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February 2021

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Mechanism by which exercise strengthens bones and immunity — ScienceDaily

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Scientists at the Children’s Medical Center Research Institute at UT Southwestern (CRI) have identified the specialized environment, known as a niche, in the bone marrow where new bone and immune cells are produced. The study, published in Nature, also shows that movement-induced stimulation is required for the maintenance of this niche, as well as the bone and immune-forming cells that it contains. Together, these findings identify a new way that exercise strengthens bones and immune function.

Researchers from the Morrison laboratory discovered that forces created from walking or running are transmitted from bone surfaces along arteriolar blood vessels into the marrow inside bones. Bone-forming cells that line the outside of the arterioles sense these forces and are induced to proliferate. This not only allows the formation of new bone cells, which helps to thicken bones, but the bone-forming cells also secrete a growth factor that increases the frequency of cells that form lymphocytes around the arterioles. Lymphocytes are the B and T cells that allow the immune system to fight infections.

When the ability of the bone-forming cells to sense pressure caused by movement, also known as mechanical forces, was inactivated, it reduced the formation of new bone cells and lymphocytes, causing bones to become thinner and reducing the ability of mice to clear a bacterial infection.

“As we age, the environment in our bone marrow changes and the cells responsible for maintaining skeletal bone mass and immune function become depleted. We know very little about how this environment changes or why these cells decrease with age,” says Sean Morrison, Ph.D., the director of CRI and a Howard Hughes Medical Institute Investigator. “Past research has shown exercise can improve bone strength and immune function, and our study discovered a new mechanism by which this occurs.”

Previous work from the Morrison laboratory discovered the skeletal stem cells that give rise to most of the new bone cells that form during adulthood in the bone marrow. They are Leptin Receptor+ (LepR+) cells. They line the outside of blood vessels in the bone marrow and form critical growth factors for the maintenance of blood-forming cells. The Morrison lab also found that a subset of LepR+ cells synthesize a previously undiscovered bone-forming growth factor called Osteolectin. Osteolectin promotes the maintenance of the adult skeleton by causing LepR+ to form new bone cells.

In the current study, Bo Shen, Ph.D., a postdoctoral fellow in the Morrison laboratory, looked more carefully at the subset of LepR+ cells that make Osteolectin. He discovered that these cells reside exclusively around arteriolar blood vessels in the bone marrow and that they maintain nearby lymphoid progenitors by synthesizing stem cell factor (SCF) — a growth factor on which those cells depend. Deleting SCF from Osteolectin-positive cells depleted lymphoid progenitors and undermined the ability of mice to mount an immune response to bacterial infection.

“Together with our previous work, the findings in this study show Osteolectin-positive cells create a specialized niche for bone-forming and lymphoid progenitors around the arterioles. Therapeutic interventions that expand the number of Osteolectin-positive cells could increase bone formation and immune responses, particularly in the elderly,” says Shen.

Shen found that the number of Osteolectin-positive cells and lymphoid progenitors decreased with age. Curious if he could reverse this trend, Shen put running wheels in the cages so that the mice could exercise. He found the bones of these mice became stronger with exercise, while the number of Osteolectin-positive cells and lymphoid progenitors around the arterioles increased. This was the first indication that mechanical stimulation regulates a niche in the bone marrow.

Shen found that Osteolectin-positive cells expressed a receptor on their surfaces — known as Piezo1 — that signals inside the cell in response to mechanical forces. When Piezo1 was deleted from Osteolectin-positive cells of mice, these cells and the lymphoid progenitors they support became depleted, weakening bones and impairing immune responses.

“We think we’ve found an important mechanism by which exercise promotes immunity and strengthens bones, on top of other mechanisms previously identified by others,” says Morrison.

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Scientists repair injured spinal cord using patients’ own stem cells — ScienceDaily

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Intravenous injection of bone marrow derived stem cells (MSCs) in patients with spinal cord injuries led to significant improvement in motor functions, researchers from Yale University and Japan report Feb. 18 in the Journal of Clinical Neurology and Neurosurgery.

