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March 2020

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New mechanism for regulating the activity of stem cells discovered — ScienceDaily

Scientists from the German Cancer Research Center (DKFZ) and the Heidelberg Institute of Stem Cell Technology and Experimental Medicine (HI-STEM) and the Max Planck Institute in Freiburg have identified a new control mechanism that enables stem cells to adapt their activity in emergency situations. For this purpose, the stem cells simultaneously modify the blueprints for hundreds of proteins encoded in the gene transcripts. In this way, they control the amount of protein produced and can also control the formation of certain proteinisoforms. If this mechanism is inactivated, stem cells lose their self-renewal potential and can no longer react adequately to danger signals or inflammation.

Messenger RNA molecules (mRNAs), the transcripts of genes, serve as the blueprint for the construction of proteins. In all higher organisms, the cell attaches a long chain of adenine nucleotides, the so-called poly(A) tail, to the rear end of the transcripts in a process known as polyadenylation. The length and position of the chain varies from organism to organism and serves to stabilize the RNA molecule.

Different signaling motifs show the participating enzymes the site where the poly(A) chain is to be attached to the transcript. This does not always happen at the same site of the mRNA. The differential use of these sites is known as “alternative polyadenylation.” This mechanism affects the length of the so-called 3′-untranslated end of the mRNA, a region that contains information beyond the protein sequence. This 3′-untranslated region is particularly important for stability, localisation and the efficiency with which the transcripts are translated into proteins. “Only recently it has been known that some cell types use this mechanism to control how much protein is produced per transcript and which isoform is to be expressed,” says Pia Sommerkamp, the lead author of the study conducted by DKFZ and HI-STEM.

By applying a novel sequencing method, the scientists were able to identify numerous genes that are essential for stem cell development and are regulated via alternative polyadenylation during differentiation or in response to inflammation. These include the central metabolic enzyme glutaminase, which can be produced in two differently active isoforms. As the researchers found out, the activation of blood stem cells leads to a change from the less active to the highly active glutaminase isoform. This switch is coordinated by alternative polyadenylation.

“Only this isoform switch enables the stem cells to adapt all the necessary metabolic pathways according to their needs. This includes rapid increases in activity that are necessary in the case of infections or inflammations,” explains Nina Cabezas-Wallscheid, who was co-supervisor of the study at the MPI in Freiburg. “With alternative polyadenylation, we have now discovered another control level with which stem cells regulate vital processes. We now want to investigate in more detail whether cancer stem cells also use this mechanism for their own purposes in leukemias. We hope that this will provide us with new approaches for fighting the disease,” explains Andreas Trumpp, Director of HI-STEM gGmbH at DKFZ and senior author of the study.

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Human immune cells produced in a dish in world first — ScienceDaily

One day the advance could lead to a patient’s own skin cells being used to produce new cells for cancer immunotherapy or to test autoimmune disease interventions.

The group, led by Professors Ed Stanley and Andrew Elefanty, from the Murdoch Children’s Research Institute in Melbourne, Australia, said the work has added definitive evidence about how the body’s earliest immune cells are formed.

These lymphocytes are produced by cells which form the embryo’s first organs rather than the blood-producing stem cells that sit inside the body’s bone marrow.

The research combined two powerful laboratory techniques, genetic engineering and a novel way of growing stem cells, to make the breakthrough, which has been published in the  journal Nature Cell Biology.

First, the team engineered pluripotent stem cells to glow green when a specific protein marker of early immune cells, RAG1, was switched on. RAG1 is responsible for creating the immune response to infections and vaccines.

Next, the team isolated the glowing green RAG1-positive cells and showed that they could also form multiple immune cell types, including cells required for shaping the development of the whole immune system.

“We think these early cells might be important for the correct maturation of the thymus, the organ that acts as a nursery for T-cells” said Professor Stanley.

“These RAG1 cells are like the painters and decorators who set up that nursery, making it a safe and cozy environment for later-born immune cells,” he said.

