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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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Development could lead to better disease models in the lab to test treatments for efficacy — ScienceDaily

Boston researchers have developed a new way to generate groups of intestinal cells that can be used, among others, to make disease models in the lab to test treatments for diseases affecting the gastrointestinal system. Using human induced pluripotent stem cells, this novel approach combined a variety of techniques that enabled the development of three-dimensional groups of intestinal cells called organoids in vitro, which can expand disease treatment testing in the lab using human cells.

Published online in Nature Communications, this process provides a novel platform to improve drug screenings and uncover novel therapies to treat a variety of diseases impacting the intestine, such as inflammatory bowel disease, colon cancer and Cystic Fibrosis.

Researchers at the Center for Regenerative Medicine (CReM) of Boston University and Boston Medical Center used donated human induced pluripotent stem cells (hiPSCs), which are created by reprogramming adult cells into a primitive state. For this study, these cells were pushed to differentiate into intestinal cells using specific growth factors in order to create organoids in a gel. This new protocol allowed the cells to develop without mesenchyme, which typically in other protocols, provides support for the intestinal epithelial cells to grow. By taking out the mesenchyme, the researchers could study exclusively epithelial cells, which make up the intestinal tract.

In addition, using CRISPR technology, the researchers were able to modify and create a novel iPSC stem cell line that glowed green when differentiated into intestinal cells. This allowed the researchers to follow the process of how intestinal cells differentiate in vitro.

“Generating organoids in our lab allows us to create more accurate disease models, which are used to test treatments and therapies targeted to a specific genetic defect or tissue — and it’s all possible without harming the patient,” said Gustavo Mostoslavsky, MD, PhD, co-director of CReM and faculty in the gastroenterology section at Boston Medical Center. “This approach allows us to determine what treatments could be most effective, and which are ineffective, against a disease.”

Using this new protocol, the researchers generated intestinal organoids from iPSCs containing a mutation that causes Cystic Fibrosis, which typically affects several organs, including the gastrointestinal tract. Using CRISPR technology, the researchers corrected the mutation in the intestinal organoids. The intestinal organoids with the mutation did not respond to a drug while the genetically corrected cells did respond, demonstrating their future potential for disease modeling and therapeutic screening applications.

The protocol developed in this study provides strong evidence to continue using human iPSCs to study development at the cellular level, tissue engineering and disease modeling in order to advance the understanding — and possibilities — of regenerative medicine.

“I hope that this study helps move forward our collective understanding about how diseases impact the gastrointestinal tract at the cellular level,” said Mostoslavsky, who also is associate professor of medicine and microbiology at Boston University School of Medicine. “The continual development of novel techniques in creating highly differentiated cells that can be used to develop disease models in a lab setting will pave the way for the development of more targeted approaches to treat many different diseases.”

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Blood stem cells boost immunity by keeping a record of previous infections — ScienceDaily

These findings should have a significant impact on future vaccination strategies and pave the way for new treatments of an underperforming or over-reacting immune system. The results of this research are published in Cell Stem Cell on March 12, 2020.

Stem cells in our bodies act as reservoirs of cells that divide to produce new stem cells, as well as a myriad of different types of specialized cells, required to secure tissue renewal and function. Commonly called “blood stem cells,” the hematopoietic stem cells (HSC) are nestled in the bone marrow, the soft tissue that is in the center of large bones such as the hips or thighs. Their role is to renew the repertoire of blood cells, including cells of the immune system which are crucial to fight infections and other diseases.

Until a decade ago, the dogma was that HSCs were unspecialized cells, blind to external signals such as infections. Only their specialized daughter cells would sense these signals and activate an immune response. But work from Prof. Michael Sieweke’s laboratory and others over the past years has proven this dogma wrong and shown that HSCs can actually sense external factors to specifically produce subtypes of immune cells “on demand” to fight an infection. Beyond their role in an emergency immune response, the question remained as to the function of HSCs in responding to repeated infectious episodes. The immune system is known to have a memory that allows it to better respond to returning infectious agents. The present study now establishes a central role for blood stem cells in this memory.