For more than half of the patients, substantial improvements in key functions — such as ability to walk, or to use their hands — were observed within weeks of stem cell injection, the researchers report. No substantial side effects were reported.

The patients had sustained, non-penetrating spinal cord injuries, in many cases from falls or minor trauma, several weeks prior to implantation of the stem cells. Their symptoms involved loss of motor function and coordination, sensory loss, as well as bowel and bladder dysfunction. The stem cells were prepared from the patients’ own bone marrow, via a culture protocol that took a few weeks in a specialized cell processing center. The cells were injected intravenously in this series, with each patient serving as their own control. Results were not blinded and there were no placebo controls.

Yale scientists Jeffery D. Kocsis, professor of neurology and neuroscience, and Stephen G. Waxman, professor of neurology, neuroscience and pharmacology, were senior authors of the study, which was carried out with investigators at Sapporo Medical University in Japan. Key investigators of the Sapporo team, Osamu Honmou and Masanori Sasaki, both hold adjunct professor positions in neurology at Yale.

Kocsis and Waxman stress that additional studies will be needed to confirm the results of this preliminary, unblinded trial. They also stress that this could take years. Despite the challenges, they remain optimistic.

“Similar results with stem cells in patients with stroke increases our confidence that this approach may be clinically useful,” noted Kocsis. “This clinical study is the culmination of extensive preclinical laboratory work using MSCs between Yale and Sapporo colleagues over many years.”

“The idea that we may be able to restore function after injury to the brain and spinal cord using the patient’s own stem cells has intrigued us for years,” Waxman said. “Now we have a hint, in humans, that it may be possible.”

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Materials provided by Yale University. Original written by Lakshmi Bangalore. Note: Content may be edited for style and length.

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How a longevity gene protects brain stem cells from stress — ScienceDaily

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A gene linked to unusually long lifespans in humans protects brain stem cells from the harmful effects of stress, according to a new study by Weill Cornell Medicine investigators.

Studies of humans who live longer than 100 years have shown that many share an unusual version of a gene called Forkhead box protein O3 (FOXO3). That discovery led Dr. Jihye Paik, associate professor of pathology and laboratory medicine at Weill Cornell Medicine, and her colleagues to investigate how this gene contributes to brain health during aging.

In 2018, Dr. Paik and her team showed that mice who lack the FOXO3 gene in their brain are unable to cope with stressful conditions in the brain, which leads to the progressive death of brain cells. Their new study, published Jan. 28 in Nature Communications, reveals that FOXO3 preserves the brain’s ability to regenerate by preventing stem cells from dividing until the environment will support the new cells’ survival.

“Stem cells produce new brain cells, which are essential for learning and memory throughout our adult lives,” said Dr. Paik, who is also a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. “If stem cells divide without control, they get depleted. The FOXO3 gene appears to do its job by stopping the stem cells from dividing until after the stress has passed.”

Many challenges like inflammation, radiation or a lack of adequate nutrients can stress the brain. But Dr. Paik and her colleagues looked specifically what happens when brain stem cells are exposed to oxidative stress, which occurs when harmful types of oxygen build up in the body.

“We learned that the FOXO3 protein is directly modified by oxidative stress,” she said. This modification sends the protein into the nucleus of the stem cell where it turns on stress response genes.

The resulting stress response leads to the depletion of a nutrient called s-adenosylmethionine (SAM). This nutrient is needed to help a protein called lamin form a protective envelope around the DNA in the nucleus of the stem cell.

“Without SAM, lamin can’t form this strong barrier and DNA starts leaking out,” she said.

The cell mistakes this DNA for a virus infection, which triggers an immune response called the type-I interferon response. This causes the stem cell to go dormant and stop producing new neurons.

“This response is actually very good for the stem cells because the outside environment is not ideal for newly born neurons,” Dr. Paik explained. “If new cells were made in such stressful conditions they would be killed. It’s better for stem cells to remain dormant and wait until the stress is gone to produce neurons.”

