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July 2020

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Mouse model suggests that glioblastoma tumors may originate in a brain region distinct from where it becomes a lethal disease — ScienceDaily

A mouse model of glioblastoma, an aggressive type of cancer that can occur in the brain, suggests that this recalcitrant cancer originates from a pool of stem cells that can be a significant distance away from the resulting tumors. The findings of a new study, led by Children’s National Hospital researchers and published July 22 in the journal Nature Communications, suggest new ways to fight this deadly disease.

Despite decades of research, glioblastoma remains the most common and lethal primary brain tumor in adults, with a median survival of only 15 months from diagnosis, says study leader Yuan Zhu, Ph.D., the scientific director and endowed professor of the Gilbert Family Neurofibromatosis Institute at Children’s National. Unlike many cancers, which start out as low-grade tumors that are more treatable when they’re caught at an early stage, most glioblastomas are almost universally discovered as high-grade and aggressive lesions that are difficult to treat with the currently available modalities, including surgery, radiation and chemotherapy.

“Once the patient has neurological symptoms like headache, nausea, and vomiting, the tumor is already at an end state, and disease progression is very rapid,” Dr. Zhu says. “We know that the earlier you catch and treat cancers, the better the prognosis will be. But here, there’s no way to catch the disease early.”

However, some recent research in glioblastoma patients shows that the subventricular zone (SVZ) — an area that serves as the largest source of stem cells in the adult brain — contains cells with cancer-driving mutations that are shared with tumors found in other often far-distant brain regions.

To see if the SVZ might be the source for glioblastoma tumors, Dr. Zhu and his colleagues worked with mouse models that carried a single genetic glitch: a mutation in a gene known as p53 that typically suppresses tumors. Mutations in p53 are known to be involved in glioblastoma and many other forms of cancer.

Starting from about 5.5 months old, these animals received weekly brain scans to look for tumors that arise when the stem cells subsequently acquire more mutations. Those mice that developed brain tumors fell into two categories. While about 30% developed a single mass that appeared at a high grade, the majority of these animals developed high-grade tumors at multiple spatially segregated areas.

Using genetic tests and an approach akin to those used to study evolution, the researchers traced the cells that spurred both kinds of tumors back to the SVZ. Although both single and multiple tumors had spontaneously acquired mutations in a gene called Pten, another type of tumor suppressor, precursor cells for the single tumors appeared to acquire this mutation before they left the SVZ, while precursor cells for the multiple tumors developed this mutation after they left the stem cell niche. When the researchers genetically altered the animals to shut down the molecular pathway that loss of Pten activates, it didn’t stop cancer cells from forming. However, rather than migrate to distal areas of the brain, these malignant cells remained in the SVZ.

Dr. Zhu notes that these findings could help explain why glioblastoma is so difficult to identify the early precursor lesions and treat. This work may offer potential new options for attacking this cancer. If new glioblastoma tumors are seeded by cells from a repository in the SVZ, he explains, attacking those tumors won’t be enough to eradicate the cancer. Instead, new treatments might focus on this stem cell niche as target for treatment or even a zone for surveillance to prevent glioblastoma from developing in the first place.

Another option might be to silence the Pten-suppressed pathway through drugs, a strategy that’s currently being explored in various clinical trials. Although these agents haven’t shown yet that they can stop or reverse glioblastomas, they might be used to contain cancers in the SVZ as this strategy did in the mouse model — a single location that might be easier to attack than tumors in multiple locations.

“The more we continue to learn about glioblastoma,” Dr. Zhu says, “the more hope we can give to these patients who currently have few effective options.”

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Materials provided by Children’s National Hospital. Note: Content may be edited for style and length.

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How airway cells work together in regeneration and aging — ScienceDaily

Researchers at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA have identified the process by which stem cells in the airways of the lungs switch between two distinct phases — creating more of themselves and producing mature airway cells — to regenerate lung tissue after an injury.

The study, published in Cell Stem Cell, also sheds light on how aging can cause lung regeneration to go awry, which can lead to lung cancer and other diseases.

“There currently are few therapies that target the biology of lung diseases,” said Dr. Brigitte Gomperts, a professor and vice chair of research in pediatric hematology-oncology at the UCLA Children’s Discovery and Innovation Institute and the paper’s senior author. “These findings will inform our efforts to develop a targeted therapy to improve airway health.”

The airways, which carry the air that is breathed in from the nose and mouth to the lungs, are the body’s first line of defense against airborne particles — like germs and pollution — that can cause illness.

Two types of airway cells play a vital role in this process: mucus cells, which secrete mucus to trap harmful particles, and ciliated cells, which use their finger-like projections to sweep the mucus-engulfed particles up to the back of the throat, where they can be cleared out of the lungs.

