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August 2020

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Breakthrough in using stem cells to treat enteric nervous system disorders — ScienceDaily

Scientists have made a breakthrough in understanding how the enteric nervous system forms, which could pave the way for new treatments for neurodegenerative diseases such as Parkinson’s.

The findings, published in the journal Stem Cell Reports, pave the way for using stem cells to understand and treat a range of diseases linked to the enteric nervous system — which is embedded in the walls of the esophagus, stomach, small and large intestines, pancreas, gallbladder and biliary tree.

Researchers from the University of Sheffield and University College London (UCL) identified a key stage in the formation of the enteric nervous system using pluripotent stem cells, which can generate any cell type in the body, and were able to generate enteric neurons in the lab.

The enteric nervous system contains between 400-600 million nerves and is crucial for everyday functions such as digestion, fluid absorption and communicating with the immune system.

Faults in the enteric nervous system are often linked to life-threatening digestive disorders such as Hirschprung’s disease, where nerves in the system are missing. Ongoing research has also suggested that Parkinson’s disease is initiated in the enteric nervous system before reaching the brain.

Dr Anestis Tsakiridis,Group Leader of the Study from the University of Sheffield’s Centre for Stem Cell Biology, said: “Our findings show new promise for using stem cells to treat a range of diseases. We now plan to utilise these findings as the basis for developing stem cell-based approaches to treat and model diseases caused by dysfunction of the enteric nervous system.”

Dr Tom Frith, from the Francis Crick Institute who led the study said: “This work was the result of an exciting collaboration with experts from the UCL Great Ormond Street Institute of Child Health.

“These results are a key first step into generating cells in a dish that may one day be used to help treat patients.”

The team involved in the study have been awarded a £1.2 million grant from the Medical Research Council (MRC), which focuses on the development of a stem cell therapy for the treatment of Hirschprung’s disease.

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

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Researchers pinpoint hierarchy of breast cancer cells as potential cause for treatment resistance — ScienceDaily

University of Cincinnati instructor Syn Yeo, PhD, thinks the same analogy applies when it comes to cells and the growth of cancer, particularly breast cancer.

In his recent study, published in the journal eLife, Yeo, research instructor in the department of cancer biology at the UC College of Medicine and co-lead author, says it can take cells in different forms or “life stages” to cause cancer to grow and spread.

“Our recent findings emphasize the need to account for the specific cell states that are present within a tumor,” says Yeo, who is a member in the lab of Jun-Lin Guan, PhD, the Francis Brunning Endowed Chair and professor of cancer biology. “This could potentially help determine the combination of drugs that are required to eliminate all the cell states that are present to eliminate treatment resistance.”

Yeo says that when it comes to breast cancers, it is known that cells within a tumor are varied.

“This diversity poses a problem to treating patients because particular subsets of tumor cells may be drug resistant and eventually lead to disease recurrence,” he says. “One of the factors contributing to this diversity is the fact that tumor cells can exist in different cellular states, ranging from more stem-like cells that can become other cell types to more differentiated cells that have been coded to serve a purpose, or do a certain ‘job’ within the system.

“Cancer cells with stem-like properties are known to cause drug resistance, and they are generally seen as being at the top of the tumor hierarchy, like the kKing or queen of the village, with more differentiated tumor cells towards the bottom of the hierarchy, like the common townspeople.”

In this study, researchers used breast cancer animal models to determine tumor hierarchies beyond “ruler” and “common people” cells, Yeo says. They identified and categorized singular cells which helped them understand each, individual cell’s purpose. Yeo adds that bulk tumor cell analysis would have masked the cellular details.

“We were able to find a complex spectrum of cell states between different tumor types that can range from stem-cells to the ‘beginner cells’ to more differentiated cells,” he says. “In our village [scenario], these would be the governors and mayors, followed by the common townspeople. Furthermore, depending on the lineage of the tumor, some may show a spectrum of cell states that are higher up in the hierarchy and vice versa.