The study may help explain why certain versions of the FOXO3 are linked to extraordinarily long and healthy lives — they may help people keep a good reserve of brain stem cells. It may also help explain why regular exercise, which boosts FOXO3 helps preserve mental sharpness. But Dr. Paik cautioned it is too early to know whether this new information could be used to create new therapies for brain diseases.

“It could be a double-edged sword,” Dr. Paik explained. “Over activating FOXO3 could be very harmful. We don’t want to keep this on all the time.”

To better understand the processes involved, she and her colleagues will continue to study how FOXO3 is regulated and whether briefly turning it on or off would be beneficial for health.

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Researchers identify mechanisms that are essential for proper skin development — ScienceDaily

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Mount Sinai researchers have discovered that Polycomb complexes, groups of proteins that maintain gene expression patterns, are essential for proper skin development, according to a paper published in Genes & Development on February 18. This latest discovery could improve development of future stem cell therapies to generate “skin on a dish” to transplant into burn victims and patients with skin-blistering disorders.

Polycomb complexes are groups of proteins that maintain the gene-expression patterns during early development by regulating the structure of DNA and proteins in cells. They play a critical role in the repression of gene expression, or the switching-off of individual genes to help control responses to changing environments and stimuli. The researchers found that Polycomb repressive complex 1 (PRC1) and Polycomb repressive complex 2 (PRC2) each help maintain the skin-specific gene expression pattern necessary for proper development of the skin.

The researchers studied Polycomb complexes in the developing skin of mice. Mice that were bred missing either Polycomb complex still had a functioning skin barrier, albeit with minor defects in skin thickness. In contrast, when researchers bred mice missing both complexes, it resulted in severe skin defects including a significantly thin epidermis that lacked essential layers required for survival. The researchers found that PRC1 and PRC2 help maintain regular function of gene repression, in particular the repression of transcription factors essential for the formation of non-skin tissues.

“We show that Polycomb complexes function redundantly to control proper development of the skin,” said the study’s corresponding author Elena Ezhkova, PhD, Professor of Cell, Developmental and Regenerative Biology, and Dermatology in the Black Family Stem Cell Institute at the Icahn School of Medicine at Mount Sinai. “Polycomb complexes function together to repress non-skin lineage programs and thus control proper skin development.”

The researchers said their discovery has implications for development of stem cell therapies to produce “skin on a dish” to use for transplantation. Since Mount Sinai researchers have established that both Polycomb complexes are vital for skin formation, this discovery could improve current protocols for generating skin cells from stem cells. Polycomb complexes are also often overexpressed in epithelial cancers, including skin cancers, and treatments using Polycomb inhibitors are currently being studied in clinical trials. This study suggests that parallel inhibition, use of both PRC1 and PRC2 inhibitors, may be a more powerful form of treatment for cancer patients.

While Polycomb complexes are important for skin function, their role in other tissues remains unknown. Future studies should explore the role of Polycomb complexes in developing and regenerating tissues, the researcher said.

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Focus on adult AML has revealed encouraging results — ScienceDaily

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A McMaster stem cell research team has made an important early step in developing a new class of therapeutics for patients with a deadly blood cancer.

The team has discovered that for acute myeloid leukemia (AML) patients, there is a dopamine receptor pathway that becomes abnormally activated in the cancer stem cells. This inspired the clinical investigation of a dopamine receptor-inhibiting drug thioridazine as a new therapy for patients, and their focus on adult AML has revealed encouraging results.

AML is a particularly deadly cancer that starts with a DNA mutation in the blood stem cells of the bone marrow that produce too many infection-fighting white blood cells. According to the Canadian Cancer Society about 21% of people diagnosed with AML will survive at least five years.

“We have successfully understood the mechanism by which the drug benefited patients, and we are using this information to develop a new, more tolerable formulation of the drug that is likely to work in some of the patients,” said senior author of the paper Mick Bhatia, a professor of biochemistry and biomedical sciences at McMaster. He also holds the Canada Research Chair in Human Stem Cell Biology.

