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Newswise DALLAS June 20, 2014 The Childrens Medical Center Research Institute at UTSouthwestern (CRI) has identified a biomarker that enables researchers to accurately characterize the properties and function of mesenchymal stem cells (MSCs) in the body. MSCs are the focus of nearly 200 active clinical trials registered with the National Institutes of Health, targeting conditions such as bone fractures, cartilage injury, degenerative disc disease, and osteoarthritis.

The finding, published in the journal Cell Stem Cell on June 19, significantly advances the field of MSC biology, and if the same biomarker identified in CRIs studies with mice works in humans, the outlook for clinical trials that use MSCs will be improved by the ability to better identify and characterize the relevant cells.

There has been an increasing amount of clinical interest in MSCs, but advances have been slow because researchers to date have been unable to identify MSCs and study their normal physiological function in the body, said Dr. Sean Morrison, Director of the Childrens Research Institute, Professor of Pediatrics at UTSouthwestern Medical Center, and a Howard Hughes Medical Institute Investigator. We found that a protein known as leptin receptor can serve as a biomarker to accurately identify MSCs in adult bone marrow in vivo, and that those MSCs are the primary source of new bone formation and bone repair after injury.

In the course of their investigation, the CRI researchers found that leptin receptor-positive MSCs are also the main source of factors that promote the maintenance of blood-forming stem cells in the bone marrow.

Unfortunately, many clinical trials that are testing potential therapies using MSCs have been hampered by the use of poorly characterized and impure collections of cultured cells, said Dr. Morrison, senior author of the study and holder of the Mary McDermott Cook Chair in Pediatric Genetics at UTSouthwestern. If this finding is duplicated in our studies with human MSCs, then it will improve the characterization of MSCs that are used clinically and could increase the probability of success for well-designed clinical trials using MSCs.

Dr. Bo Zhou, a postdoctoral research fellow in Dr. Morrisons laboratory, was first author of the paper. Other CRI researchers involved in the study were Drs. Rui Yue and Malea Murphy, both postdoctoral research fellows. The research was supported by the National Heart, Lung, and Blood Institute, the Cancer Prevention and Research Institute of Texas, and donors to the Childrens Medical Center Foundation.

About CRI

Childrens Medical Center Research Institute at UTSouthwestern (CRI) is a joint venture established in2011 to build upon the comprehensive clinical expertise of Childrens Medical Center of Dallas and the internationally recognized scientific excellence of UTSouthwestern Medical Center. CRIs mission is to perform transformative biomedical research to better understand the biological basis of disease, seeking breakthroughs that can change scientific fields and yield new strategies for treating disease. Located in Dallas, Texas, CRI is creating interdisciplinary groups of exceptional scientists and physicians to pursue research at the interface of regenerative medicine, cancer biology and metabolism, fields that hold uncommon potential for advancing science and medicine. More information about CRI is available on its website: cri.utsw.edu

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Children's Research Institute Finds Key to Identifying, Enriching Mesenchymal Stem Cells

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 stochastic -- that 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."

In previous models of gene networks, "Instead of focusing on proteins actually binding to DNA, they just say, 'Well, there's a certain high level of this protein or low level of that protein,'" Wolynes said. "At first, that sounds easier to study because you can measure how much protein you've got. But you don't always know if it is bound. It has become increasingly clear that the rate of protein binding to DNA plays an important role in gene expression, particularly in eukaryotic systems."

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Many bodies prompt stem cells to change

It's possible to alter genetic material of stem cells to provide HIV resistance A DNA sequence can be removed from the cells and replaced with another The replacements can be taken from people with natural HIV resistance These altered stem cells can then be used to create HIV-resistant white blood cells

By Emma Innes

Published: 07:57 EST, 11 June 2014 | Updated: 12:03 EST, 11 June 2014

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HIV could be cured by genetically editing stem cells, researchers believe.

U.S. scientists say they have already demonstrated that it is possible to alter the genetic material of some stem cells.