“We discovered that HSCs could drive a more rapid and efficient immune response if they had previously been exposed to LPS, a bacterial molecule that mimics infection,” said Dr. Sandrine Sarrazin, Inserm researcher and senior-author of the publication. Prof. Michael Sieweke, Humboldt Professor at TU Dresden, CNRS Research Director and last author of the publication, explained how they found the memory was stored within the cells: “The first exposure to LPS causes marks to be deposited on the DNA of the stem cells, right around genes that are important for an immune response. Much like bookmarks, the marks on the DNA ensure that these genes are easily found, accessible and activated for a rapid response if a second infection by a similar agent was to come.”

The authors further explored how the memory was inscribed on the DNA, and found C/EBP? to be the major actor, describing a new function for this factor, which is also important for emergency immune responses. Together, these findings should lead to improvements in tuning the immune system or better vaccination strategies.

“The ability of the immune system to keep track of previous infections and respond more efficiently the second time they are encountered is the founding principle of vaccines. Now that we understand how blood stem cells book mark immune response circuits, we should be able to optimize immunization strategies to broaden the protection to infectious agents. It could also more generally lead to new ways to boost the immune response when it underperforms or turn it off when it overreacts,” concluded Prof. Michael Sieweke.

The research group of Prof. Michael Sieweke works at the interface of immunology and stem cell research. The scientists focus on the study of hematopoietic stem cells and macrophages, long-lived mature cells of the immune system that fulfil an important role in tissue regeneration. In 2018, Prof. Michael Sieweke received the most valuable research award in Germany: the Alexander von Humboldt Professorship, which brings top international researchers to German universities. In addition to his position as Research Director at the Centre for Immunology at the University of Marseille Luminy, he now acts as Deputy Director at the Center for Regenerative Therapies at TU Dresden (CRTD). CRTD is 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, hematological diseases such as leukaemia, metabolic diseases such as diabetes, retina and bone diseases.

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New technique ‘prints’ cells to create diverse biological environments — ScienceDaily

Like humans, cells can be easily influenced by peer pressure.

Take a neural stem cell in the brain: Whether this cell remains a stem cell or differentiates into a fully formed brain cell is ultimately determined by a complex set of molecular messages the cell receives from countless neighbors. Understanding these messages is key for scientists hoping to harness these stem cells to treat neurological conditions like Alzheimer’s or Parkinson’s.

With the help of photolithography and a creative use of programmable DNA, University of California, Berkeley, researchers have created a new technique that can rapidly “print” two-dimensional arrays of cells and proteins that mimic a wide variety of cellular environments in the body — be it the brain tissue surrounding a neural stem cell, the lining of the intestine or liver or the cellular configuration inside a tumor.

This technique could help scientists develop a better understanding of the complex cell-to-cell messaging that dictates a cell’s final fate, from neural stem cell differentiating into a brain cell to a tumor cell with the potential to metastasize to an embryonic stem cell becoming an organ cell.

“What’s really powerful about this platform is you can create in vitro tissues that capture the spatial organization of cells in the body, from the intestinal lining of your digestive tract to the arrangements of different cell types in the liver,” said Olivia Scheideler, who completed the research as a graduate student at Berkeley. “I think you could apply this technique to recreate any tissue where you want to explore how cellular interactions contribute to tissue function.”

In a paper appearing today (Wednesday, March 18) in the journal Science Advances, Scheideler and her collaborators show that the new technique can be used to rapidly print intricate patterns of up to 10 different kinds cells or proteins onto a flat surface.

“Essentially, what this technique allows us to do is pattern different kinds of conditions in one shot and in a high-throughput manner,” said Lydia Sohn, Chancellor’s Professor of Mechanical Engineering at UC Berkeley and senior author of the paper. “It provides a whole range of options for what you could study, because it’s so flexible. You can pattern many different kinds of cells or proteins.”

Caught on a DNA tether

In the new technique, each cell or protein is tethered to a substrate with a short string of DNA. While similar methods have been developed that attach tethered cells or proteins one by one, the new technique takes advantage of a patterning process called photolithography to attach, or print, each type of cell protein in one quick batch, greatly speeding up the process.

“It’s like color laser printing, where you print one color and then print another,” Sohn said.

