aged and defective stem cells, which are thought to be linked to development of malignancies.

"Our data shows that SIRT1 is a protein that is required to maintain the health of blood stem cells and supports the possibility that reduced function of this protein with age may compromise healthy aging," says Saghi Ghaffari, MD, PhD, Associate Professor of Developmental and Regenerative Biology at Mount Sinai's Black Family Stem Cell Institute, Icahn School of Medicine. "Further studies in the laboratory could improve are understanding between aging stem cells and disease."

Next for the team, which includes Pauline Rimmel, PhD, is to investigate whether or not increasing SIRT1 levels in blood stem cells protects them from unhealthy aging or rejuvenates old blood stem cells. The investigators also plan to look at whether SIRT1 therapy could treat diseases already linked to aging, faulty blood stem cells.

They also believe that SIRT1 might be important to maintaining the health of other types of stem cells in the body, which may be linked to overall aging.

The notion that SIRT1 is a powerful regulator of aging has been highly debated, but its connection to the health of blood stem cells "is now clear," says Dr. Ghaffari. "Identifying regulators of stem cell aging is of major significance for public health because of their potential power to promote healthy aging and provide targets to combat diseases of aging," Dr. Ghaffari says.

Researchers from Harvard Medical School and Children's Hospital in Boston participated in the study.

About the Mount Sinai Health System The Mount Sinai Health System is an integrated health system committed to providing distinguished care, conducting transformative research, and advancing biomedical education. Structured around seven member hospital campuses and a single medical school, the Health System has an extensive ambulatory network and a range of inpatient and outpatient servicesfrom community-based facilities to tertiary and quaternary care.

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Mount Sinai Researchers Identify Protein That Keeps Blood Stem Cells Healthy as They Age

Stem cells are a soft touch for nano-engineered biomaterials

Scientists from Queen Mary University of London have shown that stem cell behaviour can be modified by manipulating the nanoscale properties of the material they are grown on - improving the potential of regenerative medicine and tissue engineering as a result.

Stem cells are special because they are essential to the normal function of our organs and tissues. Previous research shows stem cells grown on hard substrates go on to multiply but do not differentiate: a process by which the cells specialise to perform specific functions in the body. In contrast, stem cells grown on softer surfaces do go on to differentiate.

In this new study, published in the journal Nano Letters, the researchers used tiny material patches known as nanopatches to alter the surface of the substrate and mimic the properties of a softer material.

"By changing the surface properties like the shape of the substrate at the nanoscale level, we tricked the stem cells to behave differently," explains co-author Dr Julien Gautrot, from QMUL's School of Engineering and Materials Science and the Institute of Bioengineering.

The team tested different sizes of nanopatches - from 3 microns to 100 nanometres (about one thousandth of the diameter of a hair). The stem cells behaved as if they were on a soft surface when in contact with the smallest patches because they can't firmly grip them.

Dr Gautrot added: "This development will be useful when there's a need to create a rigid implant to be inserted into the body. Potentially, such nanopatches could provide a soft touch to the surface of the implant so that cells from the neighbouring tissues are not perturbed by such a hard material."

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Eye in a Dish: Researchers Make Retina From Stem Cells

NBC News -- Researchers have grown part of an eye in a lab dish, using a type of stem cell made from a piece of skin.

They said the little retina started growing and developing on its own an important step towards creating custom-tailored organs in the lab.

We have basically created a miniature human retina in a dish that not only has the architectural organization of the retina but also has the ability to sense light," said M. Valeria Canto-Soler, an assistant professor of ophthalmology at the Johns Hopkins University School of Medicine.

The team used cells called induced pluripotent stem cells, or iPS cells, which are immature stem cells whose powers resemble those of embryonic stem cells they can morph into any cell type in the body.

Theyre made by tricking an ordinary cell, like a skin cell, into reverting back into embryonic mode. Then the researchers activate genes to get the cell to redirect itself into forming the desired cells in this case cells of the retina.

To the surprise of the researchers, the cells started developing as if they were in a growing human embryo.

"We knew that a 3-D cellular structure was necessary if we wanted to reproduce functional characteristics of the retina, but when we began this work, we didn't think stem cells would be able to build up a retina almost on their own. In our system, somehow the cells knew what to do, Canto-Soler said in a statement.

The experiment may ultimately lead to technologies that restore vision in people with retinal diseases, she added.

Tests showed the cells responded to light, the team reported in the journal Nature Communications. "Is our lab retina capable of producing a visual signal that the brain can interpret into an image? Probably not, but this is a good start," Canto-Soler said.

Other teams have used iPS cells to make a piece of human liver and are using them to study a range of human diseases.

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Eye in a Dish: Researchers Make Retina From Stem Cells

Light-sensitive 3D retina created in lab

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New York, June 11 : Using a type of human stem cell, researchers have now created a three-dimensional (3D) functional human retinal tissue in the laboratory for the first time.

"We have basically created a miniature human retina in a dish that not only has the architectural organisation of the retina but also has the ability to sense light," claimed M. Valeria Canto-Soler, an assistant professor at John Hopkins University's school of medicine.

The retinal tissue created in the laboratory - using human induced pluripotent stem cells (iPS) - includes functioning photoreceptor cells capable of responding to light, the first step in the process of converting it into visual images.