Professor Elefanty said, “Although a clinical application is likely still years away, we can use this new knowledge to test ideas about how diseases like childhood leukemia and type 1 diabetes develop. Understanding more about the steps these cells go through, and how we can more efficiently nudge them down a desired pathway, is going to be crucial to that process.”

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In a first, researchers unveil stem cell models of human spine development — ScienceDaily

More than 20 years ago, the lab of developmental biologist Olivier Pourquié discovered a sort of cellular clock in chicken embryos where each “tick” stimulates the formation of a structure called a somite that ultimately becomes a vertebra.

In the ensuing years, Pourquié and others further illuminated the mechanics of this so-called segmentation clock across many organisms, including creation of the first models of the clock in a lab dish using mouse cells.

While the work has improved knowledge of normal and abnormal spine development, no one has been able to confirm whether the clock exists in humans — until now.

Pourquié led one of two separate teams reporting Jan. 8 in Nature that after decades of effort, they have created the first lab-dish models of the segmentation clock that use stem cells derived from adult human tissue.

The achievements not only provide the first evidence that the segmentation clock ticks in humans but also give the scientific community the first in vitro systems enabling the study of very early spine development in humans.

“We know virtually nothing about human development of somites, which form between the third and fourth week after fertilization, before most people know they’re pregnant,” said Pourquié, professor of genetics in the Blavatnik Institute at Harvard Medical School and a principal faculty member of the Harvard Stem Cell Institute. “Our system should be a powerful one to study the underlying regulation of the segmentation clock.”

“Our innovative experimental system now allows us to compare mouse and human development side by side,” said Margarete Diaz-Cuadros, a graduate student in the Pourquié lab and co-first author of the Harvard Medical School-led study. “I am excited to unravel what makes human development unique.”

Both models open new doors for understanding developmental conditions of the spine, such as congenital scoliosis, as well as diseases involving tissues that arise from the same region of the embryo, known as the paraxial mesoderm. These include skeletal muscle and brown fat in the entire body, as well as bones, skin and lining of blood vessels in the trunk and back.

Pourquié hopes that researchers will be able to use the new stem cell models to generate differentiated tissue for research and clinical applications, such as skeletal muscle cells to study muscular dystrophy and brown fat cells to study type 2 diabetes. Such work would provide a foundation for devising new treatments.

“If you want to generate systems that are useful for clinical applications, you need to understand the biology first,” said Pourquié, who is also the Harvard Medical School Frank Burr Mallory Professor of Pathology at Brigham and Women’s Hospital. “Then you can make muscle tissue and it will work.”

Although scientists have derived many kinds of tissue by reprogramming adult cells into pluripotent stem cells and then coaxing them along specific developmental paths, musculoskeletal tissue proved stubborn. In the end, however, Pourquié and colleagues discovered that they could facilitate the transformation by adding just two chemical compounds to the stem cells while they were bathed in a standard growth culture medium.

“We can produce paraxial mesoderm tissue with about 90 percent efficiency,” said Pourquié. “It’s a remarkably good start.”

His team created a similar model derived from embryonic mouse cells.

The HMS researchers were surprised to find that the segmentation clock began ticking in both the mouse and human cell dishes and that the cells didn’t first need to be arranged on a 3D scaffold more closely resembling the body.

“It’s pretty spectacular that it worked in a two-dimensional model,” said Pourquié. “It’s a dream system.”

The team found that the segmentation clock ticks every 5 hours in the human cells and every 2.5 hours in the mouse cells. The difference in frequency parallels the difference in gestation time between mice and humans, the authors said.

Among the next projects for Pourquié’s lab are investigating what controls the clock’s variable speed and, more ambitiously, what regulates the length of embryonic development in different species.

“There are many very interesting problems to pursue,” he said.

A third group publishing in the same issue of Nature uncovered new insights into how cells synchronize in the segmentation clock using mouse embryos engineered to incorporate fluorescent proteins.

Pourquié is senior author of the HMS-led paper. Postdoctoral researcher Daniel Wagner of HMS is co-first author. Additional authors are affiliated with Kyoto University, RIKEN Center for Brain Science and Brandeis University.