Like photography, photolithography works by exposing a coated surface or substrate to a pattern of light, which initiates a chemical reaction that dissolves the coating in the illuminated areas, leaving a templated substrate. In the new technique, the substrate is then bathed in strands of single-sided DNA, whose ends have been chemically altered to firmly latch on where the coating has been dissolved.

Each single-sided DNA strand is programmed have a specific sequence of the nucleotides adenine (A), thymine (T), guanine (G) and cytosine (C). Single-sided DNA strands with the complementary nucleotide sequence are embedded or attached to cells or proteins of interest.

Finally, the surface is washed with a mixture of cells or proteins attached to the complementary strands of single-sided DNA, which bond with the single-sided DNA already attached to the surface to form double-helix “tethers.”

“All the cells and proteins attach exactly where they should be because of the DNA programming,” Sohn said.

By repeating the process, up to 10 different kinds of cells or proteins can be tethered to the surface in an arbitrary pattern.

Conflicting messages

To demonstrate one of the many applications of the technique, Scheideler and co-author David Schaffer, Hubbard Howe Jr. Distinguished Professor of Biochemical Engineering at UC Berkeley, used the platform to study the chemical signaling that cues neural stem cells to differentiate into mature cells.

“Stem cells have programs embedded inside their DNA that tell them (to) either stay a stem cell or to differentiate into a mature cell,'” Schaffer said. “And they receive a lot of information about what to do and which programs to activate from the environment, from other cells around them. If we could learn how to make stem cells do our bidding, how to turn them into a particular cell type, then we could harness the stem cells to mass produce specialized cell types that were lost due to disease or injury.”

Neural stem cells in the brain regularly receive conflicting messages from their neighbors about how they should behave, Scheideler said. One messenger, the FGF-2 protein, tells them to make more stem cells. The other, the ephrin-B2 protein, tells them to differentiate into a mature neuron.

Scheideler used the new technique to pattern neural stem cells onto thousands of different arrays of the two proteins, FGF-2 and ephrin-B2, to see how the spatial organization of the two signals helps determine the cells’ ultimate fate.

She found that many stem cells differentiated into mature neurons, even when they were primarily in contact with FGF-2, or “stay a stem cell,” messengers. When she looked closer, however, she found that those cells that differentiated were more likely to have small, finger-like extensions, or “neurites,” that touched the ephrin-B2 or “differentiate” messengers.

“The great thing about this patterning technology is you can easily replicate these little patterns hundreds or thousands of times across a slide,” Schaffer said. “It is like running a thousand little independent experiments, each of which is a trial run to see how a stem cell listens to the cells around it. And then you can get very, very deep statistics about the various ways that it can be regulated.”

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First genomic study of puberty yields insights into development and cancer — ScienceDaily

In the first-ever genome-scale analysis of the puberty process in humans, researchers at Huntsman Cancer Institute (HCI) at the University of Utah (U of U) outline distinct and critical changes to stem cells in males during adolescence. They further outline how testosterone, and the cells that produce testosterone, impact stem cells in male reproductive organs. The researchers believe this study adds dramatically to a foundation of knowledge that may yield insights into critical areas of human health, including infertility and cellular changes that lead to cancer and other diseases.

The study, published today in the journal Cell Stem Cell, was led by Bradley Cairns, PhD, cancer researcher at HCI and professor and chair of oncological sciences at the U of U, in collaboration with colleagues Jingtao Guo, PhD, a postdoctoral fellow in the Cairns lab at HCI, James Hotaling, MD, associate professor of surgery at the U of U, and Anne Goriely, PhD, associate professor of human genetics at the University of Oxford.

Puberty spurs numerous developmental changes in humans and other mammals. Hallmarks of puberty include physical characteristics easily visible to the naked eye, like rapid growth. These physical and hormonal changes signal the process of a maturing body preparing for reproductive years.

In the testis, the male reproductive organ that makes and stores sperm and produces testosterone, puberty introduces monumental changes at a cellular and physiological level. Thanks to new genomic technologies, researchers are able to examine the expression of thousands of genes in each individual cell in an entire organ, providing unprecedented insights into cellular behavior during puberty.