The infectious or toxic particles that people breathe in every day can injure the airways and when that happens, airway basal stem cells — which are capable of self-renewing and producing the mucus and ciliated cells that line the airways — activate to repair the damage.

To keep the right balance of each cell type, airway basal stem cells must transition from the proliferative phase, during which they produce more of themselves, to the differentiation phase, during which they give rise to mature airway cells.

“These stem cells have to maintain a really delicate equilibrium,” said Gomperts, who is also co-director of the cancer and stem cell biology program at the UCLA Jonsson Comprehensive Cancer Center. “They have to produce just the right amount of mucus and ciliated cells to keep harmful particles out of the lungs, but they also have to self-replicate to ensure there will be enough stem cells to respond to the next injury.”

In the new study, the researchers examined mice with lung injuries, analyzing how the different types of cells found in the niche — the supportive environment that surrounds airway basal stem cells — work together to orchestrate the repair response.

They found that a group of molecules known as the Wnt/beta-catenin signaling pathway activates to stimulate the airway basal stem cells to respond to injury. The researchers were surprised to discover that this group of molecules originates in one cell type to initiate proliferation and another cell type to initiate differentiation.

In the proliferation phase of repair, a connective tissue cell called a fibroblast secretes the Wnt molecule, which signals to the stem cells that it’s time to self-renew. In the differentiation phase of repair, the Wnt molecule is secreted by an epithelial cell, which make up the lining of tissues and organs, to signal to the stem cells that it’s time to produce mature airway cells.

Understanding how regeneration occurs in healthy lungs is a critical first step to understanding how disease can arise when the process goes wrong. Seeking insights into what role this process and the cells that activate it might play in disease, the scientists studied its activity in older mice.

“We were surprised to find that in the aging airways, the Wnt/beta-catenin signaling pathway is active in the stem cells even when there is no injury, in contrast to the young airways where it is only activated when necessary,” said Cody Aros, the paper’s first author, a UCLA medical student who recently completed his doctoral research. “When this pathway is active, it stimulates the stem cells to produce more of themselves and more airway cells — even if they’re not needed.”

Previous research by Gomperts’ lab has established a link between a more active Wnt/beta-catenin pathway and lung cancer.

“The more a cell divides, the more likely it is that a proofreading error or mutation can occur and lead to cancer,” Gomperts said.

The new paper builds on that work by establishing not just what goes wrong but precisely when it goes wrong in otherwise healthy people as part of the aging process.

“These findings give us insight into which cell types are important, which pathway is important and when we might want to think about intervening with therapies to prevent the formation of cancer,” Aros said.

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New roles of autophagy in stem cell renewal and differentiation uncovered — ScienceDaily

The self-eating process in embryonic stem cells known as chaperone-mediated autophagy (CMA) and a related metabolite may serve as promising new therapeutic targets to repair or regenerate damaged cells and organs, Penn Medicine researchers show in a new study published online in Science.

Human bodies contain over 200 different types of specialized cells. All of them can be derived from embryonic stem (ES) cells, which relentlessly self-renew while retaining the ability to differentiate into any cell type in adult animals, a state known as pluripotency. Researchers have known that the cells’ metabolism plays a role in this process; however, it wasn’t clear exactly how the cells’ internal wiring works to keep that state and ultimately decide stem cell fate.

The new preclinical study, for the first time, shows how the stem cells keeps CMA at low levels to promote that self-renewal, and when the stem cell is ready, it switches that suppression off to enhance CMA, among other activities, and differentiate into specialized cells.

“It’s an intriguing discovery in the field of stem cell biology and for researchers looking to develop therapies for tissue or organ regeneration,” said senior author Xiaolu Yang, PhD, a professor of Cancer Biology at the Abramson Family Cancer Research Institute in the Perelman School of Medicine at the University of Pennsylvania. “We reveal two novel ways to potentially manipulate the self-renewal and differentiation of stem cells: CMA and a metabolite, known as alpha-ketoglutarate, that is regulated by CMA. Rationally intervening or guiding these functions could be a powerful way to increase the efficiency of regenerative medicine approaches.”

Autophagy is a cell-eating mechanism necessary for survival and function of most living organisms. When cells self-eat, the intracellular materials are delivered to lysosomes, which are organelles that help break down these materials. There are a few forms of autophagy. However, unlike the other forms, which are present in all eukaryotic cells, CMA is unique to mammals. To date, the physiological role of CMA remains unclear.

Using metabolomic and genetic laboratory techniques on the embryonic stem cells of mice, the researchers sought to better understand significant changes that took place during their pluripotent state and subsequent differentiation.