“These findings are important because they show we need to know more about how these specific cell states contribute to tumor growth so we can target them with combination drug therapies, potentially helping more people who may otherwise experience drug resistance.”

Funding for this research was provided by the National Institutes of Health (R01-CA211066, R01-HL073394 and R01-NS094144). Xiaoting Zhu was the other co-lead author who was partially supported by R01-HL111829. Other contributors include Takako Okamoto, Mingang Hao, Cailian Wang, Peixin Lu, Long Jason Lu and Jun-Lin Guan. Researchers cite no conflict of interest.

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Materials provided by University of Cincinnati. Original written by Katie Pence. Note: Content may be edited for style and length.

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A new molecular guardian of intestinal stem cells — ScienceDaily

Intestinal stem cells keep a fine balance between two potential forms: remaining as stem cells, or developing into intestinal epithelial cells. In a new study, researchers from Tokyo Medical and Dental University (TMDU) discovered a novel molecular mechanism that regulates this balance and preserves the stemness of intestinal stem cells — that is, their ability to develop into any intestinal epithelial cell type.

The inner lining of intestines, the intestinal epithelium, ensures adequate digestion and adsorption of nutrients. It is made up of several different cell types, all of which fulfill a specific function. Intestinal stem cells ensure proper functioning of the intestines, which requires constantly replacing old and damaged cells with young cells, by developing, or differentiating, into one of the different intestinal epithelial cell types when needed. Because there is a constant demand for new cells, intestinal stem cells have the ability to self-renew, thereby providing a constant supply of stem cells as well. However, little is known about the mechanisms that regulate this balance between self-renewal and differentiation.

“Just like any other type of stem cell, intestinal stem cells have the ability to differentiate into any cell within their lineage,” says corresponding author of the study Professor Toshiaki Ohteki. “But they have to do it in a regulated manner, only differentiating when needed. The goal of our study was to understand the regulatory mechanism that preserves the stemness of intestinal stem cells.”

To achieve their goal, Taku Sato, a main contributor of this project, and collaborators focused on a molecular signaling pathway that they had previously shown to preserve the stemness of hematopoietic stem cells (HSCs) that give rise to blood cells. Interferons are molecules that are produced especially during viral and bacterial infections, but more recently it was also shown that they are present even in the absence of infections to regulate various biological processes. In either case, interferons induce the expression of certain genes, a process that is regulated by the protein interferon regulatory factor-2 (IRF2) to ensure that the actions of interferons are balanced. In the case of HSCs, IRF2 turned out to be a critical factor for their stemness.

In the current study, the researchers found that IRF2 is produced throughout the intestinal epithelium and that IRF2-deficient mice had normal anatomical structure during homeostasis (the absence of an infection or any other damaging factor). However, in the presence of 5-fluorouracil, which is known to damage the intestinal epithelium, normal mice were able to regenerate completely, but IRF2-deficient mice showed a blunted regenerative response indicating that intestinal stem cells were not able to function properly in the absence of IRF2. Interestingly, immature Paneth cells, which are specialized secretory cells, were highly abundant in IRF2-deficient mice. The researchers had the same finding in normal mice exposed to lymphocytic choriomeningitis virus (LCMV), which causes chronic infection.

“These are striking results that show how excess interferon signaling in the absence of IRF2 impairs the ability to self-renew and directs intestinal stem cells towards the secretory cell lineage. Our findings provide new insight into the biology of intestinal stem cells and show that regulated interferon signaling is a means to preserve the stemness of intestinal stem cells,” says Professor Ohteki.

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Materials provided by Tokyo Medical and Dental University. Note: Content may be edited for style and length.

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Becoming a nerve cell: Timing is of the essence

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Researchers find that mitochondria regulate a key event during brain development: how neural stem cells become nerve cells. Mitochondria influence this cell fate switch during a precise period that is twice as long in humans compared to mice. This highlights an unexpected function for mitochondria that may help explain how humans developed a bigger brain during evolution, and how mitochondrial defects lead to neurodevelopmental diseases.

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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.

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

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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.

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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.

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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.”

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