Category

News

Home / News
News

Introducing ‘Kuma mutant’ mice for islet transplantation research — ScienceDaily

Scientists have used a gene editing technique to establish a novel mouse model of permanent neonatal diabetes — the immune-deficient Kuma mutant mice with a specific deletion in the Insulin2 (Ins2) gene. This model is expected to be useful for studying the mechanisms governing insulin-producing cell dysfunctions in the pancreas as well as for evaluating human stem-cell derived or interspecies-derived insulin-producing cell transplantation.

Diabetes seldom occurs in newborns — a condition known as neonatal diabetes. But when it does, it’s mostly due to a mutation in a single gene such as the KCNJ11 or insulin (INS). This early-onset type of diabetes differs from type-1 diabetes in that it occurs within the first six months of life and can be either transient or permanent. Most of the mutations that underly this disease prevent the pancreas from producing sufficient insulin, which leads to high blood glucose levels or hyperglycemia.

To understand what causes permanent neonatal diabetes and to find a cure, scientists often use mouse and pig models having Insulin2 (Ins2)C96Y gene mutations. These models develop permanent early-onset diabetes resembling neonatal diabetes. However, a major limitation of these models is that by using them, inter-species transplantation of pancreatic insulin-producing cells (pancreatic beta cells), called islet transplantation, cannot be evaluated, due to adverse immune system reactions characterizing such interspecies transplantation.

Now, in a paper published in Scientific Reports, scientists from Tokyo Tech describe how they established a new mouse model of permanent neonatal diabetes, which exhibits severe insulin-deficiency and beta-cell dysfunction in an immune deficient background. As Professor Shoen Kume, who led the study explains, “We wanted to create a mouse model that would allow us to evaluate the efficacy of transplanting human stem cell-derived or xenogeneic pancreatic beta cells into these mice without having to consider immune responses”

To achieve this goal, the scientists used the CRISPR/Cas9 gene editing technique to introduce a three base pair deletion in the Ins2 gene of a severely-immunodeficient BRJ mouse, that lacked mature T and B lymphocytes and natural killer (NK) cells. This mutation causes a Gln (Q) deletion (p.Q104del), hampering insulin production. The scientists named the mutation ‘Kuma mutation’.

Upon examining the Kuma mice as they aged, the scientists discovered that both male and female Kuma mutants developed hyperglycemia three weeks after their birth. They conjectured that this may be due to the low stability of the mutant insulin protein. The scientists also noted that these mice had markedly reduced beta-cell area, size, and mass, as well as a significantly decreased number and size of insulin granules within the beta cells. This meant that the mice could serve as a permanent neonatal diabetes model for islet transplantation.

To corroborate this, their treatment with insulin implants over four weeks successfully reversed their hyperglycemia.

Based on these findings, Prof Kume and his team believe that “the Kuma mutant can not only be used for molecular studies of the Insulin gene and beta cell dysfunction, but its immune-deficient background allows it to be an attractive model for studies examining the functionality of transplanted beta-cells generated from human- or xenogeneic-derived stem cells.”

Moreover, as the Kuma mutation is well conserved across different species, the same gene-editing approach can be applied to creating permanent neonatal diabetic models in other animal species, making advancement in the research on this disease condition a little bit easier.

Story Source:

Materials provided by Tokyo Institute of Technology. Note: Content may be edited for style and length.

Source link

News

Implanted neural stem cell grafts show functionality in spinal cord injuries — ScienceDaily

Using stem cells to restore lost functions due to spinal cord injury (SCI) has long been an ambition of scientists and doctors. Nearly 18,000 people in the United States suffer SCIs each year, with another 294,000 persons living with an SCI, usually involving some degree of permanent paralysis or diminished physical function, such as bladder control or difficulty breathing.

In a new study, published August 5, 2020 in Cell Stem Cell, researchers at University of California San Diego School of Medicine report successfully implanting highly specialized grafts of neural stem cells directly into spinal cord injuries in mice, then documenting how the grafts grew and filled the injury sites, integrating with and mimicking the animals’ existing neuronal network.