Several types of cells within the testis regulate reproductive health. Like the human body that changes along the path from infancy to adulthood, these cells undergo major changes as the body matures. These cells include spermatogonial stem cells that ultimately generate sperm production, and niche cells that help form parts of the testis, such as the seminiferous tubule, a tube-like structure within which sperm is formed. In this study, researchers characterized how, just prior to puberty, spermatogonial stem cells first expand significantly in number. These stem cells progress toward meiosis, a special type of cell division that splits the number of chromosomes from the parent cell in half, and also separates the male X and Y sex chromosomes to create cells that, after fertilization of eggs and considerable subsequent development, will ultimately result in either male (Y-containing) or female (X-containing) children. Late in puberty, these stem cells commit to creating mature sperm, which includes a tail piece for motility. The researchers showed how two of the cells that form the stem cell niche and chaperone this process — the myoid cells and Leydig cells — derive from a common precursor, and mature during early puberty.

A major novel insight of this study was the first-ever genomic analysis of the testis of adult transfemales (individuals assigned male at birth, but who self-identify as female). For these individuals, gender confirmation surgery is preceded by hormone therapy that induces long-term testosterone suppression, enabling the examination of testis lacking testosterone. By using samples donated after surgery, researchers uncovered critical insights into the role of testosterone in maintaining testis development. Genomic analysis of the cells from the testis of transfemales showed that stem cells and other cells revert to earlier states of development when compared to samples from male adolescents. Thus, Cairns and his colleagues identified that testosterone is critical to maintaining the mature state of the testis: if testosterone is no longer present, the testis reverts to an earlier developmental state.

The major changes that occur in humans during puberty give rise to numerous functions in normal development, like reproductive health and fertility. But, when these processes go awry, confounding challenges can result. Infertility is a relatively common health issue. About 50 percent of the time, the underlying cause is attributed to the male reproductive functions, which often include errors that occur during puberty. The team hopes these insights into how cells develop will help yield insights into what happens when developmental issues during puberty cause changes that result in infertility.

The study also informs understanding of cancer and other diseases that arise due to errors in cellular processes. “The majority of the time, testicular cancers arise when stem cells in the testis are misregulated,” said Cairns. “We want to understand how these changes can cause testicular tumors; however, we need to know what should normally happen before we can identify ways to prevent or more effectively treat these cancers.”

In juveniles, cancers and reproductive health intersect via a medical process called oncofertility; that is, the study of how to retain fertility in adolescent and young adult cancer patients whose reproductive health and fertility may be impacted by their cancer, or as a result of side effects of cancer treatment. “Some chemotherapies can result in young men with cancer not being able to have children — the chemotherapy can cause changes to their stem cells,” said Cairns. “My hope and expectation is that our research will provide a foundation for creating options to support the reproductive health of young men affected by cancer through a better understanding of how these stem cells survive, are supported, and develop.”

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Programmable biomaterials for bone regeneration introduced — ScienceDaily

Specifically programmed materials can, under specific conditions, encourage stem cells to transform into bone cells. To do this, scientists implemented a so-called shape-memory polymer in stem cell research.

Stem cells are known for their ability to turn into many different types of cell, be they muscle cells, cartilage, or bone cells. Just like the body they are part of, stem cells sense what happens around them and react accordingly. For decades, researchers have been learning how to steer this differentiation process by changing the cells’ environment. The knowledge acquired is already being used in tissue engineering, in other words, to generate substitute materials that restore or maintain damaged biological tissues. However, most research has been done on static scaffolds. Now, researchers from the Helmholtz-Zentrum Geesthacht (HZG), the Berlin-Brandenburg Centre for Regenerative Therapies, the Freien Universität Berlin and the Helmholtz Virtual Institute for Multifunctional Biomaterials in medicine have used a dynamic scaffold.

New method created

The researchers took a polymer sheet that acts like an artificial muscle. The sheet has the unusual property in that it is trained to reversibly morph when exposed to repeated temperature changes. The researchers simply moulded a grid onto the underside of the sheet and programmed it to stretch as the temperature went from body temperature (37 °C) to 10 °C and to contract when re-heated. They then seeded the sheet with stem cells, and carefully observed the changing shape of the gridded sheet and cells. With the help of this “artificial muscle,” the scientists could use one physical signal — the temperature change — to simultaneously send a second mechanical signal to the stem cells. With these synchronised stimuli it is possible to encourage the stem cells to turn themselves into bone cells.