The phase one study of 13 patients is being featured on the cover of the journal Cell Reports Medicine published today.

Bhatia said the team has continued to carefully analyze and further refine their therapeutic approach and results of the initial trial.

“Together, these achievements highlight the importance of the new paradigm of that issues impacting patients can be taken to the lab bench and solutions back to patients. These “bed to bench, and back to bed” approaches and partnerships to advance novel therapeutics Canadians suffering from cancer,” he added.

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Unlocking the mystery behind skeletal aging — ScienceDaily

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Researchers from the UCLA School of Dentistry have identified the role a critical enzyme plays in skeletal aging and bone loss, putting them one step closer to understanding the complex biological mechanisms that lead to osteoporosis, the bone disease that afflicts some 200 million people worldwide.

The findings from their study in mice, published online in the journal Cell Stem Cell, could hold an important key to developing more effective treatments for osteoporosis and improving the lives of an aging population, they say.

Cells in the bone marrow known as mesenchymal stem cells serve as the building blocks of the body’s skeletal tissues, but whether these stem cells ultimately develop into bone or fat tissues is controlled in part by what are known as epigenetic factors — molecules that regulate genes, silencing some and activating others.

The UCLA researchers, led by distinguished professor Dr. Cun-Yu Wang, chair of oral biology at the dentistry school, demonstrated that when the epigenetic factor KDM4B is absent from mesenchymal stem cells, these cells are far more likely to differentiate into fat cells than bone cells, resulting in an unhealthy imbalance that exacerbates skeletal aging and leads to brittle bones and fractures over time.

“We know that bone loss comes with age, but the mechanisms behind extreme cases such as osteoporosis have, up until recently, been very vague,” said Dr Wang, the study’s corresponding author and the Dr. No-Hee Park Professor of Dentistry at UCLA. “In this study, we built on more than seven years of research managed by my postdoctoral scholar and lead author Dr. Peng Deng in the hope that we can eventually prevent skeletal aging and osteoporosis.”

While scientists have long understood the cellular pathway involved in bone tissue formation, the role of epigenetic factors has been murkier. Previous research by Wang, Deng and others had identified that the enzyme KDM4B plays an important epigenetic role in bone formation, but they were unsure of how its absence might affect the processes of bone formation and bone loss.

To test this, the research team created a mouse model in which KDM4B was absent or removed in several different scenarios. They found that the removal of the enzyme pushed mesenchymal stem cells to create more fat instead of bone tissue, leading to bone loss over time, which mimics skeletal aging.

In one important scenario, the scientists examined stem cell senescence, or deterioration and exhaustion — the natural process by which mesenchymal stem cells stop rejuvenating or creating more of themselves over time. The team unexpectedly found that senescence, which leads to natural skeletal aging, was characterized by a loss of KDM4B.

In addition to age, other environmental factors are thought to reduce bone quality and exacerbate bone loss, including a high-fat diet. The team demonstrated that a loss of KDM4B significantly promoted bone loss and the accumulation of marrow fat in mice placed on a high-fat diet.

Finally, the team showed that parathyroid hormone, an anabolic drug approved by the U.S. Food and Drug Administration for the treatment of aging-related bone loss, helps to maintain the pool of mesenchymal stem cells in aging mice in a KDM4B-dependent manner.

The results not only confirm the critical role KDM4B plays in mesenchymal stem cell fate decision, skeletal aging and osteoporosis, but they show that the loss of KDM4B exacerbates bone loss under a number of conditions and, surprisingly, that KDM4B controls the ability of mesenchymal stem cells to self-renew. This study is the first in vivo research to demonstrate that the loss of an epigenetic factor promotes adult stem cell deterioration and exhaustion in skeletal aging.

The findings, the researchers say, hold promise for the eventual development of strategies to reverse bone-fat imbalance, as well as for new prevention and treatment methods that address skeletal aging and osteoporosis by rejuvenating adult stem cells.

