Carbon Chemist

Tag: Cell

  • New ovarian atlas paves the way for extended fertility and hormone restoration

    New ovarian atlas paves the way for extended fertility and hormone restoration

    [ad_1]

    A new “atlas” of the human ovary provides insights that could lead to treatments restoring ovarian hormone production and the ability to have biologically related children, according to University of Michigan engineers.

    This deeper understanding of the ovary means researchers could potentially create artificial ovaries in the lab using tissues that were stored and frozen before exposure to toxic medical treatments such as chemotherapy and radiation. Currently, surgeons can implant previously frozen ovarian tissue to temporarily restore hormone and egg production. However, this does not work for long because so few follicles-;the structures that produce hormones and carry eggs-;survive through reimplantation, the researchers say.

    The new atlas reveals the factors that enable a follicle to mature, as most follicles wither away without releasing hormones or an egg. Using new tools that can identify what genes are being expressed at a single-cell level within a tissue, the team was able to home in on ovarian follicles that carry the immature precursors of eggs, known as oocytes. 

    “Now that we know which genes are expressed in the oocytes, we can test whether affecting these genes could result in creating a functional follicle. This can be used to create an artificial ovary that could eventually be transplanted back into the body,” said Ariella Shikanov, U-M associate professor of biomedical engineering and corresponding author of the new study in Science Advances. 

    The majority of the follicles, called primordial follicles, remain dormant and are located in the outer layer of the ovary, called the cortex. A small portion of these follicles activate periodically and migrate into the ovary, to a region known as the growing pool. Only a few of those growing follicles go on to produce mature eggs that get released into the fallopian tube.

    With the ability to guide follicle development and tune ovarian environment, the team believes that engineered ovarian tissue could function for much longer than unmodified implanted tissue. This means that patients would have a longer fertility window as well as a longer period in which their bodies produce hormones that help regulate the menstrual cycle and support muscular, skeletal, sexual and cardiovascular health. 

    We’re not talking about utilizing a surrogate mother, or artificial insemination. The magic we’re working toward is being able to trigger an immature cell into maturity, but without knowing which molecules drive that process, we’re blind.”

    Jun Z. Li, associate chair of U-M’s Department of Computational Medicine and Bioinformatics and co-corresponding author of the study

    U-M’s team utilized a relatively new technology, called spatial transcriptomics, to track all of the gene activity-;and where it occurs-;in tissue samples. They do this by reading strands of RNA, which are like notes taken from the DNA strand, revealing which genes are being read. Working with an organ procurement organization, U-M researchers performed RNA sequencing of ovaries from five human donors. 

    “This was the first time where we could target ovarian follicles and oocytes and perform a transcription analysis, which enables us to see which genes are active,” Shikanov said. 

    “The majority of ovarian follicles, already present at birth, never enter the growing pool and eventually self-destruct. This new data allows us to start building our understanding of what makes a good egg-;what determines which follicle is going to grow, ovulate, be fertilized and become a baby.”

    U-M’s work is part of the Human Cell Atlas project, which seeks to create “maps of all the different cells, their molecular characteristics and where they are located, to understand how the human body works and what goes wrong in disease.”

    Shikanov, Li and U-M collaborators such as Sue Hammoud, U-M associate professor of human genetics and urology, are mapping other parts of the female reproductive system, including the uterus, fallopian tubes and ovaries. Other contributors include Andrea Suzanne Kuliahsa Jones, formerly of U-M and now at Duke University, and D. Ford Hannum, a U-M graduate student research assistant in bioinformatics.

    The research was partially funded by the Chan Zuckerberg Initiative. Additional financial support was provided by the National Institutes of Health. 

    Source:

    Journal reference:

    Jones, A. S. K., et al. (2024) Cellular atlas of the human ovary using morphologically guided spatial transcriptomics and single-cell sequencing. Science Advances. doi.org/10.1126/sciadv.adm7506.

    [ad_2]

    Source link

  • Mitochondrial fusion critical for adult neurogenesis and brain circuit refinement

    Mitochondrial fusion critical for adult neurogenesis and brain circuit refinement

    [ad_1]

    Nerve cells (neurons) are amongst the most complex cell types in our body. They achieve this complexity during development by extending ramified branches called dendrites and axons and establishing thousands of synapses to form intricate networks. The production of most neurons is confined to embryonic development, yet few brain regions are exceptionally endowed with neurogenesis throughout adulthood. It is unclear how neurons born in these regions successfully mature and remain competitive to exert their functions within a fully formed organ. However, understanding these processes holds great potential for brain repair approaches during disease.