Pourquié has started a company called Anagenesis Biotechnologies based on protocols developed for this study. It uses high-throughput screening to search for cell therapies for musculoskeletal diseases and injuries.

This work was funded by National Institutes of Health grant 5R01HD085121.

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Plant-derived SVC112 hits cancer stem cells, leaves healthy cells alone — ScienceDaily

The red, tube-shaped flowers of the firecracker bush (Bouvardia ternifolia), native to Mexico and the American Southwest, attract hummingbirds. The bush also provides the chemical bouvardin, which the lab of University of Colorado Cancer Center and CU Boulder researcher, Tin Tin Su, PhD, and others have shown to slow a cancer’s ability to make proteins that tell cancer cells to grow and spread. Now a paper based on nearly half a decade of work, published in the journal Cancer Research, shows that the molecule SVC112, based on bouvardin and synthesized by Su’s Colorado-based pharmaceutical startup, SuviCa, Inc. acts specifically against head and neck cancer stem cells (CSCs), resulting in better tumor control with less toxicity to healthy cells than existing, FDA-approved protein synthesis inhibitors. The group hopes these promising preclinical results will lay the groundwork for human clinical trials of SVC112 in head and neck cancer patients.

“Proteins are the keys to initiating genetic programs in the cells to tell them Now you grow, now you stay put, now you metastasize. And those proteins are called transcription factors,” says paper co-senior author, Antonio Jimeno, MD, PhD, director of the Head and Neck Cancer Clinical Research Program and co-leader of the Developmental Therapeutics Program at CU Cancer Center, member of the Gates Center for Regenerative Medicine, and the Daniel and Janet Mordecai Endowed Chair for Cancer Stem Cell Research at the CU School of Medicine.

Cancer stem cells (CSCs) are a subpopulation of cancer cells that, like healthy stem cells, act as factories, manufacturing cells that make up the bulk of a cancer’s tissue. Unfortunately, CSCs often resist treatments like radiation and chemotherapy, and can survive to restart tumor growth once treatment ends.

“Many groups have linked the production of transcription factors to the survival and growth of cancer stem cells, but inhibitors have just been too toxic — they come with too many side effects. Definitely our studies suggest that this drug could be an advantage over existing drugs. It inhibits protein synthesis in a way that no other drug does and that’s why we’re excited,” says Su, who is also co-leader of the CU Cancer Center Molecular and Cellular Oncology Program.

Importantly, the group’s work showed that SVC112 acts specifically against proteins like Myc and Sox2 needed by cancer stem cells, while leaving healthy cells relatively unharmed. They did this by comparing the effects of the drug in “matched pairs” of cancer cells and healthy cells grown from samples graciously donated by five head and neck cancer patients in Colorado. For further comparison, the group did the same experiments with the FDA-approved protein synthesis inhibitor known as omacetaxine mepesuccinate (also called homoharringtonin, or HHT).

“Having cancer cells along with matched non-cancer cells from the same patient is pretty unique. When we tested these matched pairs with SVC112 and with HHT, what we saw is the approved drug eliminated both cancer and normal cells, whereas SVC112 had selectivity — it affected cancer cells but not healthy cells — so theoretically the effects on the normal tissue will be less,” Su says. In fact, healthy cells were between 3.8 and 5.6 times less sensitive to SVC112 than were cancer cells (healthy cells and cancer cells were equally sensitive to the FDA-approved drug HHT).

The next step was using SVC112 to treat head and neck tumors grown in mouse models from samples of human tumors. Earlier work had shown that SVC112 sensitized previously radiation-resistant CSCs to radiation treatment, and so the group tested SVC112 and radiation alone and in combination.

“What we saw is that only when you decrease the population of cancer stem cells to under 1 percent of the total makeup of a tumor did the tumor shrink,” Jimeno says. “It’s like cancer stem cells are in the control tower, directing the growth of the tumor. If you impair enough of these directors, other cancer cells don’t know what to do and cancer growth slows down or stops.”

