RNA discoveries could improve stem cell research – Phys.Org

August 30, 2017 by Will Doss A hairpin loop from a pre-mRNA. Highlighted are the nucleobases (green) and the ribose-phosphate backbone (blue). Note that this is a single strand of RNA that folds back upon itself. Credit: Vossman/ Wikipedia

A recently described variety of RNA closely associated with gene expression was found to be largely cell-type specific, raising the possibility this variety of RNA sequences may be able to be used as a marker in stem cell research.

The study was published in Nature Structural and Molecular Biology and co-authored by Vasil Galat, PhD, research assistant professor of Pathology.

Only about 20 percent of RNA codes for proteins, and the remaining 80 percent, called non-coding RNA, is thought to be involved in a variety of cellular processes including RNA translation, splicing and DNA replication.

Non-coding RNA can be further divided into micro RNA and long non-coding RNA, and over half of long non-coding RNA is chromatin-enriched (cheRNA), where chromatin loops around strands of RNA, which are then bound by RNA polymerase II near the sites of gene promotors, according to previous research. This physical proximity translates to functional connectivity, according to Galat.

In the current study, Galat and the other co-authors of the study discovered that the cheRNA sequences are also specifically associated with different types of cells' eventual genetic expression.

"Because they are so well associated with a promotor region, they can be used as a predictor of the promotor region's particular genes," Galat said. "Once you see the cheRNA expressed, you can judge the location of genes."

There are several methods biologists currently use to locate gene promotor regions, but this method could be more reliable and precise, according to Galat. Now, the discovery that cheRNA is cell-type specific has particularly tantalizing applications in his primary line of research: pluripotent stem cells.

Pluripotent stem cells are undifferentiated, meaning they could develop into almost any type of cell in the human body. It can be tricky to keep them in the pluripotent stage, which is why Galat's lab was invited to collaborate with this University of Chicago-led project.

"Our lab has a great deal of experience working with pluripotent cells," Galat said. "These cells require experience to maintain. They are spontaneously differentiating all the time in culture."

Theoretically, by establishing a database of cell types and associated cheRNAs, cheRNA could be used as a marker to narrow down the type of cell a pluripotent stem cell is transforming intoa difficult task with current equipment.

"Many types of cells all look very similar in culture," Galat said. "You can check markers, but many markers overlapso to distinguish cell type you have to use many markers. Instead, if you can isolate the cheRNA, it could define the kind of cells you're dealing with and how functionally mature they are."

He even hopes scientists could use cheRNA to actively direct differentiation, at some point in the future.

More precise manipulation of pluripotent cells could hasten the process of genetic engineering cells with a specific functionfor example, creating highly functional cells of the immune system, which are involved in almost every aspect of health.

"That's the most interesting feature of cheRNA," Galat said. "It could serve as a way of characterizing cell type, but also as a method to direct a pluripotent cell to develop into a particular cell type."

Explore further: New tools to study the origin of embryonic stem cells

More information: Michael S Werner et al. Chromatin-enriched lncRNAs can act as cell-type specific activators of proximal gene transcription, Nature Structural & Molecular Biology (2017). DOI: 10.1038/nsmb.3424

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RNA discoveries could improve stem cell research - Phys.Org

Bone Marrow Protein May Be Target for Improving Stem Cell … – Penn: Office of University Communications

Penn: Office of University Communications

Bone Marrow Protein May Be Target for Improving Stem Cell ... Penn: Office of University Communications Researchers discovered a protein that helps bone marrow stem cells spring into action to make new blood cells. The protein, Del-1, plays a role following bone ... and more »

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Brainstorm Health: Hospitals and Harvey, VR Dementia Research, Stem Cell ‘Bad Actors’ – Fortune

Good morning, readers! This is Sy.

Hurricane Harvey has absolutely devastated Texas cities like Houston with powerful winds and torrential downpours. At least ten deaths have been reported so far (the full figure may become much higher once the flood recedes and authorities can check up on residents), and oil refining capacity has been hit hard, catalyzing a spike in gas prices.

Amid the damage, some area trauma centers have been forced to evacuate and transfer patients to other hospitals. But how does a medical facility even prepare for this level of natural disasterespecially considering the innate unpredictability of a storm?

I spoke with a physician who works at the world renowned University of Texas MD Anderson Cancer Center on the lessons its administrators learned from Hurricane Allison back in 2001. As you might guess, preparation and constant communication are key. You can read my full writeup of our chat here .