They found that CMA activity is kept at a minimum due to two cellular factors critical for pluripotency — Oct4 and Sox2 — that suppresses a gene known as LAMP2A, which provides instructions for making a protein called lysosomal associated membrane protein-2 necessary in CMA. The minimal CMA activity allows stem cells to maintain high levels of alpha-ketoglutarate, a metabolite that is crucial to reinforce a cell’s pluripotent state, the researchers found.

When it’s time for differentiation, the cells begin to upregulate CMA due to the reduction in Oct4 and Sox2. Augmented CMA activity leads to the degradation of key enzymes responsible for the production of alpha-ketoglutarate. This leads to a reduction in alpha-ketoglutarate levels as well as an increases in other cellular activities to promote differentiation. These findings reveal that CMA and alpha-ketoglutarate dictate the fate of embryonic stem cells.

Embryonic stem cells are often called pluripotent due to their remarkable ability to give rise to every cell type in the body, except the placenta and umbilical cord. Embryonic stem cells not only provide a superb system to study early mammalian development, but also hold great promise for regenerative therapies to treat various human disorders. The development of stem-cell based regenerative medicine therapies has rapidly increased in the last decade, with several approaches in studies shown to repair damaged heart tissue, replace cells in solid organ transplantation, and in some cases address neurological disorders.

“This newly discovered role of autophagy in the stem cell is the beginning of further investigations that could lead to researchers and physician-scientists to better therapies to treat various disorders,” Yang said.

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Skin stem cells shuffle sugars as they age — ScienceDaily

Age shows nowhere better than on the skin. The ravages of time on skin and the epidermal stem cells that differentiate to replenish its outer layer have been hypothesized, but there has been no method to evaluate their aging at the molecular level. Now, researchers at the University of Tsukuba and the National Institute of Advanced Industrial Science and Technology (AIST) have revealed that changes in the complex sugars called glycans that coat the surface of epidermal stem cells can serve as a potential biological marker of aging.

Skin is the largest human organ and a vital barrier against infection and fluid loss. Aging impairs environmental defenses and wound healing, while increasing hair loss and cancer risk. A key process underlying epidermal function in health and disease is cellular glycosylation that mediates cell-cell interactions and cell-matrix adhesions. Glycosylation involves attaching glycans to proteins; the profile of all glycans on and in a cell — collectively ‘the cell glycome’ — could reflect its functional scope and serve as an index of its age.

The researchers first isolated epidermal stem cells from the skin of young and old laboratory mice, including both hair follicle cells and interfollicular epidermal cells. These cells underwent glycan profiling using the lectin microarray platform; this technique uses lectins — proteins that bind specific glycans — and enables glycome analysis even for cells sparsely dispersed in tissues.

“Our results clearly showed that high mannose-type N-glycans are replaced by a2-3/6 sialylated complex type N-glycans in older epidermal stem cells,” senior author, Professor Hiromi Yanagisawa, explains. “We followed this with gene expression analysis; this revealed up-regulation of a glycosylation-related mannosidase and two sialyltransferase genes, suggesting that this ‘glycome shift’ may be mediated by age-modulated glycosyltransferase and glycosidase expression.”

Finally, to check whether the glycan changes were the cause or merely the result of aging, the research team overexpressed the up-regulated glycogenes in primary epidermal mouse keratinocytes in vitro. The keratinocytes showed decreased mannose and increased Sia modifications, replicating the in vivo glycosylation pattern of aging epidermal stem cells. In addition, their decreased ability to proliferate suggested that these alterations may reflect the waning ability of aging epidermal stem cells to proliferate.

Professor Aiko Sada, currently Principal Investigator at Kumamoto University, and Professor Hiroaki Tateno at AIST, co-corresponding authors, explain the implications of their results. “Our work is broadly targeted at investigating stem cell dysfunction specifically in aging skin. Future advances may help manage skin disorders at the stem cell level, including age-related degenerative changes, impaired wound healing and cancer.”

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The same cell types that cause goosebumps are responsible for controlling hair growth — ScienceDaily

If you’ve ever wondered why we get goosebumps, you’re in good company — so did Charles Darwin, who mused about them in his writings on evolution. Goosebumps might protect animals with thick fur from the cold, but we humans don’t seem to benefit from the reaction much — so why has it been preserved during evolution all this time?

In a new study, Harvard University scientists have discovered the reason: the cell types that cause goosebumps are also important for regulating the stem cells that regenerate the hair follicle and hair. Underneath the skin, the muscle that contracts to create goosebumps is necessary to bridge the sympathetic nerve’s connection to hair follicle stem cells. The sympathetic nerve reacts to cold by contracting the muscle and causing goosebumps in the short term, and by driving hair follicle stem cell activation and new hair growth over the long term.