    A team of researchers led by Professor Dr. Matteo Bergami at the University of Cologne’s CECAD Cluster of Excellence in Aging Research addressed this question in mouse models, using a combination of imaging, viral tracing and electrophysiological techniques. They found that, as new neurons mature, their mitochondria (the cells’ power houses) along dendrites undergo a boost in fusion dynamics to acquire more elongated shapes. This process is key in sustaining the plasticity of new synapses and refining pre-existing brain circuits in response to complex experiences. The study ‘Enhanced mitochondrial fusion during a critical period of synaptic plasticity in adult-born neurons’ has been published in the journal Neuron.

    Mitochondrial fusion grants new neurons a competitive advantage

    Adult neurogenesis takes place in the hippocampus, a brain region controlling aspects of cognition and emotional behavior. Consistently, altered rates of hippocampal neurogenesis have been shown to correlate with neurodegenerative and depressive disorders. While it is known that the newly produced neurons in this region mature over prolonged periods of time to ensure high levels of tissue plasticity, our understanding of the underlying mechanisms is limited. The findings of Bergami and his team suggest that the pace of mitochondrial fusion in the dendrites of new neurons controls their plasticity at synapses rather than neuronal maturation per se.

    We were surprised to see that new neurons actually develop almost perfectly in the absence of mitochondrial fusion, but that their survival suddenly dropped without obvious signs of degeneration. This argues for a role of fusion in regulating neuronal competition at synapses, which is part of a selection process new neurons undergo while integrating into the network.”


    Professor Dr. Matteo Bergami, University of Cologne’s CECAD Cluster of Excellence in Aging Research

    The findings extend the knowledge that dysfunctional mitochondrial dynamics (such as fusion) cause neurological disorders in humans and suggest that fusion may play a much more complex role than previously thought in controlling synaptic function and its malfunction in diseases such as Alzheimer’s and Parkinson’s.

    Besides revealing a fundamental aspect of neuronal plasticity in physiological conditions, the scientists hope that these results will guide them towards specific interventions to restore neuronal plasticity and cognitive functions in conditions of disease.

    Source:

    Journal reference:

    Kochan, S. M. V., et al. (2024) Enhanced mitochondrial fusion during a critical period of synaptic plasticity in adult-born neurons. Neuron. doi.org/10.1016/j.neuron.2024.03.013.

    [ad_2]

    Source link

  • Modeled human embryo produces a membrane that surrounds the developing embryo

    Modeled human embryo produces a membrane that surrounds the developing embryo

    [ad_1]

    A MedUni Vienna study team led by geneticist Markus Hengstschläger has used a stem cell model to model the earliest stages of embryonic development and to characterize the membrane that surrounds the embryo, conferring shape and stability. This membrane is responsible for the specification and organization of the embryo’s cells and allows it to grow in a controlled manner. The findings form the basis for further research with the aim to better understand the causes of abnormal embryonic development. The results were recently published in the top journal Developmental Cell.

    Approximately every second human embryo is affected by an abnormal development which, for example, causes the embryo not being able to implant into the uterus or results in a miscarriage. In addition to maternal factors or genetic abnormalities of the embryo (the latter can be investigated using pre-implantation genetic diagnosis in the course of in-vitro-fertilization (IVF)), it can also be assumed that aberrations of the cellular order and morphology of the embryo could play a role. The causes of such aberrations have not yet been clarified, particularly because research on human embryos is prohibited by law in many countries around the world, including Austria, for ethical reasons.

    Markus Hengstschläger, Head of the Institute of Medical Genetics at MedUni Vienna, leads one of a few laboratories worldwide that are capable of generating models of the human embryo from pluripotent stem cells in a Petri dish, so-called embryoids. Using such embryoids, which have only recently become available and cannot develop into a human being, the researchers are now able to model and to explore the earliest developmental phases of human life.