Read on for the day's news.

This VR game may help neuroscientists test dementia. A collection of European organizationsincluding London game design firm Glitchers, German mobile carrier Deutsche Telekom AG, a variety of universities, patient groups, and tech giants Samsung and Facebookhave collaborated with each other to create a game that may help neuroscientists gather more data on dementia and design a new test for the condition. Sea Hero Quest VR is being released today for the Samsung Gear VR headset and Facebook's Oculus Rift. ( Bloomberg )

AstraZeneca, Takeda join forces on Parkinson's drug. British pharma giant AstraZeneca is teaming up with Japan-based Takeda to co-develop an experimental treatment for Parkinson's disease. AstraZeneca will receive up to $400 million as part of the deal, and it gives the company an opportunity to have a neuroscience specialist like Takeda assist in a therapeutic space where AZ hasn't had much historical focus. ( Reuters )

FDA grants MDMA "breakthrough" status as PTSD drug. The Food and Drug Administration has granted its coveted "breakthrough" therapy status to MDMA, known for being the main ingredient in the recreational party drug ecstasy, as a treatment for post traumatic stress disorder. In recent years, small trials have shown that the substance may have a significantly positive effect on PTSD patients compared with current therapies. The new designation brings MDMA one step further down the regulatory pathway. ( Forbes )

FDA cracks down on stem cell clinics hawking unapproved products. The FDA is beginning to come down on stem cell clinics that sell products not cleared by the agencyincluding ones that were using modified small pox vaccines as cancer treatments."There are a small number of unscrupulous actors who have seized on the clinical promise of regenerative medicine, while exploiting the uncertainty, in order to make deceptive, and sometimes corrupt assurances to patients based on unproven and, in some cases, dangerously dubious products," said FDA Commissioner Scott Gottlieb in a statement. ( NPR )

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Brainstorm Health: Hospitals and Harvey, VR Dementia Research, Stem Cell 'Bad Actors' - Fortune

Stem cell research could double avo production – Fruitnet

Researchers at the University of Queensland (UQ) have developed a stem cell multiplication method that could double the states avocado production.

The growing method could lead to 500 times more avocado plants being supplied to the industry, and could reduce the time it takes for avocado orchards to mature.

Neena Mitter from the Queensland Alliance for Agriculture & Food Innovation, said the technology would be a potential game changer the global avocado industry,which is currently experiencing a backlog of plant orders until 2020.

At present, to supply new trees, the avocado industry follows the same process they have for the last 40 years, which is to take cuttings from high quality trees and root them, Mitter said. However, this is a cumbersome, labour and resource intensive process, as it takes about 18 months from the cutting stage to having a plant for sale, which creates a huge bottleneck for nurseries across the globe in the number of trees that they can supply trees to growers."

The non-GM and environmentally friendly technology, however, can grow and root multiple avocado plants from the shoot tip of an existing plant.

[With the new technology] ten-thousand plants can be generated in a 10m2 room on a soil-less media, Mitter said.

More than 600 plants developed by the stem cell multiplication method will be tested at different sites across Australia, with the research team also looking into whether heat-adapted avocado trees can grow alongside banana plants.

The Queensland Alliance for Agriculture & Food Innovation is a UQ research institute, with funding from the Queensland government.

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Stem cell research could double avo production - Fruitnet

Stem Cell Treatment for Children With Spina Bifida Helps Dogs First … – UC Davis

UC Davis

Stem Cell Treatment for Children With Spina Bifida Helps Dogs First ... UC Davis A pair of English bulldog puppies are the first patients to be successfully treated with a unique therapy a combination of surgery and stem cells developed ... and more »

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Human stem cell defenses activated by irradiation, study finds – Phys.Org

August 25, 2017 Credit: MIPT

Researchers from several Russian institutes, including MIPT, have found out how prolonged exposure to ionizing radiation affects human stem cells. They discovered that it causes a cell cycle delay, which leads to faster repairs of radiation-induced DNA double-strand breaks, with fewer errors. It is unclear what the health implications are, in particular, how this affects the risk of developing cancer. The paper was published in Oncotarget.