Published in the journal Cell, these findings in mice give researchers a better understanding of how different cell types interact to link stem cell activity with changes in the outside environment.

“We have always been interested in understanding how stem cell behaviors are regulated by external stimuli. The skin is a fascinating system: it has multiple stem cells surrounded by diverse cell types, and is located at the interface between our body and the outside world. Therefore, its stem cells could potentially respond to a diverse array of stimuli — from the niche, the whole body, or even the outside environment,” said Ya-Chieh Hsu, the Alvin and Esta Star Associate Professor of Stem Cell and Regenerative Biology, who led the study in collaboration with Professor Sung-Jan Lin of National Taiwan University. “In this study, we identify an interesting dual-component niche that not only regulates the stem cells under steady state, but also modulates stem cell behaviors according to temperature changes outside.”

A system for regulating hair growth

Many organs are made of three types of tissue: epithelium, mesenchyme, and nerve. In the skin, these three lineages are organized in a special arrangement. The sympathetic nerve, part of our nervous system that controls body homeostasis and our responses to external stimuli, connects with a tiny smooth muscle in the mesenchyme. This smooth muscle in turn connects to hair follicle stem cells, a type of epithelial stem cell critical for regenerating the hair follicle as well as repairing wounds.

The connection between the sympathetic nerve and the muscle has been well known, since they are the cellular basis behind goosebumps: the cold triggers sympathetic neurons to send a nerve signal, and the muscle reacts by contracting and causing the hair to stand on end. However, when examining the skin under extremely high resolution using electron microscopy, the researchers found that the sympathetic nerve not only associated with the muscle, but also formed a direct connection to the hair follicle stem cells. In fact, the nerve fibers wrapped around the hair follicle stem cells like a ribbon.

“We could really see at an ultrastructure level how the nerve and the stem cell interact. Neurons tend to regulate excitable cells, like other neurons or muscle with synapses. But we were surprised to find that they form similar synapse-like structures with an epithelial stem cell, which is not a very typical target for neurons,” Hsu said.

Next, the researchers confirmed that the nerve indeed targeted the stem cells. The sympathetic nervous system is normally activated at a constant low level to maintain body homeostasis, and the researchers found that this low level of nerve activity maintained the stem cells in a poised state ready for regeneration. Under prolonged cold, the nerve was activated at a much higher level and more neurotransmitters were released, causing the stem cells to activate quickly, regenerate the hair follicle, and grow new hair.

The researchers also investigated what maintained the nerve connections to the hair follicle stem cells. When they removed the muscle connected to the hair follicle, the sympathetic nerve retracted and the nerve connection to the hair follicle stem cells was lost, showing that the muscle was a necessary structural support to bridge the sympathetic nerve to the hair follicle.

How the system develops

In addition to studying the hair follicle in its fully formed state, the researchers investigated how the system initially develops — how the muscle and nerve reach the hair follicle in the first place.

“We discovered that the signal comes from the developing hair follicle itself. It secretes a protein that regulates the formation of the smooth muscle, which then attracts the sympathetic nerve. Then in the adult, the interaction turns around, with the nerve and muscle together regulating the hair follicle stem cells to regenerate the new hair follicle. It’s closing the whole circle — the developing hair follicle is establishing its own niche,” said Yulia Shwartz, a postdoctoral fellow in the Hsu lab. She was a co-first author of the study, along with Meryem Gonzalez-Celeiro, a graduate student in the Hsu Lab, and Chih-Lung Chen, a postdoctoral fellow in the Lin lab.

Responding to the environment

With these experiments, the researchers identified a two-component system that regulates hair follicle stem cells. The nerve is the signaling component that activates the stem cells through neurotransmitters, while the muscle is the structural component that allows the nerve fibers to directly connect with hair follicle stem cells.

“You can regulate hair follicle stem cells in so many different ways, and they are wonderful models to study tissue regeneration,” Shwartz said. “This particular reaction is helpful for coupling tissue regeneration with changes in the outside world, such as temperature. It’s a two-layer response: goosebumps are a quick way to provide some sort of relief in the short term. But when the cold lasts, this becomes a nice mechanism for the stem cells to know it’s maybe time to regenerate new hair coat.”

In the future, the researchers will further explore how the external environment might influence the stem cells in the skin, both under homeostasis and in repair situations such as wound healing.

“We live in a constantly changing environment. Since the skin is always in contact with the outside world, it gives us a chance to study what mechanisms stem cells in our body use to integrate tissue production with changing demands, which is essential for organisms to thrive in this dynamic world,” Hsu said.