    In a study published in Developmental Cell, the world’s leading journal for developmental biology, the two authors Margit Rosner and Markus Hengstschläger have now succeeded in showing for the first time that the modeled human embryo itself produces a membrane (basement membrane) that surrounds the developing embryo, without which it cannot survive and which is responsible for the way it looks. This membrane gives the embryo shape and stability, is responsible for the specification and organization of the embryo’s cells and allows it to grow in a controlled manner.

    Gene responsible for the development of the basement membrane identified

    In addition, the authors have identified Oct4 from thousands of human genes as one gene that is significantly involved in the formation and development of this basement membrane. With this, they have thus been able to assign a previously undescribed function to this transcription factor.

    This study sheds light on molecular mechanisms that are of great importance for the development of human life and forms the basis for further research with the aim to better understand the causes of those aberrations that cause the human embryo not being able to initiate a pregnancy or lead to a miscarriage, in addition, many human diseases have their origin in early embryonic development. However, we still know very little about this relation because until now early human development has been completely inaccessible to research.”


    Markus Hengstschläger, Head of the Institute of Medical Genetics at MedUni Vienna

    Source:

    Medical University of Vienna

    [ad_2]

    Source link

  • Neuroscientists identify age-defying RNAs in the brain

    Neuroscientists identify age-defying RNAs in the brain

    [ad_1]

    Certain RNA molecules in the nerve cells in the brain last a life time without being renewed. Neuroscientists from Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU) have now demonstrated that this is the case together with researchers from Germany, Austria and the USA. RNAs are generally short-lived molecules that are constantly reconstructed to adjust to environmental conditions. With their findings that have now been published in the journal Science, the research group hopes to decipher the complex aging process of the brain and gain a better understanding of related degenerative diseases.

    Most cells in the human body are regularly renewed, thereby retaining their vitality. However, there are exceptions: the heart, the pancreas and the brain consist of cells that do not renew throughout the whole lifespan, and yet still have to remain in full working order.

    Aging neurons are an important risk factor for neurodegenerative illnesses such as Alzheimer’s. A basic understanding of the aging process and which key components are involved in maintaining cell function is crucial for effective treatment concepts:”


    Prof. Dr. Tomohisa Toda, Professor of Neural Epigenomics at FAU and at the Max Planck Center for Physics and Medicine in Erlangen

    In a joint study conducted together with neuroscientists from Dresden, La Jolla (USA) and Klosterneuburg (Austria), the working group led by Toda has now identified a key component of brain aging: the researchers were able to demonstrate for the first time that certain types of ribonucleic acid (RNA) that protect genetic material exist just as long as the neurons themselves. “This is surprising, as unlike DNA, which as a rule never changes, most RNA molecules are extremely short-lived and are constantly being exchanged,” Toda explains.

    In order to determine the life span of the RNA molecules, the Toda group worked together with the team from Prof. Dr. Martin Hetzer, a cell biologist at the Institute of Science and Technology Austria (ISTA). “We succeeded in marking the RNAs with fluorescent molecules and tracking their lifespan in mice brain cells,” explains Tomohisa Toda, who has unique expertise in epigenetics and neurobiology and who was awarded an ERC Consolidator Grant for his research in 2023. “We were even able to identify the marked long-lived RNAs in two year old animals, and not just in their neurons, but also in somatic adult neural stem cells in the brain.”

    In addition, the researchers discovered that the long-lived RNAs, that they referred to as LL-RNA for short, tend to be located in the cells’ nuclei, closely connected to chromatin, a complex of DNA and proteins that forms chromosomes. This indicates that LL-RNA play a key role in regulating chromatin. In order to confirm this hypothesis, the team reduced the concentration of LL-RNA in an in-vitro experiment with adult neural stem cell models, with the result that the integrity of the chromatin was strongly impaired. 

    “We are convinced that LL-RNAs play an important role in the long-term regulation of genome stability and therefore in the life-long conservation of nerve cells,” explains Tomohisa Toda. “Future research projects should give a deeper insight into the biophysical mechanisms behind the long-term conservation of LL-RNAs. We want to find out more about their biological function in chromatin regulation and what effect aging has on all these mechanisms.”

    Source:

    Friedrich-Alexander-Universität Erlangen-Nürnberg

    Journal reference:

    Zocher, S., et al. (2024) Lifelong persistence of nuclear RNAs in the mouse brain. Science. doi.org/10.1126/science.adf3481.