Until this study, said the study’s first author Steven Ceto, a postdoctoral fellow in the lab of Mark H. Tuszynski, MD, PhD, professor of neurosciences and director of the Translational Neuroscience Institute at UC San Diego School of Medicine, neural stem cell grafts being developed in the lab were sort of a black box.

Although previous research, including published work by Tuszynski and colleagues, had shown improved functioning in SCI animal models after neural stem cell grafts, scientists did not know exactly what was happening.

“We knew that damaged host axons grew extensively into (injury sites), and that graft neurons in turn extended large numbers of axons into the spinal cord, but we had no idea what kind of activity was actually occurring inside the graft itself,” said Ceto. “We didn’t know if host and graft axons were actually making functional connections, or if they just looked like they could be.”

Ceto, Tuszynski and colleagues took advantage of recent technological advances that allow researchers to both stimulate and record the activity of genetically and anatomically defined neuron populations with light rather than electricity. This ensured they knew exactly which host and graft neurons were in play, without having to worry about electric currents spreading through tissue and giving potentially misleading results.

They discovered that even in the absence of a specific stimulus, graft neurons fired spontaneously in distinct clusters of neurons with highly correlated activity, much like in the neural networks of the normal spinal cord. When researchers stimulated regenerating axons coming from the animals’ brain, they found that some of the same spontaneously active clusters of graft neurons responded robustly, indicating that these networks receive functional synaptic connections from inputs that typically drive movement. Sensory stimuli, such as a light touch and pinch, also activated graft neurons.

“We showed that we could turn on spinal cord neurons below the injury site by stimulating graft axons extending into these areas,” said Ceto. “Putting all these results together, it turns out that neural stem cell grafts have a remarkable ability to self-assemble into spinal cord-like neural networks that functionally integrate with the host nervous system. After years of speculation and inference, we showed directly that each of the building blocks of a neuronal relay across spinal cord injury are in fact functional.”

Tuszynski said his team is now working on several avenues to enhance the functional connectivity of stem cell grafts, such as organizing the topology of grafts to mimic that of the normal spinal cord with scaffolds and using electrical stimulation to strengthen the synapses between host and graft neurons.

“While the perfect combination of stem cells, stimulation, rehabilitation and other interventions may be years off, patients are living with spinal cord injury right now,” Tuszynski said. “Therefore, we are currently working with regulatory authorities to move our stem cell graft approach into clinical trials as soon as possible. If everything goes well, we could have a therapy within the decade.”

Co-authors of the study are Kohel J. Sekiguchi and Axel Nimmerjahn, Salk Institute for Biological Studies and Yoshio Takashima, UC San Diego and Veterans Administration Medical Center, San Diego.

Source link

News

A never-before-seen cell state may explain cancer’s ability to resist drugs — ScienceDaily

Cancer’s knack for developing resistance to chemotherapy has long been a major obstacle to achieving lasting remissions or cures. While tumors may shrink soon after chemotherapy, many times they eventually grow back.

Scientists once thought that unique genetic mutations in tumors underlay this drug resistance. But more and more, they are casting their eyes on other, nongenetic changes in cancer cells to explain their adaptability.

For example, one way that cancer cells can develop resistance is by changing their identity. A prostate cancer cell that is sensitive to hormone-blocking therapy might morph into a cell type that does not require the hormone for its growth.

Rather than specific mutations driving them, identity changes like these come about through changes in gene expression — cells turning specific genes on or off. As a result of these changes, a single tumor can become very different in its cellular makeup. This heterogeneity creates challenges for treatment, since a single drug is unlikely to work against so many different cell types.

A new study from a team of researchers at the Sloan Kettering Institute, the Koch Institute for Integrative Cancer Research at MIT, and the Klarman Cell Observatory at the Broad Institute finds that this tumor heterogeneity can be traced to a common source: a particularly flexible cell state that is characteristic of a subset of cells in a tumor and can generate many other diverse cell types.

“The high-plasticity cell state is the starting point for much of the heterogeneity we see in tumors,” says Tuomas Tammela, an Assistant Member in the Cancer Biology and Genetics Program at SKI and the corresponding author on the new paper, published July 23 in the journal Cancer Cell. “It’s kind of like a busy intersection of many roads: Wherever a cell wants to end up identity-wise, it has to go through this cell state.”