This in turn provides HIV resistance, they report.

A new 'genome editing' technique could be the key to curing HIV. Image shows HIV in human tissue

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Could 'editing' genes be the key to curing HIV? Giving patients altered blood cells could make them resistant to the ...

(PRWEB UK) 14 June 2014

There is a non-invasive way of obtaining stem cells that has the potential for lifetime storage, by utilising a child's milk tooth after it has fallen out naturally. Although some companies advocate that the extraction of a wobbly tooth is best, specialist tooth cell bank BioEden says that providing you have a quality process, extraction is not a requirement. The tooth can be left to fall out naturally, meaning no distress for the child who may be a little worried about a trip to the dentist.

It is a fact that a blood supply must be actively working to preserve the stem cells. However, as this occurs naturally all the way to exfoliation, the intervention of dentists is not a requirement.

Teeth can be put into two categories: deciduous or permanent. Deciduous (milk) teeth are the ones that will fall out naturally over time, whereas permanent teeth are obviously the ones that won't. It is well documented that naturally shed milk teeth provide more and faster dividing cells that extracted milk teeth, something that BioEden have also found in their own laboratories. With naturally shed teeth the stem cells are being actively recruited to the place of remodelling and direct the remodelling process.

Some companies utilise a method of transporting a tooth to the lab in a transport solution which after a limited period of time would destroy the tooth cells. Therefore having a tooth extracted by a dentist would be the only way of getting the tooth delivered in time to avoid this problem. This method has been heavily criticised by parents and the media.

BioEden uses a superior method of transportation that means for up to 5 days the quality or quantity of the cells will not be affected. Although overnight delivery is recommended to minimise any delivery related delays, this process allows extra flexibility to accommodate the busy lifestyles of today's parents and avoids any moral concerns of removing a healthy tooth for money.

Source: J Endod 2011 http:/http://www.ncbi.nlm.nih.gov/pubmed/21689554 and http:/http://www.ncbi.nlm.nih.gov/pubmed/22674471

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Obtaining stem cells for treatment can now be natural, without medical or dental intervention

Scientists have successfully managed to transfer human stem cells into pigs that have been especially genetically modified for the purpose.

The cells thrived following the transplant and researchers believe they are now one step closer to finding treatments for a number of human disease.

The rejection of transplanted cells by the host body is one of the major hurdles in stem cell research.

By managing to ensure pigs will accept human cells is a huge leap forward in stem cell therapy research, and could lead to treatments for patients with severe immune deficiency.

The past research into regenerative medicine has relied on rodent testing, but significant differences in the immune system of mice and people has put limits on the application of the findings.

One of the study's authors, Randall Prather, says: "Many medical researchers prefer conducting studies with pigs because they are more anatomically similar to humans than other animals such as mice or rodents. Physically, pigs are much close to the size and scale of humans than other animals, and they respond to health threats similarly.

"This means that research in pigs is more likely to have results similar to those in humans for many different tests and treatments."

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Human stem cells implanted in pigs

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Defective brain neurons are responsible for the mobility problems seen in people with Parkinsons disease.

A neurosurgery team will next month transplant cells from aborted human fetuses into the brain of a person with Parkinsons disease. The operation breaks a decade-long international moratorium on the controversial therapy that was imposed after many patients failed to benefit and no one could work out why.

But the trial comes just as other sources of replacement cells derived from human stem cells are rapidly approaching the clinic. And this time, scientists want to make sure that things go better. So the teams involved in all the planned trials have formed a working group to standardize their research and clinical protocols in the hope that their results will be more easily interpretable.

People with Parkinsons disease suffer from a degeneration of neurons that produce the neurotransmitter dopamine, which is crucial for normal movement. This often leaves patients with severe mobility problems. Standard treatment includes the drug l-dopa, which replaces dopamine in the brain but can cause side effects. The cellular therapies aim to replace the missing neurons with dopamine-producing (dopaminergic) cells from fetal brains or with those derived from human stem cells.