"The work advances opportunities for vision-saving research and may ultimately lead to technologies that restore vision in people with retinal diseases," she noted.

Using a simple, straightforward technique they developed to foster the growth of the retinal progenitors, the researchers saw retinal cells and then tissues growing in petri dishes.

The growth corresponded in timing and duration to retinal development in a human foetus in the womb.

Moreover, the photoreceptors were mature enough to develop outer segments - a structure essential for photoreceptors to function.

However, Canto-Soler cautioned that photoreceptors are only part of the story in the complex eye-brain process of vision, and her lab has not yet recreated all of the functions of the human eye and its links to the visual cortex of the brain.

The achievement could eventually enable genetically engineered retinal cell transplants that halt or even reverse a patient's march toward blindness.

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Light-sensitive 3D retina created in lab

New Method Reveals Single Protein Interaction Key to Embryonic Stem Cell Differentiation

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Newswise Proteins are responsible for the vast majority of the cellular functions that shape life, but like guests at a crowded dinner party, they interact transiently and in complex networks, making it difficult to determine which specific interactions are most important.

Now, researchers from the University of Chicago have pioneered a new technique to simplify the study of protein networks and identify the importance of individual protein interactions. By designing synthetic proteins that can only interact with a pre-determined partner, and introducing them into cells, the team revealed a key interaction that regulates the ability of embryonic stem cells to change into other cell types. They describe their findings June 5 in Molecular Cell.

Our work suggests that the apparent complexity of protein networks is deceiving, and that a circuit involving a small number of proteins might control each cellular function, said senior author Shohei Koide, PhD, professor of biochemistry & molecular biophysics at the University of Chicago.

For a cell to perform biological functions and respond to the environment, proteins must interact with one another in immensely complex networks, which when diagrammed can resemble a subway map out of a nightmare. These networks have traditionally been studied by removing a protein of interest through genetic engineering and observing whether the removal destroys the function of interest or not. However, this does not provide information on the importance of specific protein-to-protein interactions.

To approach this challenge, Koide and his team pioneered a new technique that they dub directed network wiring. Studying mouse embryonic stem cells, they removed Grb2, a protein essential to the ability of the stem cell to transform into other cell types, from the cells. The researchers then designed synthetic versions of Grb2 that could only interact with one protein from a pool of dozens that normal Grb2 is known to network with. The team then introduced these synthetic proteins back into the cell to see which specific interactions would restore the stem cells transformative abilities.

The name, directed network wiring, comes from the fact that we create minimalist networks, Koide said. We first remove all communication lines associated with a protein of interest and add back a single line. It is analysis by addition.

Despite the complexity of the protein network associated with stem cell development, the team discovered that restoring only one interactionbetween Grb2 and a protein known as Ptpn11/Shp2 phosphatasewas enough to allow stem cells to again change into other cell types.

We were really surprised to find that consolidating many interactions down to a single particular connection for the protein was sufficient to support development of the cells to the next stage, which involves many complicated processes, Koide said. Our results show that signals travel discrete and simple routes in the cell.

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New Method Reveals Single Protein Interaction Key to Embryonic Stem Cell Differentiation

Stem cells hold keys to body's plan

PUBLIC RELEASE DATE:

5-Jun-2014

Contact: Jeannette Spalding jeannette.spalding@case.edu 216-368-3004 Case Western Reserve University

Cleveland June 5, 2014 Case Western Reserve researchers have discovered landmarks within pluripotent stem cells that guide how they develop to serve different purposes within the body. This breakthrough offers promise that scientists eventually will be able to direct stem cells in ways that prevent disease or repair damage from injury or illness. The study and its results appear in the June 5 edition of the journal Cell Stem Cell.

Pluripotent stem cells are so named because they can evolve into any of the cell types that exist within the body. Their immense potential captured the attention of two accomplished faculty with complementary areas of expertise.

We had a unique opportunity to bring together two interdisciplinary groups, said co-senior author Paul Tesar, PhD, Assistant Professor of Genetics and Genome Sciences at CWRU School of Medicine and the Dr. Donald and Ruth Weber Goodman Professor.

"We have exploited the Tesar labs expertise in stem cell biology and my labs expertise in genomics to uncover a new class of genetic switches, which we call seed enhancers, said co-senior author Peter Scacheri, PhD, Associate Professor of Genetics and Genome Sciences at CWRU School of Medicine. Seed enhancers give us new clues to how cells morph from one cell type to another during development."

The breakthrough came from studying two closely related stem cell types that represent the earliest phases of development embryonic stem cells and epiblast stem cells, first described in research by Tesar in 2007. These two stem cell types give us unprecedented access to the earliest stages of mammalian development, said Daniel Factor, graduate student in the Tesar lab and co-first author of the study.

Olivia Corradin, graduate student in the Scacheri lab and co-first author, agrees. Stem cells are touted for their promise to make replacement tissues for regenerative medicine, she said. But first, we have to understand precisely how these cells function to create diverse tissues.

Enhancers are sections of DNA that control the expression of nearby genes. By comparing these two closely related types of pluripotent stem cells (embryonic and epiblast), Corradin and Factor identified a new class of enhancers, which they refer to as seed enhancers. Unlike most enhancers, which are only active in specific times or places in the body, seed enhancers play roles from before birth to adulthood.

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Stem cells hold keys to body's plan