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Cellular benefits of gene therapy seen decades after treatment — ScienceDaily

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An international collaboration between Great Ormond Street Hospital, the UCL GOS Institute for Child Health and Harvard Medical School has shown that the beneficial effects of gene therapy can be seen decades after the transplanted blood stem cells has been cleared by the body.

The research team monitored five patients who were successfully cured of SCID-X1 using gene therapy at GOSH. For 3-18 years patients’ blood was regularly analysed to detect which cell types and biomarker chemicals were present in their blood. The results showed that even though the stem cells transplanted as part of gene therapy had been cleared by the patients, the all-important corrected immune cells, called T-cells, were still forming.

Gene therapy works by first removing some of the patients’ blood-forming stem cells, which create all types of blood and immune cells. Next, a viral vector is used to deliver a new copy of the faulty gene into the DNA of the patients’ cells in a laboratory. These corrected stem cells are then returned to patients in a so-called ‘autologous transplant’, where they go on to produce a continual supply of healthy immune cells capable of fighting infection.

In the gene therapy for SCID-X1 the corrected stem cells have been eventually cleared by the body but the patients remained cured of their condition. This team of researchers suggested that the ‘cure’ was down to the fact that the body was still able to continually produce newly-engineered T cells — an important part of the body’s immune system.

They used state-of-the-art gene tracking technology and numerous tests to give unprecedented details of the T cells in SCID-X1 patients decades after gene therapy.

The team believe that this gene therapy has created the ideal conditions for the human thymus (the part of the body where T cells develop) to host a long-term store of the correct type of progenitor cells that can form new T cells. Further investigation of how this happens and how it can be exploited could be crucial for the development of next generation gene therapy and cancer immunotherapy approaches.

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Altered cell divisions cause hair thinning — ScienceDaily

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Hair grows from stem cells residing in hair follicles. During aging, the capability of hair follicles to grow hair is successively lost, leading to hair thinning and ultimately hair loss. In a new study, researchers from Tokyo Medical and Dental University (TMDU) and the University of Tokyo identified a novel mechanism by which hair follicles lose their regenerative capabilities.

Hair follicles are mini-organs from which new hair constantly grows. The basis for new hair growth is the proper function of hair follicle stem cells (HFSCs). HFSCs undergo cyclic symmetric and asymmetric cell divisions (SCDs and ACDs). SCDs generate two identical cells that go on to have the same fate, while ACDs generate a differentiating cell and a self-renewing stem cell. The combination ensures that the stem cell population continues to exist, yet how those contribute to the loss of HFSC function due to aging is not yet completely understood.

“For proper tissue function, symmetric and asymmetric cell divisions have to be in balance,” says corresponding author of the study Emi Nishimura. “Once stem cells preferentially undergo one of either or, worse yet, deviate from the typical process of either type of cell division, the organ suffers. In this study, we wanted to understand how stem cell division plays into hair grows during aging.”

To achieve their goal, the researchers investigated stem cell division in HFSCs in young and aged mice by employing two different types of assays: Cell fate tracing and cell division axis analyses. In the former, HFSCs were marked with a fluorescent protein so they could be followed over time, while in the latter the angle of HFSC division was measured. Strikingly, the researchers were able to show that while HFSCs in young mice underwent typical symmetric and asymmetric cell divisions to regenerate hair follicles, during aging they adopted an atypical senescent type of asymmetric cell division.

But why does the mode of cell division change so drastically during aging? To answer this question, the researchers focused on hemidesmosomes, a class of protein that connect the cells to the extracellular matrix (ECM; proteins surrounding cells). Cell-ECM have long been known to confer polarity to cells, i.e., that the cells can sense their localization within a given space through the action of specific proteins. The researchers found that during aging both hemidesmosomal and cell polarity proteins become destabilized, resulting in the generation of aberrantly differentiating cells during division of HFSCs. As a result, HFSCs become exhausted and lost (leading to hair thinning and hair loss) over time.

“These are striking results that show how hair follicles lose their ability to regenerate hair over time,” says first author of the study Hiroyuki Matsumura. “Our results may contribute to the development of new approaches to regulate organ aging and aging-associated diseases.”