“The work of Dr. Wang, his lab members and collaborators provides new molecular insight into the changes associated with skeletal aging,” said Dr. Paul Krebsbach, dean of the UCLA School of Dentistry. “These findings are an important step towards what may lead to more effective treatment for the millions of people who suffer from bone loss and osteoporosis.”

The work was supported by grants from the National Institute of Dental and Craniofacial Research (part of the National Institutes of Health), the UCLA Clinical and Translational Science Institute and the Hsien Family Foundation charitable funds.

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Clinical hair regeneration — ScienceDaily

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Researchers at the RIKEN Center for Biosystems Dynamics Research in Japan have discovered a recipe for continuous cyclical regeneration of cultured hair follicles from hair follicle stem cells.

Scientists have been making waves in recent years by developing ways to grow a variety of useful items in laboratories, from meat and diamonds to retinas and other organoids. At the RIKEN Center for Biosystems Dynamics Research in Japan, a team led by Takashi Tsuji has been working on ways to regenerate lost hair from stem cells. In an important step, a new study identifies a population of hair follicle stem cells in the skin and a recipe for normal cyclical regeneration in the lab.

The researchers took fur and whisker cells from mice and cultured them in the laboratory with other biological “ingredients.” They used 220 combinations of ingredients, and found that combining a type of collagen with five factors — the NFFSE medium — led to the highest rate of stem cell amplification in the shortest period of time..

Hair growth in mammals is a continuous cyclical process in which hair grows, falls out, and is grown again. Growth occurs in the anagen phase and hair falls out in the telogen phase. Thus, a successful hair-regeneration treatment must produce hair that recycles. To test whether stem cells cultured in the NFFSE medium produce hair that cycles, the researchers placed bioengineered hair follicle stem cells in NFFSE medium or in medium missing one of the ingredients and observed the regenerated hair for several weeks. They found 81% of hair follicles generated in NFFSE medium went through at least three hair cycles and produced normal hair. In contrast, 79% of follicles grown in the other medium produced only one hair cycle.

Knowing that stem-cell renewal can depend on what is attached to the outside of the cells, the researchers next looked for markers on the surface of cells cultured in the NFFSE medium. In addition to the expected CD34 and CD49f markers, they found the best hair cycling was related to the addition of Itgβ5. “We found almost 80% of follicles reached three hair cycles when Itgβ5 was also bioengineered into the hair follicle germ,” explains first author Makoto Takeo. “In contrast, only 13% reached three cycles when it was not present.” Analysis showed that these important cells are naturally located in the upper part of the hair follicle’s bulge region.

“Our culture system establishes a method for cyclical regeneration of hair follicles from hair follicle stem cells,” says Tsuji, “and will help make hair follicle regeneration therapy a reality in the near future.” As preclinical animal-safety tests using these cultured cells were completed in 2019, the next step in the process is clinical trials.

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Brain enzyme activates dormant neural stem cells — ScienceDaily

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Researchers studying an enzyme in fruit fly larvae have found that it plays an important role in waking up brain stem cells from their dormant ‘quiescent’ state, enabling them to proliferate and generate new neurons. Published in the journal EMBO Reports, the study by Duke-NUS Medical School, Singapore, could help clarify how some neurodevelopmental disorders such as autism and microcephaly occur.

Quiescent neural stem cells in the fruit fly larval brainPr-set7 is an enzyme involved in maintaining genome stability, DNA repair and cell cycle regulation, as well as turning various genes on or off. This protein, which goes by a few different names, has remained largely unchanged as species have evolved. Professor Wang Hongyan, a professor and deputy director at Duke-NUS’ Neuroscience and Behavioural Disorders Programme, and her colleagues set out to understand the protein’s function during brain development.

“Genetic variants of the human version of Pr-set7 are associated with neurodevelopmental disorders, with typical symptoms including intellectual disability, seizures and developmental delay,” explained Professor Wang. “Our study is the first to show that Pr-set7 promotes neural stem cell reactivation and, therefore, plays an important role in brain development.”