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Discovery could open new doors for heart research — ScienceDaily

In a groundbreaking new study, researchers at the University of Minnesota have 3D printed a functioning centimeter-scale human heart pump in the lab. The discovery could have major implications for studying heart disease, the leading cause of death in the United States killing more than 600,000 people a year.

The study is published and appears on the cover of Circulation Research, a publication of the American Heart Association.

In the past, researchers have tried to 3D print cardiomyocytes, or heart muscle cells, that were derived from what are called pluripotent human stem cells. Pluripotent stem cells are cells with the potential to develop into any type of cell in the body. Researchers would reprogram these stem cells to heart muscle cells and then use specialized 3D printers to print them within a three-dimensional structure, called an extracellular matrix. The problem was that scientists could never reach critical cell density for the heart muscle cells to actually function.

In this new study, University of Minnesota researchers flipped the process, and it worked.

“At first, we tried 3D printing cardiomyocytes, and we failed, too,” said Brenda Ogle, the lead researcher on the study and head of the Department of Biomedical Engineering in the University of Minnesota College of Science and Engineering. “So with our team’s expertise in stem cell research and 3D printing, we decided to try a new approach. We optimized the specialized ink made from extracellular matrix proteins, combined the ink with human stem cells and used the ink-plus-cells to 3D print the chambered structure. The stem cells were expanded to high cell densities in the structure first, and then we differentiated them to the heart muscle cells.”

What the team found was that for the first time ever they could achieve the goal of high cell density within less than a month to allow the cells to beat together, just like a human heart.

“After years of research, we were ready to give up and then two of my biomedical engineering Ph.D. students, Molly Kupfer and Wei-Han Lin, suggested we try printing the stem cells first,” said Ogle, who also serves as director of the University of Minnesota’s Stem Cell Institute. “We decided to give it one last try. I couldn’t believe it when we looked at the dish in the lab and saw the whole thing contracting spontaneously and synchronously and able to move fluid.”

Ogle said this is also a critical advance in heart research because this new study shows how they were able to 3D print heart muscle cells in a way that the cells could organize and work together. Because the cells were differentiating right next to each other it’s more similar to how the stem cells would grow in the body and then undergo specification to heart muscle cells.

Compared to other high-profile research in the past, Ogle said this discovery creates a structure that is like a closed sac with a fluid inlet and fluid outlet, where they can measure how a heart moves blood within the body. This makes it an invaluable tool for studying heart function.

“We now have a model to track and trace what is happening at the cell and molecular level in pump structure that begins to approximate the human heart,” Ogle said. “We can introduce disease and damage into the model and then study the effects of medicines and other therapeutics.”

The heart muscle model is about 1.5 centimeters long and was specifically designed to fit into the abdominal cavity of a mouse for further study.

“All of this seems like a simple concept, but how you achieve this is quite complex. We see the potential and think that our new discovery could have a transformative effect on heart research,” Ogle said.

In addition to Ogle, Kupfer and Lin, other University of Minnesota researchers involved include University of Minnesota College of Science and Engineering faculty Professor Alena G. Tolkacheva (biomedical engineering) and Professor Michael McAlpine (mechanical engineering); University of Minnesota Medical School Associate Professor DeWayne Townsend (integrative biology and physiology); current and former University of Minnesota master’s, Ph.D. students and postdocs Vasanth Ravikumar (electrical engineering), Kaiyan Qiu (Ph.D., mechanical engineering), and Didarul B. Bhuiyan (Ph.D.), Megan Lenz (M.S.), and Ryan R. Mahutga (biomedical engineering); and undergraduate student Jeffrey Ai (biomedical engineering). The team also included University of Alabama Department of Biomedical Engineering Professor and Chair Jianyi Zhang and University of Alabama biomedical engineering Ph.D. student Lu Wang and research associate Ling Gao (Ph.D.).

This research was primarily funded by the National Institutes of Health (National Heart Lung and Blood Institute, National Institute of Biomedical Imaging and Bioengineering, and National Institute of General Medical Science) with additional funding from the National Science Foundation Graduate Research Fellowship Project and the University of Minnesota Doctoral Dissertation Fellowship.

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Findings could lead to new therapies for cancer, heart abnormalities — ScienceDaily

Look deep inside our cells, and you’ll find that each has an identical genome -a complete set of genes that provides the instructions for our cells’ form and function.

But if each blueprint is identical, why does an eye cell look and act differently than a skin cell or brain cell? How does a stem cell — the raw material with which our organ and tissue cells are made — know what to become?