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How to speed up muscle repair — ScienceDaily

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A study led by researchers at the University of California San Diego Jacobs School of Engineering provides new insights for developing therapies for muscle disease, injury and atrophy. By studying how different pluripotent stem cell lines build muscle, researchers have for the first time discovered how epigenetic mechanisms can be triggered to accelerate muscle cell growth at different stages of stem cell differentiation.

The findings were published Mar. 17 in Science Advances.

“Stem cell-based approaches that have the potential to aid muscle regeneration and growth would improve the quality of life for many people, from children who are born with congenital muscle disease to people who are losing muscle mass and strength due to aging,” said Shankar Subramaniam, distinguished professor of bioengineering, computer science and engineering, and cellular and molecular medicine at UC San Diego and lead corresponding author on the study. “Here, we have discovered that specific factors and mechanisms can be triggered by external means to favor rapid growth.”

The researchers used three different human induced pluripotent stem cell lines and studied how they differentiate into muscle cells. Out of the three, one cell line grew into muscle the fastest. The researchers looked at what factors made this line different from the rest, and then induced these factors in the other lines to see if they could accelerate muscle growth.

They found that triggering several epigenetic mechanisms at different time points sped up muscle growth in the “slower” pluripotent stem cell lines. These include inhibiting a gene called ZIC3 at the outset of differentiation, followed by adding proteins called beta-catenin transcriptional cofactors later on in the growth process.

“A key takeaway here is that all pluripotent stem cells do not have the same capacity to regenerate,” Subramaniam said. “Identifying factors that will prime these cells for specific regeneration will go a long way in regenerative medicine.”

Next, the team will explore therapeutic intervention, such as drugs, that can stimulate and accelerate muscle growth at different stages of differentiation in human induced pluripotent stem cells. They will also see whether implanting specific pluripotent stem cells in dystrophic muscle can stimulate new muscle growth in animals. Ultimately, they would like to see if such a stem cell-based approach could regenerate muscle in aging humans.

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Materials provided by University of California – San Diego. Original written by Liezel Labios. Note: Content may be edited for style and length.

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Double trouble for drug-resistant cancers — ScienceDaily

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ETC-159, a made-in-Singapore anti-cancer drug that is currently in early phase clinical trials for use in a subset of colorectal and gynaecological cancers, could also prevent some tumours from resisting therapies by blocking a key DNA repair mechanism, researchers from Duke-NUS Medical School and the Agency for Science, Technology and Research (A*STAR) in Singapore reported in the journal EMBO Molecular Medicine.

Among the many therapies used to treat cancers, inhibitors of the enzyme poly (ADP ribose) polymerase (PARP) prevent cancer cells from repairing naturally occurring DNA damage, including unwanted/harmful breaks in the DNA. When too many breaks accumulate, the cell dies.

“Some cancers have an overactive Wnt signalling pathway that may make them resistant to this sort of DNA damage,” said Assistant Professor Babita Madan, from Duke-NUS’ Cancer and Stem Cell Biology (CSCB) Programme and a senior author of the study. “Understanding how this pathway drives resistance to existing therapies could lead to the development of novel anti-cancer treatments.”

Normally, Wnt signalling proteins interact with cell receptors to activate the translocation of another protein, called beta-catenin, into the nucleus, where it regulates the activation of several genes.

“We found that, when Wnt signalling sends beta-catenin into the nucleus, it activates a family of DNA break repair genes,” said Professor David Virshup, director of the CSCB Programme and co-senior author of the study. “Cancers with excessive Wnt signalling, like colorectal cancer, therefore, have an enhanced ability to repair DNA breaks and thus escape the effects of PARP inhibitors.”

The team found that blocking Wnt signalling with a drug called ETC-159 reversed PARP inhibitor resistance in several cancer cell lines.