The moratorium on replacement-therapy trials was introduced in 2003 because the early fetal-cell studies had produced varying results that were impossible to interpret.

We want to avoid a repeat of this situation, says neurologist Roger Barker at the University of Cambridge, UK, who helped to organize the working groups inaugural meeting in London last month. The group, known as the Parkinsons Disease Global Force, includes scientists from the European, US and Japanese teams about to embark on the trials. At the meeting, they pledged to share their knowledge and experiences.

The first human transplantation of fetal brain cells took place in 1987 at Lund University in Sweden, where the technique was pioneered. Surgical teams took immature fetal cells destined to become dopaminergic neurons from the midbrain of aborted fetuses and transplanted them into the striatum of patients brains, the area of greatest dopamine loss in Parkinsons disease.

More than 100 patients worldwide received the therapy as part of clinical trials before the moratorium. But centres used different procedures and protocols it was impossible to work out why some patients did very well and others didnt benefit at all, says Barker.

In 2006, Barker, together with neuroscientist Anders Bjrklund at Lund University, set up a network to bring together the original seven teams that had performed the transplants, to assess all protocol details and patient data retrospectively.

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Fetal-cell revival for Parkinsons

By Estel Grace Masangkay

A team of researchers from Johns Hopkins University School of Medicine reports that they have built a 3D complement of human retinal tissue in a lab dish, which contains functional photoreceptor cells that are sensitive to light.

The cells sensitivity to light precedes conversion of the stimulus 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 [The work] advances opportunities for vision-saving research and may ultimately lead to technologies that restore vision in people with retinal diseases, says study leader M. Valeria Canto-Soler, an assistant professor of ophthalmology at the Johns Hopkins University School of Medicine.

The team experimented with human induced pluripotent stem cells (iPS), which could eventually lead the way to genetically engineered cells transplants capable of halting or even reversing progressive blindness. The researchers grew the iPS into retinal progenitor cells that make up the light-sensitive retinal tissue found lining the back of the eye.

According to Xiufeng Zhong, postdoctoral researcher in Canto-Solers lab, the growth corresponded to the timing and duration of a fetus retinal development in the womb. The photoreceptor cells also matured enough to develop outer segments, structures critical to the cells function. 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 didnt 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, said Professor Canto-Soler.

The researchers tested the dish-grown mini retinas by placing an electrode in a single photoreceptor cell and then giving a pulse of light to the cell, which showed a biochemical pattern reaction similar to photoreceptor behavior in people exposed to light.

The system used by the team allows for the generation of hundreds of mini-retinas at the same time, directly from a patient affected by certain retinal diseases such as retinitis pigmentosa. This offers a novel biological system to directly study retinal disease causes in human tissue instead of depending on animal models. More significantly, the system opens possibilities for personalized treatment for patients.

The teams work was published online in the journal Nature Communications.

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Johns Hopkins Team Builds Light-Sensitive Retina Using Human Stem Cells

June 11, 2014 Sophie Langley

Stem cells could be future source for 'eco-friendly' meat, a study has found

The scientific progress that has made it possible to dream of a future in which faulty organs could be regrown from stem cells also holds potential as an ethical and greener source for meat, according to researchers from Wageningen University in The Netherlands.

The researchers suggested in an article published in the Cell Press journal Trends in Biotechnology that every town or village could one day have its very own small-scale, cultured meat factory.

We believe that cultured meat is part of the future, said Cor van der Weele of Wageningen University in The Netherlands.

It is already possible to make meat from stem cells. To prove it, Mark Post, a professor of tissue engineering at Maastricht University, The Netherlands, presented the first lab-grown hamburger in 2013.

However, in their new research paper, Professor van der Weele and Professor Tramper outlined a potential meat manufacturing process, starting with a vial of cells taken from a cell bank and ending with a pressed cake of minced meat. But they said there would be challenges when it came to maintaining a continuous stem cell line and producing cultured meat that was cheaper than meat obtained in the usual way. Most likely, the researchers said, the price of normal meat would first have to rise considerably.