In a study published July 8, University of Colorado Boulder researchers come one step closer to answering that fundamental question, concluding that the molecular messenger RNA (ribonucleic acid) plays an indispensable role in cell differentiation, serving as a bridge between our genes and the so-called “epigenetic” machinery that turns them on and off.

When that bridge is missing or flawed, the researchers report in the journal Nature Genetics, a stem cell on the path to becoming a heart cell never learns how to beat.

The paper comes at a time when pharmaceutical companies are taking unprecedented interest in RNA. And, while the research is young, it could ultimately inform development of new RNA-targeted therapies, from cancer treatments to therapies for cardiac abnormalities.

“All genes are not expressed all the time in all cells. Instead, each tissue type has its own epigenetic program that determines which genes get turned on or off at any moment,” said co-senior author Thomas Cech, a Nobel laureate and distinguished professor of biochemistry. “We determined in great detail that RNA is a master regulator of this epigenetic silencing and that in the absence of RNA, this system cannot work. It is critical for life.”

Scientists have known for decades that while each cell has identical genes, cells in different organs and tissues express them differently. Epigenetics, or the machinery that switches genes on or off, makes this possible.

But just how that machinery works has remained unclear.

In 2006, John Rinn, now a professor of biochemistry at CU Boulder and co-senior-author on the new paper, proposed for the first time that RNA — the oft-overlooked sibling of DNA (deoxyribonucleic acid) — might be key.

In a landmark paper in Cell, Rinn showed that inside the nucleus, RNA attaches itself to a folded cluster of proteins called polycomb repressive complex (PRC2), which is believed to regulate gene expression. Numerous other studies have since found the same and added that different RNAs also bind to different protein complexes.

The hotly debated question: Does this actually matter in determining a cell’s fate?

No fewer than 502 papers have been published since. Some determined RNA is key in epigenetics; others dismissed its role as tangential at best.

So, in 2015, Yicheng Long, a biochemist and postdoctoral researcher in Cech’s lab, set out to ask the question again using the latest available tools. After a chance meeting in a breakroom at the BioFrontiers Institute where both their labs are housed, Long bumped into Taeyoung Hwang, a computational biologist in Rinn’s lab.

A unique partnership was born.

“We were able to use data science approaches and high-powered computing to understand molecular patterns and evaluate RNA’s role in a novel, quantitative way,” said Hwang, who along with Long is co-first-author on the new paper.

In the lab, the team then used a simple enzyme to remove all RNA in cells to understand whether the epigenetic machinery still found its way to DNA to silence genes. The answer was ‘no.’

“RNA seemed to be playing the role of air traffic controller, guiding the plane — or protein complex — to the right spot on the DNA to land and silence genes,” said Long.

For a third step, they used the gene-editing technology known as CRISPR to develop a line of stem cells destined to become human heart muscle cells but in which the protein complex, PRC2, was incapable of binding to RNA. In essence, the plane couldn’t connect with air-traffic control and lost its way, and the process fell apart.

By day 7, the normal stem cells had begun to look and act like heart cells. But the mutant cells didn’t beat. Notably, when normal PRC2 was restored, they began to behave more normally.

“We can now say, unequivocally, that RNA is critical in this process of cell differentiation,” said Long.

Previous research has already shown that genetic mutations in humans that disrupt RNA’s ability to bind to these proteins boost risk of certain cancers and fetal heart abnormalities. Ultimately, the researchers envision a day when RNA-targeted therapies could be used to address such problems.

“These findings will set a new scientific stage showing an inextricable link between epigenetics and RNA biology,” said Rinn. “They could have broad implications for understanding, and addressing, human disease going forward.”

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New clues from fruit flies about the critical role of sex hormones in stem cell control — ScienceDaily

In one of the first studies addressing the role of sex hormones’ impact on stem cells in the gut, scientists outline new insights showing how a steroidal sex hormone, that is structurally and functionally similar to human steroid hormones, drastically alters the way intestinal stem cells behave, ultimately affecting the overarching structure and function of this critical organ. The authors found that ecdysone, a steroid hormone produced by fruit flies, stimulates intestinal stem cell growth and causes the gut of the female fruit fly to grow in size, and induces other critical changes. The study also provides a mechanism to account for sex-specific roles for intestinal stem cells in normal gut function. Moreover, the research presents evidence that gut hormones may accelerate tumor development. The findings, reported jointly by Huntsman Cancer Institute (HCI) at the University of Utah (U of U) and the German Cancer Research Center (DKFZ), are published today in the journal Nature.