ETC-159 inhibits an enzyme called porcupine, which in turn, prevent the secretion of Wnt proteins. ETC-159 is being tested in a clinical trial for use in cancers with overactive Wnt signalling, amongst other therapeutic indications

Analysis of this pre-clinical study shows that therapeutic doses of ETC-159 appear to be well tolerated by the gut, without causing toxicity. This means that a low dose of ETC-159, when given alongside PARP inhibitors, could prevent cancer resistance to treatment with PARP inhibitors while sparing intestinal stem cells, providing further options for treating cancers with hyperactive Wnt signalling.

Through this study, the researchers also learned that the same signal for DNA repair helps to prevent mutations from developing in stem cells residing inside the intestinal epithelium, further confirming the importance of normal Wnt signalling in stem cell maintenance.

ETC-159 was jointly developed by Duke-NUS and the Experimental Drug Development Centre (EDDC), a national platform for drug discovery and development hosted by A*STAR. The Wnt-pathway inhibitor is a novel small-molecule drug candidate that targets a range of cancers. It is currently progressing through clinical trials as a treatment for a subset of colorectal and gynaecological cancers.

“These findings improve our understanding of how Wnt signalling enhances DNA repair in stem cells and cancers, maintaining their genomic integrity,” said Dr May Ann Lee, a group head at EDDC and also a senior author of the study. “Conversely, interventions that block Wnt signalling could cause some cancers to be more sensitive to radiation and other DNA damaging agents.”

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Treatment for type-2 diabetic heart disease — ScienceDaily

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University of Otago researchers have discovered one of the reasons why more than 50 per cent of people with type 2 diabetes die from heart disease.

And perhaps more significantly, they have found how to treat it.

Associate Professor Rajesh Katare, of the Department of Physiology, says it has been known that stem cells in the heart of diabetic patients are impaired. While stem cell therapy has proved effective in treating heart disease, it is not the case in diabetic hearts.

It has not been known why; until now.

It comes down to tiny molecules called microRNA which control gene expression.

“Based on the results of laboratory testing, we identified the number of microRNAs that are impaired in stem cells of the diabetic heart,” Associate Professor Katare says.

“Among several microRNAs we identified that one particular microRNA called miR-30c — which is crucial for the stem cells’ survival, growth and new blood vessel formation — is reduced in the diabetic stem cells. All these functions are required for stem cell therapy to be successful in the heart.

“Importantly, we also confirmed that this microRNA is decreased in the stem cells collected from the heart tissue of the patients undergoing heart surgery at Dunedin Hospital.”

Researchers were able to then increase the level of the lacking miR-30c in the heart by a “simple injection.”

“This resulted in significantly improving the survival and growth of stem cells in the diabetic heart,” Associate Professor Katare says.

“This fascinating discovery has newly identified that impairment in the microRNAs is the underlying reason for the stem cells being not functional in the diabetic heart. More importantly, the results have identified a novel therapy for activation of stem cells in the heart using microRNA, without the need to inject stem cells, which is a time and cost consuming process.”

Associate Professor Katare calls the finding “significant” and says it could help diabetes- sufferers — who are ten per cent of New Zealanders — lead a longer, quality life.

“Apart from identifying the reasons for poor stem cells function in a patient with diabetes, the novel therapy of using microRNA could change the treatment method for heart disease in diabetic individuals.”

Researchers will now undertake more laboratory testing before moving on to humans.

“Our initial analysis revealed that there might be another four potential candidate microRNAs. Therefore, it is essential to test the function of those microRNAs as well. It may be possible that combination therapy with more than one microRNA could further increase the beneficial effects.”

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Retracing the history of the mutation that gave rise to cancer decades later — ScienceDaily

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There is no stronger risk factor for cancer than age. At the time of diagnosis, the median age of patients across all cancers is 66. That moment, however, is the culmination of years of clandestine tumor growth, and the answer to an important question has thus far remained elusive: When does a cancer first arise?

At least in some cases, the original cancer-causing mutation could have appeared as long as 40 years ago, according to a new study by researchers at Harvard Medical School and the Dana-Farber Cancer Institute.

Reconstructing the lineage history of cancer cells in two individuals with a rare blood cancer, the team calculated when the genetic mutation that gave rise to the disease first appeared. In a 63-year-old patient, it occurred at around age 19; in a 34-year-old patient, at around age 9.