“Our polymer actuator sheet has a so-called shape-memory function. In our experiments, this allows it to act like a transducer, with which we can effectively instruct the cells to do as we wish. We found that the changes in temperature, combined with the repeated stretching motion of the film was enough to encourage the stem cells to differentiate into bone cells” explained Professor Andreas Lendlein an author of the paper and head of the HZG’s Institute of Biomaterial Science in Teltow, Germany.

Potential application in complex bone fractures

“The programmed polymer sheets could, for example, later be used to treat bones broken so severely that the body can’t repair it by itself. Stem cells from a patient’s bone marrow could be cultured on the sheet and adaptively wrap around the bone during an operation. The previously “trained” cells could then directly strengthen the bones,” said Professor Lendlein.

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Heart problems, graft-versus-host disease are concerns — ScienceDaily

A stem cell transplant — also called a bone marrow transplant — is a common treatment for blood cancers, such as acute myeloid leukemia (AML). Such treatment can cure blood cancers but also can lead to life-threatening complications, including heart problems and graft-versus-host disease, in which new immune cells from the donor attack a patient’s healthy tissues.

A new study from Washington University School of Medicine in St. Louis suggests that extremely rare, harmful genetic mutations present in healthy donors’ stem cells — though not causing health problems in the donors — may be passed on to cancer patients receiving stem cell transplants. The intense chemo- and radiation therapy prior to transplant and the immunosuppression given after allow cells with these rare mutations the opportunity to quickly replicate, potentially creating health problems for the patients who receive them, suggests the research, published Jan. 15 in the journal Science Translational Medicine.

Among the concerns are heart damage, graft-versus-host disease and possible new leukemias.

The study, involving samples from patients with AML and their stem cell donors, suggests such rare, harmful mutations are present in surprisingly young donors and can cause problems for recipients even if the mutations are so rare as to be undetectable in the donor by typical genome sequencing techniques. The research opens the door to a larger study that will investigate these rare mutations in many more healthy donors, potentially leading to ways to prevent or mitigate the health effects of such genetic errors in patients receiving stem cell transplants.

“There have been suspicions that genetic errors in donor stem cells may be causing problems in cancer patients, but until now we didn’t have a way to identify them because they are so rare,” said senior author Todd E. Druley, MD, PhD, an associate professor of pediatrics. “This study raises concerns that even young, healthy donors’ blood stem cells may have harmful mutations and provides strong evidence that we need to explore the potential effects of these mutations further.”

Added co-author Sima T. Bhatt, MD, an assistant professor of pediatrics who treats pediatric patients with blood cancers at Siteman Kids at St. Louis Children’s Hospital and Washington University School of Medicine: “Transplant physicians tend to seek younger donors because we assume this will lead to fewer complications. But we now see evidence that even young and healthy donors can have mutations that will have consequences for our patients. We need to understand what those consequences are if we are to find ways to modify them.”

The study analyzed bone marrow from 25 adult patients with AML whose samples had been stored in a repository at Washington University. Samples from their healthy matched donors, who were unrelated to the patients, also were sequenced. The donors’ samples were provided by the Center for International Blood and Marrow Transplant Research in Milwaukee.

The 25 AML patients were chosen because they each had had samples banked at four separate times: before the transplant, at 30 days post-transplant, at 100 days post-transplant, and one year post-transplant.

Druley co-invented a technique called error-corrected sequencing, to identify extremely rare DNA mutations that would be missed by conventional genome sequencing. Typical next-generation sequencing techniques can correctly identify a mutation that is present in one in 100 cells. The new method, which can distinguish between true mutations and mistakes introduced by the sequencing machine, allows the researchers to find true mutations that are extremely rare — those present in as few as one in 10,000 cells.

The healthy donors ranged in age from 20 to 58, with an average age of 26. The researchers sequenced 80 genes known to be associated with AML, and they identified at least one harmful genetic mutation in 11 of the 25 donors, or 44%. They further showed that 84% of all the various mutations identified in the donors’ samples were potentially harmful, and that 100% of the harmful mutations present in the donors later were found in the recipients. These harmful mutations also persisted over time, and many increased in frequency. Such data suggest the harmful mutations from the donor confer a survival advantage to the cells that harbor them.