Ionizing radiation is capable of turning neutral atoms and molecules into charged ions. The human body is inevitably exposed to natural background radiation, with an average person receiving about 3 milligrays of radiation annually. Moreover, one X-ray exam amounts to anywhere from 0.001 to 10 milligrays of additional exposure, depending on the exact procedure. That said, overexposure is dangerousa dose of more than 1,000 milligrays received within a brief period of time causes acute radiation sickness.

To ensure radiation security, it is vital to assess the risks posed by ionizing radiation. Studies of people exposed to radiation have only conclusively established the increased risk of cancer as a result of receiving a high dose of radiation. This led regulating authorities to accept a linear model under which low doses of radiation also increase the risk of cancer. However, experiments show that low-dose radiation exposure either had no adverse biological effect or was even beneficial, as evidenced by prolonged lifespans and less frequent cancer occurrence.

Apart from that, the importance of the so-called dose rate should not be overlooked. Exposure to equal doses of radiation over shorter or longer time intervals has a different effect, with "slow" irradiation causing less harm. The extent to which dose rate affects the biological outcomes is a cause of much debate. In a real-life setting, people are more likely to face prolonged exposure to low-dose radiation, so it is crucial that we understand its effects.

DNA double-strand breaks

One of the negative effects of radiation is the formation of the so-called DNA double-strand breaks, in which both strands of the double helix are severed. Fortunately, the cell is capable of repairing damaged DNA. If one of the two strands is damaged, the other can be used to repair it. However, in the case of a double-strand break, more error-prone mechanisms have to be employed. Left unrepaired or misrepaired, such lesions can give rise to oncological diseases. This explains why research into the effects of radiation on living cells tends to focus on double-strand breaks. Not long ago, it was found that stem cellsfunctionally undifferentiated cellsplay a major part in the formation of tumors by accumulating mutations and passing them on to the specialized cells that are their descendants. However, stem cell response to prolonged irradiation remains poorly understood.

The scientists conducted several experiments using stem cells derived from gingivae, or the gums. They treated the cells with identical radiation doses administered over long and short time spans. The formation of double-strand breaks was monitored using stained H2AX and 53BP1 proteins as markers. With brief but intense radiation exposure, the incidence of both markers was found to increase linearly with the dose. But in the case of prolonged irradiation, the response was linear only up to a certain point, followed by a plateau at 1,000 milligrays. In other words, after reaching a certain number, the lesion count does not continue to rise. A balance of sorts is achieved between break formation and repair.

DNA repair

The cell comes equipped with repair systems capable of mending DNA double-strand breaks. However, following intense irradiation, the cell has to resort to a mechanism known as end joininga quick but faulty procedurein eight out of 10 double-strand breaks. This often leads to chromosomal aberrations. Such misrepairs of DNA breaks can potentially result in cell death, oncogene activation, and anti-oncogene suppression. But there is an alternative mechanism of DNA repair, called homologous recombination. It uses a similar or identical DNA molecule as a template and produces far fewer errors, but it is only available during certain phases in the cell cycle. The researchers monitored homologous recombination using Rad51, another protein marker. During a two-hour long exposure, the amount of Rad51 remained roughly constant, followed by a linear growth afterward. The team hypothesized that prolonged irradiation might activate homologous recombination.

Cell division

Stem cells can be divided into two groups, called proliferating and quiescent, in which the former undergo division, the latter have ceased reproducing, and there is a balance between the two types of cells. The researchers counted the DNA double-strand breaks in proliferating and quiescent cells separately. This is made possible by a certain protein that is only found in cells undergoing division. It turned out that in both types of cells, the number of DNA breaks grew, eventually reaching a constant value.

The researchers also observed that exposure to radiation did not change the roughly four to one ratio between proliferating and quiescent cells. However, a more detailed investigation revealed that four hours of "slow" irradiation results in a considerably increased number of cells in the S and G2 phases of the cyclethat is, DNA synthesis and final preparation for division, respectively. It is during these phases that a copy of the cell's DNA is available for the sake of division, but also to be used as a template in homologous recombination. This fact is a likely explanation for the detection of increased amounts of the Rad51 marker. To put it another way, irradiation causes a delay in the cell cycleas a result, at any given time, there are more cells in those phases that enable homologous recombination. This means it is possible to repair DNA double-strand breaks correctly.

"We have shown that prolonged irradiation of mesenchymal stem cells leads to cell cycle redistribution. This might influence the biological response to radiation," says Sergey Leonov, the director of the Phystech School of Biological and Medical Physics. "Our findings could become the basis of further research into double breaks in stem cells and their effect on tumor formation."