The findings, published in the March 4 issue of Cell Stem Cell, add to a growing body of evidence that cancers slowly develop over long periods of time before manifesting as a distinct disease. The results also present insights that could inform new approaches for early detection, prevention, or intervention.

“For both of these patients, it was almost like they had a childhood disease that just took decades and decades to manifest, which was extremely surprising,” said co-corresponding study author Sahand Hormoz, HMS assistant professor of systems biology at Dana-Farber.

“I think our study compels us to ask, when does cancer begin, and when does being healthy stop?” Hormoz said. “It increasingly appears that it’s a continuum with no clear boundary, which then raises another question: When should we be looking for cancer?”

In their study, Hormoz and colleagues focused on myeloproliferative neoplasms (MPNs), a rare type of blood cancer involving the aberrant overproduction of blood cells. The majority of MPNs are linked to a specific mutation in the gene JAK2. When the mutation occurs in bone marrow stem cells, the body’s blood cell production factories, it can erroneously activate JAK2 and trigger overproduction.

To pinpoint the origins of an individual’s cancer, the team collected bone marrow stem cells from two patients with MPN driven by the JAK2 mutation. The researchers isolated a number of stem cells that contained the mutation, as well normal stem cells, from each patient, and then sequenced the entire genome of each individual cell.

Over time and by chance, the genomes of cells randomly acquire so-called somatic mutations — nonheritable, spontaneous changes that are largely harmless. Two cells that recently divided from the same mother cell will have very similar somatic mutation fingerprints. But two distantly related cells that shared a common ancestor many generations ago will have fewer mutations in common because they had the time to accumulate mutations separately.

Cell of origin

Analyzing these fingerprints, Hormoz and colleagues created a phylogenetic tree, which maps the relationships and common ancestors between cells, for the patients’ stem cells — a process similar to studies of the relationships between chimpanzees and humans, for example.

“We can reconstruct the evolutionary history of these cancer cells, going back to that cell of origin, the common ancestor in which the first mutation occurred,” Hormoz said.

Combined with calculations of the rate at which mutations accumulate, the team could estimate when the JAK2 mutation first occurred. In the patient who was first diagnosed with MPN at age 63, the team found that the mutation arose around 44 years prior, at the age of 19. In the patient diagnosed at age 34, it arose at age 9.

By looking at the relationships between cells, the researchers could also estimate the number of cells that carried the mutation over time, allowing them to reconstruct the history of disease progression.

“Initially, there’s one cell that has the mutation. And for the next 10 years there’s only something like 100 cancer cells,” Hormoz said. “But over time, the number grows exponentially and becomes thousands and thousands. We’ve had the notion that cancer takes a very long time to become an overt disease, but no one has shown this so explicitly until now.”

The team found that the JAK2 mutation conferred a certain fitness advantage that helped cancerous cells outcompete normal bone marrow stem cells over long periods of time. The magnitude of this selective advantage is one possible explanation for some individuals’ faster disease progression, such as the patient who was diagnosed with MPN at age 34.

In additional experiments, the team carried out single-cell gene expression analyses in thousands of bone marrow stem cells from seven different MPN patients. These analyses revealed that the JAK2 mutation can push stem cells to preferentially produce certain blood cell types, insights that may help scientists better understand the differences between various MPN types.

Together, the results of the study offer insights that could motivate new diagnostics, such as technologies to identify the presence of rare cancer-causing mutations currently difficult to detect, according to the authors.

“To me, the most exciting thing is thinking about at what point can we detect these cancers,” Hormoz said. “If patients are walking into the clinic 40 years after their mutation first developed, could we have caught it earlier? And could we prevent the development of cancer before a patient ever knows they have it, which would be the ultimate dream?”

The researchers are now further refining their approach to studying the history of cancers, with the aim of helping clinical decision-making in the future.

While their approach is generalizable to other types of cancer, Hormoz notes that MPN is driven by a single mutation in a very slow growing type of stem cell. Other cancers may be driven by multiple mutations, or in faster-growing cell types, and further studies are needed to better understand the differences in evolutionary history between cancers.