Ongoing work continues in two major directions, with Su’s team continuing to propel the drug toward the clinic and Jimeno’s team working to understand of the basic biology driving the drug’s action, how to best combine it with other treatments such as radiation or immunotherapy, and its potential uses in other cancer types.

“This is the first report of the drug, from the drug’s chemical structure, its basic effects on commercial cell lines, to its mechanism of action with patient-derived cell lines and more complex action on CSCs, all the way to animal models from patient samples,” Jimeno says.

Early drug development undertaken outside the funding structure of established pharmaceutical sponsors often requires contributions from many sources, and the current project is no exception, receiving support from subcontracts to SuviCa’s Small Business Innovation Research (SBIR) award, a National Institutes of Health grant to the Su lab, pilot funding from the CU Cancer Center, and philanthropy support from the Gates Center and the CU School of Medicine.

“We are so grateful for the belief from all these organizations and individuals, and especially to our patients, whose courage has been essential in making the models we need to test this new drug,” says Jimeno.

Proposals are already underway to take the next important step: Testing SVC112 in an early human clinical trial.

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Diabetes drug could lead to new treatment — ScienceDaily

A drug designed to tackle diabetes could also be repurposed as the first treatment to prevent miscarriage by targeting the lining of the womb itself, according to a clinical trial led by the University of Warwick.

The treatment works by increasing the amount of stem cells in the lining of the womb, improving conditions in the womb to support pregnancy.

The research by Warwick Medical School is reported today (9 January) in the journal EBioMedicine from research conducted with University Hospitals Coventry and Warwickshire and supported by the NIHR Coventry and Warwickshire Clinical Research Facility. The research was funded by and took place at Tommy’s National Miscarriage Research Centre.

Recurrent miscarriage is defined as the loss of two or more consecutive pregnancies, with additional miscarriages decreasing the likelihood of a successful pregnancy. Previous research by the Warwick team revealed that a lack of stem cells in the womb lining is causing thousands of women to suffer from recurrent miscarriages. The team also demonstrated that stem cells protect specialised cells, called decidual cells, from excessive stress and inflammation. Decidual cells surround the implanting embryo and excessive stress can cause breakdown of the womb lining in pregnancy.

A new class of diabetes drugs called gliptins targets an enzyme involved in the recruitment of circulating stem cells to the womb. The researchers investigated whether inhibiting this enzyme, called DPP4, using a particular drug, sitagliptin, would improve conditions in the womb for pregnancy.

In a pilot clinical trial, thirty-eight women aged 18 to 42 who had experienced a large number of recurrent miscarriages (average five) were given either an oral course of sitagliptin or a placebo for three menstrual cycles. Biopsies of the womb were taken at the start of the course of treatment and afterwards to determine the number of stem cells present before and after the course.

They found an average increase in stem cell count of 68% in those women who took the full course of sitagliptin. This compares to no significant increase in those in the control group receiving an identical placebo pill. They also saw a 50% decrease in the number of ‘stressed’ cells present in the lining of the womb. There were minimal side effects for the participants.

The researchers now hope to take the treatment to clinical trial and, if successful, it would be the first targeted specifically at the lining of the womb to prevent miscarriage.

Professor Jan Brosens, of Warwick Medical School and Consultant in Reproductive Health at University Hospitals Coventry and Warwickshire NHS Trust, said: “There are currently very few effective treatments for miscarriage and this is the first that aims at normalising the womb before pregnancy. Although miscarriages can be caused by genetic errors in the embryo, an abnormal womb lining causes the loss of chromosomal normal pregnancies. We hope that this new treatment will prevent such losses and reduce both the physical and psychological burden of recurrent miscarriage.”

Professor Siobhan Quenby from Warwick Clinical Trials Unit and an Honorary Consultant at University Hospital Coventry and Warwickshire NHS Trust, said: “We have improved the environment that an embryo develops in and in doing so we hope to improve the chances of a successful pregnancy. Although this research was specifically designed to test whether we could increase the presence of stem cells in the womb, follow-up of participants found that there were no further losses of normal pregnancies in those who took sitagliptin. These are very early results and the treatment now needs to be further tested in a large-scale clinical trial.”