Neural stem cells normally oscillate between states of quiescence and proliferation. Maintaining an equilibrium between the two is very important. Most neural stem cells are quiescent in adult mammalian brains. They are reactivated to generate new neurons in response to stimuli, such as injury, the presence of nutrients or exercise. However, neural stem cells gradually lose their capacity to proliferate with age and in response to stress, and anxiety.

Professor Wang and her colleagues studied what happened when the gene coding for Pr-set7 is turned off in larval fruit fly brains. They found it caused a delay in the reactivation of neural stem cells from their quiescent state. To reactivate neural stem cells, Pr-set7 needs to turn on at least two genes: cyclin-dependent kinase 1 (cdk1) and earthbound 1 (Ebd1). The scientists found that overexpressing the proteins coded by these genes led to the reactivation of neural stem cells even when the Pr-set7 gene was turned off. These findings show that Pr-set7 binds to the cdk1 and Ebd1 genes to activate a signalling pathway that reactivates neural stem cells from their quiescent state.

“Since Pr-set7 is conserved across species, our findings could contribute to the understanding of the roles of its mammalian counterpart in neural stem cell proliferation and its associated neurodevelopmental disorders,” said Prof Wang.

Professor Patrick Casey, Senior Vice-Dean for Research at Duke-NUS, commented: “With this latest study, Professor Wang’s fundamental research in neuroscience has yielded valuable insights into several neurodevelopmental disorders; insights that have the potential to improve the way we care for people with such disorders.”

The scientists are now extrapolating this study to understand the roles of the mammalian and human forms of Pr-set7, called SETD8 and KMT5A respectively, in brain development.

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complete muscle replacement and movement achieved in mouse models — ScienceDaily

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When we tear a muscle ” stem cells within it repair the problem. We can see this occurring not only in severe muscle wasting diseases such as muscular dystrophy and in war veterans who survive catastrophic limb injuries, but also in our day to day lives when we pull a muscle.

Also when we age and become frail we lose much of our muscle and our stem cells don’t seem to be able to work as well as we age.

These muscle stem cells are invisible engines that drive the tissue’s growth and repair after such injuries. But growing these cells in the lab and then using them to therapeutically replace damaged muscle has been frustratingly difficult.

Researchers at the Australian Regenerative Medicine Institute at Monash University in Melbourne, Australia have discovered a factor that triggers these muscle stem cells to proliferate and heal. In a mouse model of severe muscle damage, injections of this naturally occurring protein led to the complete regeneration of muscle and the return of normal movement after severe muscle trauma.

The research led by Professor Peter Currie, Director of Monash University’s Australian Regenerative Medicine Institute, is published today in Nature.

The scientists studied the regeneration of skeletal muscle in zebrafish, fast becoming the go-to animal model for the study of stem cell regeneration because but fish are quick to reproduce, easier to experimentally manipulate, and share at least 70 percent of its genes with humans. It is also transparent which allows the scientists to witness the actual regeneration in living muscle.

By studying the cells that migrated to a muscle injury in these fish the scientists identified a group of immune cells, called macrophages, which appeared to have a role in triggering the muscle stem cells to regenerate. “What we saw were macrophages literally cuddling the muscle stem cells, which then started to divide and proliferate. Once they started this process, the macrophage would move on and cuddle then next muscle stem cell, and pretty soon the wound would heal,”? Professor Currie said

Macrophages are the cells that flock to any injury or infection site in the body, removing debris and promoting healing. “They are the clean up crew of the immune system,” Professor Currie said.

It has long been thought that two types of macrophages exist in the body: those that move to the injury rapidly and remove debris, and those that come in slower and stick around doing the longer term clean-up.

The research team, however, found that there were in fact eight genetically different types of macrophages in the injury site, and that one type, in particular, was the “cuddler.” Further investigation revealed that this affectionate macrophage released a substance called NAMPT.