The team’s current efforts include developing early detection technologies, reconstructing the histories of greater numbers of cancer cells, and investigating why some patients’ mutations never progress into full-blown cancer, but others do.

“Even if we can detect cancer-causing mutations early, the challenge is to predict which patients are at risk of developing the disease, and which are not,” Hormoz said. “Looking into the past can tell us something about the future, and I think historical analyses such as the ones we conducted can give us new insights into how we could be diagnosing and intervening.”

Study collaborators include scientists and physicians from Brigham and Women’s Hospital, Boston Children’s Hospital, Massachusetts General Hospital, and the European Bioinformatics Institute. The other co-corresponding authors of the study are Ann Mullally and Isidro Cortés-Ciriano.

The study was supported in part by the National Institutes of Health (grants R00GM118910, R01HL158269), the Jayne Koskinas Ted Giovanis Foundation for Health and Policy, the William F. Milton Fund at Harvard University, an AACR-MPM Oncology Charitable Foundation Transformative Cancer Research grant, Gabrielle’s Angel Foundation for Cancer Research, and the Claudia Adams Barr Program in Cancer Research.

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Technology may boost international research efforts to find drugs that eradicate cancer at its source — ScienceDaily

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A new method, described in a study published today in the journal Nature Communications, has the potential to boost international research efforts to find drugs that eradicate cancer at its source.

Most cancerous tissue consists of rapidly dividing cells with a limited capacity for self-renewal, meaning that the bulk of cells stop reproducing after a certain number of divisions. However, cancer stem cells can replicate indefinitely, fuelling long-term cancer growth and driving relapse.

Cancer stem cells that elude conventional treatments like chemotherapy are one of the reasons patients initially enter remission but relapse soon after. In acute myeloid leukaemia, a form of blood cancer, the high probability of relapse means fewer than 15% of elderly patients live longer than five years.

However, cancer stem cells are difficult to isolate and study because of their low abundance and similarity to other stem cells, hampering international research efforts in developing precision treatments that target malignant cells while sparing healthy ones.

Researchers from the Centre for Genomic Regulation (CRG) and the European Molecular Biology Laboratory (EMBL) have overcome this problem by creating MutaSeq, a method that can be used to distinguish cancer stem cells, mature cancer cells and otherwise healthy stem cells based on their genetics and gene expression.

“RNA provides vital information for human health. For example, PCR tests for coronavirus detect its RNA to diagnose COVID-19. Subsequent sequencing can determine the virus variant,” explains Lars Velten, Group Leader at the CRG and author of the paper. “MutaSeq works like a PCR test for coronavirus, but at a much more complex level and with a single cell as starting material.”

To determine if a single cell is a stem cell, the researchers used MutaSeq to measure thousands of RNAs at the same time. To then find out if the cell is cancerous or healthy, the researchers carried out additional sequencing and looked for mutations. The resulting data helped researchers track if stems cells are cancerous or healthy and helped determine what makes the cancer stem cells different.

“There are a huge number of small molecule drugs out there with demonstrated clinical safety, but deciding which cancers and more specifically which patients these drugs are well suited for is a daunting task,” says Lars Steinmetz, Professor at Stanford University, Group Leader at EMBL Heidelberg and author of the paper. “Our method can identify drug targets that might not have been tested in the right context. These tests will need to be carried out in controlled clinical studies, but knowing what to try is an important first step.”

The method is based on single cell sequencing, an increasingly common technique that helps researchers gather and interpret genome-wide information from thousands of individual cells. Single cell sequencing provides a highly detailed molecular profile of complex tissues and cancers, opening new avenues for research.

Explaining their next steps, Lars Velten says: “We have now brought together clinical researchers from Germany and Spain to apply this method in much larger clinical studies. We are also making the method much more streamlined. Our vision is to identify cancer stem cell specific drug targets in a personalized manner, making it ultimately as easy for patients and doctors to look for these treatments as it is testing for coronavirus”.

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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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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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