Because this cell state produces nearly all the cellular heterogeneity that emerges in tumors, it is an attractive target for potential therapies.

The particular tumors the researchers examined were lung cancer tumors growing in mice. Jason Chan, a physician-scientist doing a fellowship in the Tammela lab and one of the paper’s lead authors, says finding this unusual cell state was a surprise.

“This highly plastic cell state is something completely new,” he says. “When we saw it, we didn’t know what it was because it was so different. It didn’t look like normal lung cells where the cancer came from, and it didn’t really look like lung cancer either. It had features of embryonic germ layer stem cells, cartilage stem cells, and even kidney cells, all mixed together.”

Nevertheless, he and his colleagues found these cells in every tumor they examined, which suggested that the cells were doing something biologically very important.

A Cell State Road Map

The researchers identified these highly plastic cells by employing a relatively new laboratory technique called single cell RNA sequencing (scRNA-Seq). This technique allows researchers to take “snap shots” of individual cells’ gene expression profiles — revealing which genes are on or off. By performing scRNA-Seq on tumors as they grew over time, they were able to watch when and how different cell types emerged over the course of a tumor’s evolution. From these data, the researchers were able to create a kind of map of which cells came from which other cells.

“The map contains major highways and little dirt roads,” Dr. Tammela says. “The high-plasticity cell state that we identified sits right in the middle of the map. It has a lot of paths coming in, and it has even more paths coming out.”

This high-plasticity cell state emerged consistently in a tumor’s evolution and persisted throughout its growth. In fact, Dr. Tammela says, “it was the only cell state that we found to be present in every single tumor.”

Not Stem Cells

Plasticity — the ability of a cell to give rise to other cells that take on different identities — is a well-known feature of stem cells. Stem cells play important roles in embryonic development and in tissue repair. Many scientists think that cancers arise from specific cancer stem cells.

But Dr. Tammela and colleagues do not think these high-plasticity cells are stem cells.

“When we compare the gene expression signature of these highly plastic cells to normal stems cells or known cancer stem cells, the signatures don’t match at all. They look completely different,” he says.

And unlike stem cells, they’re not there at the very beginning of a tumor’s growth. They only emerge later.

Changing to Resist Drugs

Many prior studies have looked for possible “resistance mutations” — genetic changes that account for a tumor’s ability to resist the effects of cancer drugs. While some have been found, more often the basis of resistance remains a mysterious. The new findings offer a potential solution to the mystery.

“Our model could explain why certain cancer cells are resistant to therapy and don’t have a genetic basis for that resistance that we can identify,” Dr. Chan says.

Importantly, it’s not all the cells in the tumor that are adapting, he explains. It’s a subset of the cancer cells that are just more plastic, more malleable.

By combining chemotherapy drugs with new medications that target these highly plastic cells, the researchers think it might be possible to avert the emergence of resistance and provide longer lasting remissions.

Source link

News

Finding may lead to new therapeutic strategy for disorders causing blindness — ScienceDaily

Researchers at the University of Maryland School of Medicine (UMSOM) have for the first time identified stem cells in the region of the optic nerve, which transmits signals from the eye to the brain. The finding, published this week in the journal Proceedings of the National Academy of Sciences (PNAS), presents a new theory on why the most common form of glaucoma may develop and provides potential new ways to treat a leading cause of blindness in American adults.

“We believe these cells, called neural progenitor cells, are present in the optic nerve tissue at birth and remain for decades, helping to nourish the nerve fibers that form the optic nerve,” said study leader Steven Bernstein, MD, PhD, Professor and Vice Chair of the Department of Ophthalmology and Visual Sciences at the University of Maryland School of Medicine. “Without these cells, the fibers may lose their resistance to stress, and begin to deteriorate, causing damage to the optic nerve, which may ultimately lead to glaucoma.”

The study was funded by the National Institutes of Health’s National Eye Institute (NEI), and a number of distinguished researchers served as co-authors on the study.