“We didn’t expect this many young, healthy donors to have these types of mutations,” Druley said. “We also didn’t expect 100% of the harmful mutations to be engrafted into the recipients. That was striking.”

According to the researchers, the study raises questions about the origins of some of the well-known side effects of stem cell transplantation.

“We see a trend between mutations from the donor that persist over time and the development of chronic graft-versus-host disease,” said first author Wing Hing Wong, a doctoral student in Druley’s lab. “We plan to examine this more closely in a larger study.”

Though the study was not large enough to establish a causal link, the researchers found that 75% of the patients who received at least one harmful mutation in the 80 genes that persisted over time developed chronic graft-versus-host disease. Among patients who did not receive mutations in the 80 genes, about 50% developed the condition. Because the study was small, this difference was not statistically significant, but it is evidence that the association should be studied more closely. In general, about half of all patients who receive a stem cell transplant go on to develop some form of graft-versus-host disease.

The most common mutation seen in the donors and the cancer patients studied is in a gene associated with heart disease. Healthy people with mutations in this gene are at higher risk of heart attack due to plaque buildup in the arteries.

“We know that cardiac dysfunction is a major complication after a bone marrow transplant, but it’s always been attributed to toxicity from radiation or chemotherapy,” Druley said. “It’s never been linked to mutations in the blood-forming cells. We can’t make this claim definitively, but we have data to suggest we should study that in much more detail.”

Added Bhatt: “Now that we’ve also linked these mutations to graft-versus-host disease and cardiovascular problems, we have a larger study planned that we hope will answer some of the questions posed by this one.”

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Producing human tissue in space — ScienceDaily

On 6 March at 11:50 PM EST, the International Space Station resupply mission Space X CRS-20 took off from Cape Canaveral (USA). On board: 250 test tubes from the University of Zurich containing adult human stem cells. These stem cells will develop into bone, cartilage and other organs during the month-long stay in space. Professor Oliver Ullrich and Dr. Cora Thiel, the two research leaders at the UZH Space Hub, are testing their innovative concept of human tissue production in weightlessness for the benefit of transplantation medicine and precision medicine and as an alternative to animal experiments.

Weightlessness as a tool

“We are using weightlessness as a tool,” explains Cora Thiel. Physical forces such as gravity influence how stem cells differentiate and how the formation and regeneration of tissue is organized. The researchers assume that due to the low gravity on board the ISS, newly formed cells organize themselves into three-dimensional tissues without an additional matrix or other auxiliary structures. The experiment will take place in a mobile mini-laboratory, the CubeLab module of the US company Space Tango. The module consists of a closed and sterile system, in which the stem cells can proliferate and differentiate at constant temperature.

If the test project is successful, it is planned to gradually switch from a small laboratory to a larger production scale. In the future, the innovative process can be used to generate tissue transplants such as cartilage or new liver cells in space from stem cells which are harvested from individual patients in a routine procedure. According to Oliver Ullrich, an additional application is emerging in precision medicine: “Artificially produced autologous human tissue could be used to determine which combination of drugs is the most suitable for the patient in question. In addition, human tissue and organ-like structures produced in space could help to reduce the number of animal experiments.”

Public-private partnership between university and industry

Airbus is also convinced of the potential. The public-private partnership is structured as follows: The Airbus division “Defence and Space” has designed the inlets for the interior of the transport boxes. For their design and manufacture, innovative processes such as selective laser sintering (SLS), a special 3D printing process, were used. The inlets ensure safe transport of the cell samples with maximum volume utilization. In addition, Airbus is organizing access to the ISS, transport of the test tubes to and from the ISS and providing ground support equipment. Ullrich and Thiel are contributing the research idea and study design, and are carrying out the scientific work and providing the scientific staff.

Low Earth Orbit as a future research, development and production location

Contrary to widespread opinion, transportation into space no longer causes costs to skyrocket today. “In space projects, the main cost drivers are the custom-made hardware and the bureaucracy,” says Ullrich, Professor of Anatomy at UZH and director of the UZH Space Hub. He therefore deliberately relies on established medical serial products for equipment and instruments. Ullrich is convinced of the future benefits of space flight: “In a few decades, humankind will use the low Earth orbit as a routine place for research, development and production.”

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

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