Cultured meat has great moral promise, the researchers wrote. Worries about its unnaturalness might be met through small-scale production methods that allow close contact with cell-donor animals, thereby reversing feelings of alienation. From a technological perspective, village-scale production is also a promising option, they wrote.

Other parts of the future are partly substituting meat with vegetarian products, keeping fewer animals in better circumstances, perhaps eating insects, etc, Professor van der Weele said. This discussion is certainly part of the future in that it is part of the search for a protein transition. It is highly effective in stimulating a growing awareness and discussion of the problems of meat production and consumption, Professor van der Weele said.

Professor van der Weele and coauthor Johannes Tramper said that the rising demand for meat around the world was unsustainable in terms of environmental pollution and energy consumption.

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Stem cells could be future source for eco-friendly meat, study

A team of haematologists has engineered a particular white blood cell to be HIV resistant after hacking the genome of induced pluripotent stem cells (iPSCs).

The technique has been published in the Proceedings of the National Academy of Sciences and was devised by Yuet Wai Kan of the University of California, former President of the American Society of Haematology, and his peers.

The white blood cell the team had ideally wanted to engineer was CD+4 T, a cell that is responsible for sending signals to other cells in the immune system, and one that is heavily targeted by the HIV virus. When testing for the progress of HIV in a patient, doctors will take a CD4 cell count in a cubic millimetre of blood, with between 500 and 1,500 cells/mm3 being within the normal range. If it drops below around 250, it means HIV has taken hold -- the virus ravages these cells and uses them as an entry point.

HIV gains entry by attaching itself to a receptor protein on the CD+4 Tcell surface known as CCR5.If this protein could be altered, it could potentially stop HIV entering the immune system, however. A very small number of the population have this alteration naturally and are partially resistant to HIV as a result -- they have two copies of a mutation that prevents HIV from hooking on to CCR5 and thus the T cell.

In the past, researchers attempted to replicate the resistance by simply transplanting stem cells from those with the mutation to an individual suffering from HIV. The rarity of this working has been demonstrated by the fact that just one individual,Timothy Ray Brown(AKA the Berlin patient), has been publicly linked to the treatment and known to be HIV free today. The Californian team hoped to go right to the core of the problem instead, and artificially replicate the protective CCR5mutation.

Kan has been working for years on a precise process for cutting and sewing back together genetic information. His focus throughout much of his career has been sickle cell anaemia, and in recent years this has translated to researching mutations and how these can be removed at the iPSC stage, as they are differentiated into hematopoietic cells. He writes on his university web page: "The future goal to treatment is to take skin cells from patients, differentiate them into iPS cells, correct the mutations by homologous recombination, and differentiate into the hematopoietic cells and re-infuse them into the patients. Since the cells originate from the patients, there would not be immuno-rejection." No biggie.

This concept has now effectively been translated to the study of HIV and the CD+4 T cell.

Kan and his team used a system known as CRISPR-Cas9 to edit the genes of the iPSCs. It uses Cas9, a protein derived from bacteria, to introduce a double strand break somewhere at the genome, where part of the virus is then incorporated into the genome to act as a warning signal to other cells. An MIT team has already used the technique to correct a human disease-related mutation in mice.

When Kan and his team used the technique they ended up creating HIV resistant white blood cells, but they were not CD+4 T-cells. They are now speculating that rather than aiming to generate this particular white blood cell with inbuilt resistance, future research instead look at creating HIV resistant stem cells that will become all types of white blood cells in the body.

Of course, with this kind of therapy the risk is different and unexpected mutations could occur. In an ideal world, doctors will not want to be giving constant cell transplants, but generating an entirely new type of HIV resistant cells throughout the body carries its own risks and will need stringent evaluation if it comes at all close to being proven.

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Stem cells edited to produce an HIV-resistant immune system

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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