Bruce Edgar, PhD, a stem cell biologist at HCI and professor of oncological sciences at the U of U, together with Aurelio Teleman, PhD, division head at DKFZ and professor at Heidelberg University jointly led the work. They asked whether sex hormones affect intestinal stem cells’ ability to multiply and contribute to gut growth. “My lab and many others around the world have studied the Drosophila gut for some time to better understand how stem cells are regulated,” says Edgar. “We knew that male and female fruit flies exhibited differences in their intestine — for example, the female’s intestine is larger than the male’s, and females develop intestinal tumors much more readily than males — but we didn’t know why.” This study adds significant insights into these differences, and how they arise.

The Edgar and Teleman teams found that ecdysone, a sex-specific hormone, can drastically alter the growth properties of stem cells in an organ that, remarkably, is not directly involved in reproduction. They found that these changes affect the structure and function of the entire organ. They discovered that subjecting male flies to ecdysone caused their otherwise slow dividing stem cells to divide as fast as in females, leading to intestinal growth in males as well. This suggests that the limiting difference between the division of stem cells in male and female flies is the circulating levels of the hormone.

This process confers both advantages and disadvantages to the female fruit fly during the course of its life. Initially, more ecdysone in females helps with the evolutionarily critical processes of reproduction. It promotes gut enlargement, facilitating nutrient absorption, which helps the fly lay more eggs. But later in life, the ecdysone hormone, produced by the ovaries, eventually causes gut disfunction that can shorten the lifespan in female fruit flies by creating an environment that favors tumor growth. While humans don’t produce ecdysone, they do have related steroid hormones such as estrogen, progesterone and testosterone, which have similar mechanisms of action.

The experimental work on this study was performed primarily by Sara Ahmed, a joint PhD student between the Edgar and Teleman labs at the Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH) and the DKFZ. Ahmed designed experiments utilizing various genetic tools to switch genes on and off in different cell types in the fly’s intestine and in its ovaries, which produce ecdysone. “Our study provides conclusive evidence that sex hormones alter the behavior of non-sex organs like the intestine,” says Ahmed. She further speculates that long-term implications of this research may include exploration of new paths to treating human cancers.

According to the researchers, understanding whether a similar stem cell-hormone relationship operates in human organs will require further studies. They plan to explore this in the future. In addition to the critical role played by sex hormones in intestinal stem cell behavior, the authors believe this study in Drosophila potentially unveils a new mechanism that may play out in human physiology and pathology. Insights from this study add to a growing body of work showing that the incidence cancers of non-reproductive organs, including colon and gastric cancers, are different in males and females.

This study was supported by the National Institutes of Health including the National Cancer Institute P30 CA01420114, the National Institute of General Medical Sciences R01 124434, the European Research Council AdG268515, DKFZ, and Huntsman Cancer Foundation.

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A method that involves infecting liver cells with mosquito-bred parasites could improve the study of malaria in India — ScienceDaily

A new approach could illuminate a critical stage in the life cycle of one of the most common malaria parasites. The approach was developed by scientists at Kyoto University’s Institute for Integrated Cell-Material Sciences (iCeMS) in Japan and published in the Malaria Journal.

“The Plasmodium vivax malaria parasite can stay dormant in a person’s liver cells up to years following infection, leading to clinical relapses once the parasite is reactivated,” says Kouichi Hasegawa, an iCeMS stem cell biologist and one of the study’s corresponding authors.

P. vivax is responsible for around 7.5 million malaria cases worldwide, about half of which are in India. Currently, there is only one licensed drug to treat the liver stage of the parasite’s life cycle, but it has many side effects and cannot be used in pregnant women and infants. The liver stage is also difficult to study in the lab. For example, scientists have struggled to recreate high infection rates in cultured liver cells.

Hasegawa and his colleagues in Japan, India and Switzerland developed a successful system for breeding mature malaria parasites, culturing human liver cells, and infecting the cells with P. vivax. While it doesn’t solve the high infection rate problem, the system is providing new, localized insight into the parasite’s liver stage.

“Our study provides a proof-of-concept for detecting P. vivax infection in liver cells and provides the first characterization of this infectious stage that we know of in an endemic region in India, home to the highest burden of vivax malaria worldwide,” says Hasegawa.

The researchers bred Anopheles stephensi mosquitos in an insectarium in India. Female mosquitos were fed with blood specifically from Indian patients with P. vivax infection.

Two weeks later, mature sporozoites, the infective stage of the malaria parasite, were extracted from the mosquitos’ salivary glands and added to liver cells cultured in a petri dish.

The scientists tested different types of cultured liver cells to try to find cells that would be infected by lots of parasites like in the human body. Researchers have already tried using cells taken liver biopsies and of various liver cancer cell lines. So far, none have led to large infections.