Explore further: How breaks in DNA are repaired

More information: Anastasia Tsvetkova et al, H2AX, 53BP1 and Rad51 protein foci changes in mesenchymal stem cells during prolonged X-ray irradiation, Oncotarget (2017). DOI: 10.18632/oncotarget.19203

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Human stem cell defenses activated by irradiation, study finds - Phys.Org

For Immune System Stem Cell Studies, Mice Aren’t Enough – Science 2.0

For Immune System Stem Cell Studies, Mice Aren't Enough Science 2.0 The researchers conclude that the humanized mouse model is not suitable for studying the human immune response to transplanted stem cells or cells derived from them. "In an ideal situation, these humanized mice would reject foreign stem cells just as a ... and more »

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For Immune System Stem Cell Studies, Mice Aren't Enough - Science 2.0

North Carolina Advances in Stem Cell Therapy for Lung Diseases Could Lead to Clinical Trial Soon – Lung Disease News

University of North Carolina Health Careresearchers have made strides toward a stem cell treatment for lung diseases such as pulmonary fibrosis, COPD, and cystic fibrosis.

In fact, they are discussing the start of clinical trials with regulatory authorities.

The team discussed its work in two recent studies. One provedthat it is possible to isolate lung stem cells with a relatively non-invasive procedure. The other showed that stem cells reduce fibrosis in rats with pulmonary fibrosis.

The first study, in the journal Respiratory Research, was titledDerivation of therapeutic lung spheroid cells from minimally invasive transbronchial pulmonary biopsies.The second, inStem Cells Translational Medicine, was Safety and Efficacy of Allogeneic Lung Spheroid Cells in a Mismatched Rat Model of Pulmonary Fibrosis.

This is the first time anyone has generated potentially therapeutic lung stem cells from minimally invasive biopsy specimens, Dr. Jason Lobo, director of the universitys lung transplant and interstitial lung disease program,said in a press release. Hewas co-senior author of both studies.

We think the properties of these cells make them potentially therapeutic for a wide range of lung fibrosis diseases, added Dr. Ke Cheng, who led the studies with Lobo. He is anassociate professor in North Carolina State Universitys Department of Molecular Biomedical Sciences.

The research team had previously homed in on stem and support cells they could isolate from a lung tissue sample and grow in a lab. The tissue formed sphere-like structures in a lab dish, prompting the scientists to call them lung spheroid cells.

In 2015, the team showed that these cells had potent regenerative properties in animals with lung diseases. In fact, the stem cells they cultivated outperformed another type called mesenchymal stem cells.

Their latest project involved gathering lung spheroid cells from patients with various lung diseases. They used a procedure calleda transbronchial biopsy thatcan be done in a doctors office.

We snip tiny, seed-sized samples of airway tissue using a bronchoscope, Lobo said. This method involves far less risk to the patient than does a standard, chest-penetrating surgical biopsy of lung tissue.

From this tiny piece of airway, researchers gathered stem cells, then allowed them to multiply because stem cell treatments require infusions of millions of such cells.

When they injected the cells intravenously into mice, the discovered that most found their way into the animals lungs.

These cells are from the lung, and so in a sense theyre happiest, so to speak, living and working in the lung, Cheng said.

The team then tested the treatment in rats exposed to a chemical that triggers lung fibrosis. The lung spheroid cells gave rise to healthy lung cells, reducing both inflammation and fibrosis in the animals lungs.

Also, the treatment was safe and effective whether the lung spheroid cells were derived from the recipients own lungs or from the lungs of an unrelated strain of rats, Lobo said. In other words, even if the donated stem cells were foreign, they did not provoke a harmful immune reaction in the recipient animals, as transplanted tissue normally does.

The researchers said that in humans their goal would be to use patients own stem cells to minimize the risk of immune reactions. But because large quantities of cells are needed, it might be necessary to gather cells from healthy volunteers or organ donation networks as well.

Our vision is that we will eventually set up a universal cell donor bank, Cheng said.

The team is in discussions with the U.S. Food and Drug Administration aimed at starting the first human study by years end. The first trial would include a small group of pulmonary fibrosis patients. The team also hopes their spheroid stem cell therapy will help patients with other lung diseases.