By removing these macrophages from the zebrafish and adding the NAMPT to the aquarium water the scientists found they could stimulate the muscle stem cells to grow and heal ” effectively replacing the need for the macrophages.”

Importantly recent experiments placing a hydrogel patch containing NAPMT into a mouse model of severe muscle wasting led to what Professor Currie called significant replacement of the damaged muscle. The researchers are now in discussions with a number of biotech companies about taking NAMPT to clinical trials for the use of this compound in the treatment of muscle disease and injury.

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Hot nano-chisel used to create artificial bones in a Petri dish — ScienceDaily

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A holy grail for orthopedic research is a method for not only creating artificial bone tissue that precisely matches the real thing, but does so in such microscopic detail that it includes tiny structures potentially important for stem cell differentiation, which is key to bone regeneration.

Researchers at the NYU Tandon School of Engineering and New York Stem Cell Foundation Research Institute (NYSF) have taken a major step by creating the exact replica of a bone using a system that pairs biothermal imaging with a heated “nano-chisel.” In a study, “Cost and Time Effective Lithography of Reusable Millimeter Size Bone Tissue Replicas with Sub-15 nm Feature Size on a Biocompatible Polymer,” which appears in the journal Advanced Functional Materials, the investigators detail a system allowing them to sculpt, in a biocompatible material, the exact structure of the bone tissue, with features smaller than the size of a single protein — a billion times smaller than a meter. This platform, called, bio-thermal scanning probe lithography (bio-tSPL), takes a “photograph” of the bone tissue, and then uses the photograph to produce a bona-fide replica of it.

The team, led by Elisa Riedo, professor of chemical and biomolecular engineering at NYU Tandon, and Giuseppe Maria de Peppo, a Ralph Lauren Senior Principal Investigator at the NYSF, demonstrated that it is possible to scale up bio-tSPL to produce bone replicas on a size meaningful for biomedical studies and applications, at an affordable cost. These bone replicas support the growth of bone cells derived from a patient’s own stem cells, creating the possibility of pioneering new stem cell applications with broad research and therapeutic potential. This technology could revolutionize drug discovery and result in the development of better orthopedic implants and devices.

The research, “Cost and time effective lithography of reusable millimeter size bone tissue replicas with sub-15 nm feature size on a biocompatible polymer,” appears in Advanced Functional Materials.

In the human body, cells live in specific environments that control their behavior and support tissue regeneration via provision of morphological and chemical signals at the molecular scale. In particular, bone stem cells are embedded in a matrix of fibers — aggregates of collagen molecules, bone proteins, and minerals. The bone hierarchical structure consists of an assembly of micro- and nano- structures, whose complexity has hindered their replication by standard fabrication methods so far.

“tSPL is a powerful nanofabrication method that my lab pioneered a few years ago, and it is at present implemented by using a commercially available instrument, the NanoFrazor,” said Riedo. “However, until today, limitations in terms of throughput and biocompatibility of the materials have prevented its use in biological research. We are very excited to have broken these barriers and to have led tSPL into the realm of biomedical applications.”

Its time- and cost-effectiveness, as well as the cell compatibility and reusability of the bone replicas, make bio-tSPL an affordable platform for the production of surfaces that perfectly reproduce any biological tissue with unprecedented precision.

“I am excited about the precision achieved using bio-tSPL. Bone-mimetic surfaces, such as the one reproduced in this study, create unique possibilities for understanding cell biology and modeling bone diseases, and for developing more advanced drug screening platforms,” said de Peppo. “As a tissue engineer, I am especially excited that this new platform could also help us create more effective orthopedic implants to treat skeletal and maxillofacial defects resulting from injury or disease.”

The research was supported by the US Army Research Office, the National Science Foundation (CMMI and CBET programs), the Office of Basic Energy Sciences of the US Department of Energy, the New York Stem Cell Foundation, and the Ralph and Ricky Lauren Family Foundation. The NanoFrazor was acquired through an NSF CMMI MRI grant.

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