Jane Brewin, Chief Executive at Tommy’s said: “For far too long it has often been said by many health professionals that miscarriage is not preventable, and parents have been left with little hope given the paucity of treatment options available. This situation prompted Tommy’s to invest in the Tommy’s National Centre for Miscarriage Research and this breakthrough research by the world leading team at Warwick shows great promise for an effective treatment which will reduce miscarriage and possibly later pregnancy loss too. A large-scale trial is needed to verify the findings and we hope that this will get underway quickly.”

Stem cells play a key role in creating the decidual cells in the womb lining which support the placenta throughout pregnancy. Insufficient stem cells in the womb lining leads to an excess of stressed and inflammatory decidual cells, which in turn may cause placental bleeding and miscarriage. Sitagliptin was effective not only in increasing stem cells in the womb lining but also decreasing the abundance of stressed decidual cells.

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Discovery could lead to better understanding of poor wound healing in diabetic patients — ScienceDaily

A team of University of California, Irvine researchers have published the first comprehensive overview of the major changes that occur in mammalian skin cells as they prepare to heal wounds. Results from the study provide a blueprint for future investigation into pathological conditions associated with poor wound healing, such as in diabetic patients.

“This study is the first comprehensive dissection of the major changes in cellular heterogeneity from a normal state to wound healing in skin,” said Xing Dai, PhD, a professor of biological chemistry and dermatology in the UCI School of Medicine, and senior author. “This work also showcases the collaborative efforts between biologists, mathematician and physicists at UCI, with support from the National Institute of Arthritis & Musculoskeletal & Skin Diseases-funded UCI Skin Biology Resource-based Center and the NSF-Simons Center for Multiscale Cell Fate Research.

The study, titled, “Defining epidermal basal cell states during skin homeostasis and wound healing using single-cell transcriptomics,” was published this week in Cell Reports.

“Our research uncovered at least four distinct transcriptional states in the epidermal basal layer as part of a ‘hierarchical-lineage’ model of the epidermal homeostasis, or stable state of the skin, clarifying a long-term debate in the skin stem cell field,” said Dai.

Using single-cell RNA sequencing coupled with RNAScope and fluorescence lifetime imaging, the team identified three non-proliferative and one proliferative basal cell state in homeostatic skin that differ in metabolic preference and become spatially partitioned during wound re-epithelialization, which is the process by which the skin and mucous membranes replace superficial epithelial cells damaged or lost in a wound.

Epithelial tissue maintenance is driven by resident stem cells, the proliferation and differentiation dynamics of which need to be tailored to the tissue’s homeostatic and regenerative needs. However, our understanding of tissue-specific cellular dynamics in vivo at single-cell and tissue scales is often very limited.

“Our study lays a foundation for future investigation into the adult epidermis, specifically how the skin is maintained and how it can robustly regenerate itself upon injury,” said Dai.

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Study in mouse, human cells suggests unique anti-cancer properties of such a therapy — ScienceDaily

Immunotherapy that involves treating cancer with the body’s own immune cells, or those of a matched donor, shows promise in clinical trials for some patients, but not all.

A new study from Washington University School of Medicine in St. Louis suggests that the age of certain immune cells used in such therapy plays a role in how effective the immunotherapy is. These cells — natural killer (NK) cells — appear to be more effective the earlier they are in development, opening the door to the possibility of an immunotherapy that would not utilize cells from the patient or a matched donor. Instead, they could be developed from existing supplies of what are called human pluripotent stem cells.

“We are trying to improve the effectiveness of immunotherapy for more patients,” said senior author Christopher M. Sturgeon, PhD, an assistant professor of medicine. “This special source of natural killer cells has the potential to fill some of the gaps remaining with adult NK cell therapy. There is early evidence that they are more consistent in their effectiveness, and we would not need to process cells from a donor or the patient. They could be manufactured from existing cell supplies following the strict federal guidelines for good manufacturing practices. The characteristics of these cells let us envision a supply of them ready to pull off the shelf whenever a patient needs them.”