Hasegawa and his colleagues tried using three types of stem cells that were turned into liver cells in the lab. Notably, they took blood cells from malaria-infected patients, coaxed them into pluripotent stem cells, and then guided those to become liver cells. The researchers wondered if these cells would be genetically more susceptible to malaria infection. However, the cells were only mildly infected when exposed to the parasite sporozoites.

A low infection rate means the liver cells cannot be used for testing many different anti-malaria compounds at once. But the researchers found the cells could test if a specific anti-malaria compound would work for a specific patient’s infection. This could improve individualized treatment for patients.

The scientists were also able to study one of the many aspects of parasite liver infection. They observed the malaria protein UIS4 interacting with the human protein LC3, which protected the parasite from destruction. This demonstrates their approach can be used to further investigate this important stage in the P. vivax life cycle.

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Materials provided by Kyoto University. Note: Content may be edited for style and length.

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What the embryo can teach us about cell reprogramming — ScienceDaily

Cell reprogramming provides an outstanding opportunity for the artificial generation of stem cells for regenerative medicine approaches in the clinic. As current cell reprogramming methods are low in efficiency, researchers around the globe aim to learn lessons from the early embryo which might lead them to a more efficient and faster generation of high-quality, fully reprogrammed stem cells.

Prof. Maria-Elena Torres-Padilla, Director of the Institute of Epigenetics and Stem Cells at Helmholtz Zentrum München and her colleague Dr. Adam Burton are doing pioneering work in this field.

Why would we want to reprogram cells?

Maria-Elena: Can you imagine being able to artificially generate cells that can develop into any cell type? That would be really fantastic! We call this ability ‘totipotency’ and it is the highest level of cellular plasticity. When you think about using healthy cells to replace sick cells, for example in regeneration and replacement therapies, you need to think about how to generate those ‘new’ healthy cells. For that, you often need to ‘reprogram’ other cells, that means, to be able to change one cell into the cell type of interest.

In nature, cellular reprogramming happens in the early embryo at fertilization. It is a purely epigenetic process since the DNA content of the embryo’s cells does not change, only the genes they express. Epigenetics mediates changes in gene expression meaning the way our genes are ‘read’ from our genetic makeup, which is largely imposed by chromatin. Chromatin is the structure, in which the DNA of a cell is packed into, so that it can fit into the tiny nucleus of a cell, and heterochromatin refers to the part of our DNA that is tightly packed and not accessible.

Heterochromatin is known to be a major bottleneck for artificial cell reprogramming. In embryos, however, the process of cell reprogramming is extremely efficient, some people even think that it is 100% efficient. Therefore, we wanted to understand how the embryo ‘keeps heterochromatin in check’ so that reprogramming can occur. Adopting strategies for reprogramming based on our knowledge of how the embryo does it, is very promising. These strategies can help us to increase the efficiency of reprogramming for regenerative medicine — an outstanding opportunity and research priority of the years to come.

How does the embryo deal with heterochromatin?

Adam: Heterochromatin is tightly controlled in the embryo from early on. In a mouse model, we saw that the histone* modification H3K9me3, which is the classical marker of heterochromatin, is in fact present in the embryo from early on. Usually, H3K9me3 correlates strongly with gene silencing, meaning that the genes cannot be ‘read’ from our genetic makeup. However, we observed that in the very early embryo, this is surprisingly not the case and that H3K9me3 is compatible with gene expression! One of our major findings was to discover that the enzyme, which adds the H3K9me3 mark to the histone, is inhibited by a non-coding RNA, that means there is an active process in the early embryo that counteracts the establishment of fully functional heterochromatin. Globally, we concluded that heterochromatin in the early mammalian embryo is immature because it cannot fulfill its typical function. This is probably due to the absence of other critical heterochromatic factors, which we are now also currently investigating.

How could we use this new knowledge for artificial cell reprogramming?

Maria-Elena: Essentially, what our work documents is a potential way to ‘tune’ down heterochromatin. These findings will provide us with the factors that we can manipulate for making artificial cell reprogramming more efficient and achieve higher cell conversion rates. The key take-home message is that we can learn from the epigenetic remodeling that occurs during the natural process of reprogramming in embryos at fertilization and can transfer this knowledge to improve currently inefficient artificial reprogramming strategies. In fact, learning lessons from the embryo will enable the more efficient and timely generation of high-quality, fully reprogrammed stem cells, which are vital for the full implementation of regenerative medicine approaches in the clinic.

*Histones are basic proteins that are important for the packaging of the DNA into chromatin. The DNA wraps around a histone octamer and this structure is known as nucleosome. Generally, chromatin consists of arrays of nucleosomes and under the microscope this structure looks like beads-on-a-string.

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