More than 3 million Americans have glaucoma, which results from damage to the optic nerve, causing blindness in 120,000 U.S. patients. This nerve damage is usually related to increased pressure in the eye due to a buildup of fluid that does not drain properly. Blind spots can develop in a patient’s visual field that gradually widen over time.

“This is the first time that neural progenitor cells have been discovered in the optic nerve. Without these cells, the nerve is unable to repair itself from damage caused by glaucoma or other conditions. This may lead to permanent vision loss and disability,” said Dr. Bernstein. “The presence of neural stem/progenitor cells opens the door to new treatments to repair damage to the optic nerve, which is very exciting news.”

To make the research discovery, Dr. Bernstein and his team examined a narrow band of tissue called the optic nerve lamina. Less than 1 millimeter wide, the lamina lies between the light-sensitive retina tissue at the back of the eye and the optic nerve. The long nerve cell fibers extend from the retina through the lamina, into the optic nerve. What the researchers discovered is that the lamina progenitor cells may be responsible for insulating the fibers immediately after they leave the eye, supporting the connections between nerve cells on the pathway to the brain.

The stem cells in the lamina niche bathes these neuron extensions with growth factors, as well as aiding in the formation of the insulating sheath. The researchers were able to confirm the presence of these stem cells by using antibodies and genetically modified animals that identified the specific protein markers on neuronal stem cells.

“It took 52 trials to successfully grow the lamina progenitor cells in a culture,” said Dr. Bernstein, “so this was a challenging process.” Dr. Bernstein and his collaborators needed to identify the correct mix of growth factors and other cell culture conditions that would be most conducive for the stem cells to grow and replicate. Eventually the research team found the stem cells could be coaxed into differentiating into several different types of neural cells. These include neurons and glial cells, which are known to be important for cell repair and cell replacement in different brain regions.

This discovery may prove to be game-changing for the treatment of eye diseases that affect the optic nerve. Dr. Bernstein and his research team plan to use genetically modified mice to see how the depletion of lamina progenitor cells contributes to diseases such as glaucoma and prevents repair.

Future research is needed to explore the neural progenitors repair mechanisms. “If we can identify the critical growth factors that these cells secrete, they may be potentially useful as a cocktail to slow the progression of glaucoma and other age-related vision disorders.” Dr. Bernstein added.

The work was supported by NEI grant RO1EY015304, and by a National Institutes of Health shared instrument grant 1S10RR26870-1.

“This exciting discovery could usher in a sea change in the field of age-related diseases that cause vision loss,” said E. Albert Reece, MD, PhD, MBA, Executive Vice President for Medical Affairs, UM Baltimore, and the John Z. and Akiko K. Bowers Distinguished Professor and Dean, University of Maryland School of Medicine. “New treatment options are desperately needed for the millions of patients whose vision is severely impacted by glaucoma, and I think this research will provide new hope for them.”

Source link

News

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

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

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

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

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

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

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

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

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

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

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

Story Source:

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

Source link

News

How airway cells work together in regeneration and aging — ScienceDaily

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Source link

News

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

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

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

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

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

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

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

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

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

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

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

Source link

News

Skin stem cells shuffle sugars as they age — ScienceDaily

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

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

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

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

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

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

Story Source:

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

Source link

News

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

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

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

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

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

A system for regulating hair growth

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

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

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

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

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

How the system develops

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

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

Responding to the environment

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

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

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

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

Source link

News

Discovery could open new doors for heart research — ScienceDaily

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Source link

1 2 3 9 10
Privacy Settings
We use cookies to enhance your experience while using our website. If you are using our Services via a browser you can restrict, block or remove cookies through your web browser settings. We also use content and scripts from third parties that may use tracking technologies. You can selectively provide your consent below to allow such third party embeds. For complete information about the cookies we use, data we collect and how we process them, please check our Privacy Policy
Youtube
Consent to display content from Youtube
Vimeo
Consent to display content from Vimeo
Google Maps
Consent to display content from Google
Spotify
Consent to display content from Spotify
Sound Cloud
Consent to display content from Sound
Cart Overview