Unlike the adult versions of NK cells used in most investigational therapies, earlier versions of such cells do not originate from bone marrow. Rather, these NK cells are a special type of short-lived immune cell that forms in the yolk sac of the early mammalian embryo. But for therapeutic purposes, such cells do not need to originate from embryos — they can be developed from human pluripotent stem cells, which have the ability to give rise to many different cell types, including these specialized natural killer cells. Manufacturing such cells — which many academic medical centers already have the ability to do — would make them available quickly, eliminating the time needed to process the patient’s or donor’s cells, which can take weeks.

The study appears March 19 in the journal Developmental Cell.

“Before a certain time point in early development, there is no such thing as bone marrow, but there is still blood being made in the embryo,” Sturgeon said. “It’s a transient wave of blood that the yolk sac makes to keep the embryo going until bone marrow starts to form. And that’s the blood cell generation that’s making these unique natural killer cells. This early blood appears to be capable of things that adult blood simply can’t do.”

Studying mouse and human induced pluripotent stem cells that have been coaxed into forming these unique NK cells, the researchers showed that the NK cells are better at releasing specific anti-tumor chemicals — a process called degranulation — than their adult counterparts. Even NK cells derived from umbilical cord blood do not respond as robustly. NK cells of adult origin also release different chemicals that trigger harmful inflammation, but this response is not necessarily effective against cancer.

Past work by other groups suggested NK cells from earlier development might be more effective, but how and why this was the case remained unknown. The specific origin of these cells was also a mystery.

“Now we know where these special natural killer cells come from and that we can never get them from an adult donor, only a pluripotent stem cell,” Sturgeon said. “Based on their unique behavior alone, there is one small clinical trial of these cells that is ongoing. Now that we know how to manufacture them and how they work, it opens the door for more trials and for improving upon their function.”

According to Sturgeon, such cells could be produced from existing lines of pluripotent stem cells that would not need to come from a matched donor because, in general, NK cells do not heavily attack the body’s healthy tissues, as many T cell therapies can. T cells are another type of immune cell often used to treat blood cancer as part of a stem cell transplant, commonly called a bone marrow transplant. Even when NK cells do cause harm, they do not stay in the body for long periods of time.

From a basic science standpoint, Sturgeon also is interested in understanding why these cells are present in the early embryo in the first place and where they go in later development and after birth.

“We can only speculate at this point, but it’s possible that during early embryonic development, when there is so much rapid cell division, these cells are there as a surveillance mechanism to protect against pediatric cancers or infection,” he said.

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Materials provided by Washington University School of Medicine. Original written by Julia Evangelou Strait. Note: Content may be edited for style and length.

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Stem cells and nerves interact in tissue regeneration and cancer progression — ScienceDaily

Stem cells can generate a variety of specific tissues and are increasingly used for clinical applications such as the replacement of bone or cartilage. However, stem cells are also present in cancerous tissues and are involved in cancer progression and metastasis. Nerves are fundamental for regulating the physiological and regenerative processes involving stem cells. However, little is known about the interactions between stem cells and neurons in regenerating tissues and in cancers.

Comparing stem cell types in tissue regeneration

A team of researchers led by Thimios Mitsiadis, professor at the Institute of Oral Biology of the University of Zurich, has now published two studies that elucidate how stem cells promote neuronal growth in tissue regeneration and in cancer progression. The first study compared the interaction of neurons with two different human stem cell populations, namely dental pulp stem cells and bone marrow stem cells. Both can differentiate into various cell types such as bone, cartilage and fat cells. Human bone marrow stem cells are isolated from skeletal bones and are the gold standard for bone regenerative approaches. Extracted teeth are the source of dental pulp stem cells, which represent a promising alternative.

Dental stem cells are highly innervated

Using the “organ-on-a-chip” technology, which relies on small three-dimensional devices mimicking the basic functions of human organs and tissues, the researchers demonstrated that both types of stem cells promoted neuronal growth. The dental pulp stem cells, however, yielded better results compared to bone marrow stem cells: They induced more elongated neurons, formed dense neuronal networks and established close contacts with nerves.