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North Carolina Advances in Stem Cell Therapy for Lung Diseases Could Lead to Clinical Trial Soon - Lung Disease News

Vitamin C Regulates Stem Cell Function – Technology Networks

Not much is known about stem cell metabolism, but a new study from the Childrens Medical Center Research Institute at UT Southwestern (CRI) has found that stem cells take up unusually high levels of vitamin C, which then regulates their function and suppresses the development of leukemia.

We have known for a while that people with lower levels of ascorbate (vitamin C) are at increased cancer risk, but we havent fully understood why. Our research provides part of the explanation, at least for the blood-forming system, said Dr. Sean Morrison, the Director of CRI.

The metabolism of stem cells has historically been difficult to study because a large number of cells are required for metabolic analysis, while stem cells in each tissue of the body are rare. Techniques developed during the study, which was published in Nature, have allowed researchers to routinely measure metabolite levels in rare cell populations such as stem cells.

The techniques led researchers to discover that every type of blood-forming cell in the bone marrow had distinct metabolic signatures taking up and using nutrients in their own individual way. One of the main metabolic features of stem cells is that they soak up unusually high levels of ascorbate. To determine if ascorbate is important for stem cell function, researchers used mice that lacked gulonolactone oxidase (Gulo) a key enzyme that most mammals, including mice but not humans, use to synthesize their own ascorbate.

Loss of the enzyme requires Gulo-deficient mice to obtain ascorbate exclusively through their diet like humans do. This gave CRI scientists strict control over ascorbate intake by the mice and allowed them to mimic ascorbate levels seen in approximately 5 percent of healthy humans. At these levels, researchers expected depletion of ascorbate might lead to loss of stem cell function but were surprised to find the opposite was true stem cells actually gained function. However, this gain came at the cost of increased instances of leukemia.

Stem cells use ascorbate to regulate the abundance of certain chemical modifications on DNA, which are part of the epigenome, said Dr. Michalis Agathocleous, lead author of the study, an Assistant Instructor at CRI, and a Royal Commission for the Exhibition of 1851 Research Fellow. The epigenome is a set of mechanisms inside a cell that regulates which genes turn on and turn off. So when stem cells dont receive enough vitamin C, the epigenome can become damaged in a way that increases stem cell function but also increases the risk of leukemia.

This increased risk is partly tied to how ascorbate affects an enzyme known as Tet2, the study showed. Mutations that inactivate Tet2 are an early step in the formation of leukemia. CRI scientists showed that ascorbate depletion can limit Tet2 function in tissues in a way that increases the risk of leukemia.

These findings have implications for older patients with a common precancerous condition known as clonal hematopoiesis. This condition puts patients at a higher risk of developing leukemia and other diseases, but it is not well understood why certain patients with the condition develop leukemia and others do not. The findings in this study might offer an explanation.

One of the most common mutations in patients with clonal hematopoiesis is a loss of one copy of Tet2. Our results suggest patients with clonal hematopoiesis and a Tet2 mutation should be particularly careful to get 100 percent of their daily vitamin C requirement, Dr. Morrison said. Because these patients only have one good copy of Tet2 left, they need to maximize the residual Tet2 tumor-suppressor activity to protect themselves from cancer.

Researchers in the Hamon Laboratory for Stem Cell and Cancer Biology, in which Dr. Morrison is also appointed, intend to use the techniques developed as part of this study to find other metabolic pathways that control stem cell function and cancer development. They also plan to further explore the role of vitamin C in stem cell function and tissue regeneration.

This article has been republished frommaterialsprovided byUT Southwestern Medical Center. Note: material may have been edited for length and content. For further information, please contact the cited source.

Reference:

Agathocleous, M., Meacham, C. E., Burgess, R. J., Piskounova, E., Zhao, Z., Crane, G. M., . . . Morrison, S. J. (2017). Ascorbate regulates haematopoietic stem cell function and leukaemogenesis. Nature. doi:10.1038/nature23876

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Vitamin C Regulates Stem Cell Function - Technology Networks

Belize Biochemist’s Groundbreaking Stem Cell Research – Channel 7 Daily News

Belize Biochemist's Groundbreaking Stem Cell Research Channel 7 Daily News A young Belizean's groundbreaking research has been published in a top US medical Journal. On Monday, Aimee Flores, who is pursuing a Ph.D in Stem Cell Research and Bio-chemistry at UCLA had her paper published in the "Nature Cell Biology", ... and more »

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Belize Biochemist's Groundbreaking Stem Cell Research - Channel 7 Daily News