“Dental stem cells produce specific molecules that are fundamental for the growth and attraction of neurons. Therefore, stem cells are abundantly innervated,” says Mitsiadis. The formation of such extended networks and the establishment of numerous contacts suggest that dental stem cells create functional connections with nerves of the face. “Therefore, these cells could represent an attractive choice for the regeneration of functional, properly innervated facial tissues,” adds co-author and junior group leader Pierfrancesco Pagella.

Cancer stem cells also recruit neurons

In the second study, the researchers examined the interaction between nerves and cancer stem cells found in ameloblastoma, an aggressive tumour of the mouth. They first demonstrated that ameloblastomas have stem cell properties and are innervated by facial neurons. When ameloblastoma cells were isolated and placed in the “organ-on-a-chip” devices, they retained not only their stem cell properties but also attracted nerves and established contact with them.

“It appears that nerves are fundamental for the survival and function of cancer stem cells,” explains Pagella. “These results create new possibilities for cancer treatment using drugs that modify the communication between neurons and cancer stem cells. We hope this opens unforeseen paths towards effective therapies against cancer,” adds Mitsiadis. “The combination of advanced molecular and imaging tools and “organ-on-a-chip” technology offers an exciting opportunity to reveal the hidden functions of neurons and their interactions with various stem cell types, in both healthy and pathological conditions.”

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Solving the riddle of superbug toxin damage to gut — ScienceDaily

A powerful Monash Biomedicine Discovery Institute (BDI) collaboration has revealed that a bacterial superbug can prevent stem cells in the gut from carrying out their vital role of regenerating the inner lining of the intestine. This causes potentially severe disease, particularly in the elderly.

The research found that Clostridioides difficile infection, the most common cause of hospital-acquired diarrhea, damages colonic stem cells via a toxin called TcdB, impairing tissue repair in the gut and recovery from disease. This understanding may now lead to new treatments or prevention methods.

C. difficile is responsible for more than half of all hospital infections related to the intestine and more than 90 per cent of mortalities resulting from these infections.

It grows after antibiotic treatment is administered to a patient, where it can upset the host-microbial balance in the gut allowing the bacterium to colonise.

The superbug can be transmitted from animals to humans and vice-versa and is now being uncovered in patients who have not had a recent hospital visit or taken a recent course of antibiotics. Instances have also been seen in a younger demographic than previously recorded.

The findings could have wider implications for those going through treatments for cancer such as chemotherapy and radiation therapy that also damage the gut.

The study, published in the journal Proceedings of the National Academy of Sciences (PNAS) today, was led by senior authors Professor Dena Lyras, an expert in infectious diseases, and Professor Helen Abud, an expert in stem cell biology, in conjunction with US collaborator Professor Borden Lacy from Vanderbilt University Medical Center in Nashville, Tennessee, who specialises in the structure of toxins. Joint first authors were Dr Steven Mileto (Lyras lab) and Dr Thierry Jardé (Abud lab).

“Our study provides the first direct evidence that a microbial infection alters the functional capacity of gut stem cells,” Professor Abud said.

“It adds a layer of understanding about how the gut repairs after infection and why this superbug can cause the severe damage that it does. The reason it’s important to have that understanding is that we’re rapidly running out of antibiotics — we need to find other ways to prevent and treat these infections,” she said.

“It shows that the toxins C. difficile makes are very important — TcdB targets the stem cells and damages them directly” Professor Lyras said.

“As a consequence the gut can’t be repaired. So where it normally takes five days to regenerate the gut lining, it can take more than two weeks. This can leave patients (particularly people aged over 65 years and who are already debilitated) with pain, life-threatening diarrhea and other serious conditions.

“By understanding this new mechanism of damage and repair, maybe we can find ways to prevent the damage happening or develop new treatments,” Dr Jardé said.

The findings might also apply to other infections that behave in similar ways.

“There are a lot of different conditions that can make the gut more vulnerable — maybe there’s a common way we can target them too instead of thinking in isolation about an infectious disease problem,” said Dr Mileto.

The work was funded by a joint National Health and Medical Research Council project grant gained by the two senior Monash BDI investigators. Professor Lyras was also supported by the Australian Research Council.

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More stem cells improve learning and memory of old mice — ScienceDaily

We all will experience it at some point, unfortunately: The older we get the more our brains will find it difficult to learn and remember new things. What the reasons underlying these impairments are is yet unclear but scientists at the Center for Regenerative Therapies of TU Dresden (CRTD) wanted to investigate if increasing the number of stem cells in the brain would help in recovering cognitive functions, such as learning and memory, that are lost during ageing.

To investigate this, the research group led by Prof. Federico Calegari used a method developed in his lab to stimulate the small pool of neural stem cells that reside in the brain in order to increase their number and, as a result, to also increase the number of neurons generated by those stem cells. Surprisingly, additional neurons could survive and form new contacts with neighbouring cells in the brain of old mice. Next, the scientists examined a key cognitive ability that is lost, similarly in mice and in humans, during ageing: navigation.

It is well known that individuals learn to navigate in a new environment in a different way depending on whether they are young or old. When young, the brain can build and remember a cognitive map of the environment but this ability fades away in older brains. As an alternative solution to the problem, older brains without a cognitive map of the environment need to learn the fixed series of turns and twists that are needed to reach a certain destination. While the two strategies may superficially appear similar, only a cognitive map can allow individuals to navigate efficiently when starting from a new location or when in need of reaching a new destination.

Would boosting the number of neurons be sufficient to counteract the decreasing performance of the brain in navigation and slow down this ageing process? The teams of Prof. Calegari (CRTD) together with Prof. Gerd Kempermann (German Center for Neurodegenerative Diseases DZNE / CRTD) and Dr. Kentaroh Takagaki (Otto von Guericke University Magdeburg) found the answer to this challenging question and published it this week in the scientific journal Nature Communications.

The answer is “Yes”: Old mice with more stem cells and neurons recovered their lost ability to build a map of the environment and remembered it for longer times making them more similar to young mice. Even better, when neural stem cells were stimulated in the brain of young mice, cognitive impairments were delayed and memory was better preserved over the entire course of the animal natural life.

In young individuals, a brain area called the hippocampus is crucial for remembering places and events, and is also responsible for creating maps of new environments. However, old individuals use other structures that are more related to the development of habits. It was very interesting to see that adding more neurons in the hippocampus of old mice allowed them to use strategies typical of young animals. It was not only about how fast they were learning but, rather, how different the learning process itself was ,” explains Gabriel Berdugo-Vega, first author of the study.

“Also humans have a few stem cells in the brain and these stem cells are known to severely reduce in numbers over the course of life. Identifying the causes underlying cognitive deficits in ageing and rescuing them is crucial for our rapidly ageing societies. Our work demonstrates that age-related impairments can be rescued by hijacking the endogenous neurogenic potential of the brain, thus, rejuvenating its function. Being a human myself with my own stem cells and being the senior author of this study, I felt that I had a personal interest in this topic.” says Prof. Federico Calegari, senior author of this study.

The research group of Prof. Federico Calegari focuses on mammalian neural stem cells in the context of development, evolution and cognitive function at the CRTD. The institute is the academic home for scientists from more than 30 nations. Their mission is to discover the principles of cell and tissue regeneration and leveraging this for recognition, treatment and reversal of diseases. The CRTD links the bench to the clinic, scientists to clinicians to pool expertise in stem cells, developmental biology, gene-editing and regeneration towards innovative therapies for neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease, haematological diseases such as leukaemia, metabolic diseases such as diabetes, retina and bone diseases.

This study was funded by TU Dresden / CRTD through the German Excellence Initiative, the German Research Foundation and a European grant from the H2020 programme. In addition, it was supported by the Faculty of Natural Sciences of Otto-von-Guericke University Magdeburg, the Dresden International Graduate School for Biomedicine and Bioengineering (DIGS-BB) and the German Center for Neurodegenerative Diseases (DZNE).

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Materials provided by Technische Universität Dresden. Note: Content may be edited for style and length.

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