    [ad_2]

    Source link

  • Human neuron model identifies potential therapeutic targets for Alzheimer’s disease

    Human neuron model identifies potential therapeutic targets for Alzheimer’s disease

    [ad_1]

    Weill Cornell Medicine scientists have developed an innovative human neuron model that robustly simulates the spread of tau protein aggregates in the brain-;a process that drives cognitive decline in Alzheimer’s disease and frontotemporal dementia. This new model has led to the identification of novel therapeutic targets that could potentially block tau spread.

    The preclinical study, published April 5 in Cell, is a significant advancement in Alzheimer’s disease research.

    Currently no therapies can stop the spread of tau aggregates in the brains of patients with Alzheimer’s disease. Our human neuron model of tau spread overcomes the limitations of previous models and has unveiled potential targets for drug development that were previously unknown.”


    Dr. Li Gan, lead study author, director of the Helen and Robert Appel Alzheimer’s Disease Research Institute and the Burton P. and Judith B. Resnick Distinguished Professor in Neurodegenerative Diseases in the Feil Family Brain and Mind Research Institute at Weill Cornell Medicine

    Human pluripotent stem cells can develop into any cell of the body and can be coaxed to become neurons to model brain diseases in a lab dish. However, it had been nearly impossible to model tau propagation in these young neurons, as tau propagation requires decades in aging brains.

    Dr. Gan’s team used CRISPR technology to modify the genomes of human stem cells, prompting them to express forms of tau associated with diseased aging brains. “This model has been a game-changer, simulating tau spread in neurons within weeks-;a process that would typically take decades in the human brain,” Dr. Gan said.

    In their quest to halt tau propagation, Dr. Gan’s team employed CRISPRi screening to disable one thousand genes to ascertain their roles in tau spread. They discovered 500 genes that have a significant impact on tau abundance.

    “CRISPRi technology allowed us to use unbiased approaches to look for drug targets, not confined to what was previously reported by other scientists,” said one of the lead study authors Celeste Parra Bravo, a neuroscience doctoral candidate in the Weill Cornell Graduate School of Medical Sciences working in the Gan lab.

    One discovery includes the UFMylation cascade, a cellular process involving the attachment of a small protein named UFM1 to other proteins. This process’s connection to tau spread was previously unknown. Post-mortem studies of brains from patients with Alzheimer’s disease found that UFMylation is altered, and the team also found in preclinical models that inhibition of the enzyme required for UFMylation blocks tau propagation in neurons.

    “We are particularly encouraged by the confirmation that inhibiting UFMylation blocked tau spread in both human neurons and mouse models,” said paper co-author Dr. Shiaoching Gong, associate professor of research in neuroscience in the Appel Institute at Weill Cornell Medicine.

    Many Alzheimer’s disease treatments initially show promise in mouse models but do not succeed in clinical trials, Dr. Gan said. With the new human cell model, she is optimistic about the path ahead. “Our discoveries in human neurons open the door to developing new treatments that could truly make a difference for those suffering from this devastating disease.”

    Source:

    Journal reference:

    Bravo, C. P., et al. (2024) Human iPSC 4R tauopathy model uncovers modifiers of tau propagation. Cell. doi.org/10.1016/j.cell.2024.03.015.

    [ad_2]

    Source link

  • Protein intake during pregnancy affects offspring’s facial features

    Protein intake during pregnancy affects offspring’s facial features

    [ad_1]

    The protein content of the diet during pregnancy can affect the face of the offspring. This is shown in animal studies, and the underlying mechanism was also found in human genetic studies. The research is described in a study led by the University of Gothenburg.

    A child is expected to share facial features with their parents. However, the face is also influenced by factors beyond genetics, so-called environmental factors. Among those, lifestyle during pregnancy is an essential factor. For example, extensive alcohol consumption during pregnancy can lead to facial abnormalities in the child.

    The current study, published in Nature Communications, revealed a novel link between the child’s face and pregnancy lifestyle, specifically protein intake during pregnancy.

    A research team led by Andrei Chagin, Professor of Molecular Medicine, delved into the mechanisms that control the formation of the facial bone structure during the embryonic phase. The studies revealed that a particular signaling pathway in the cells seemed to play a crucial role in shaping the face.

    Noticeable differences in the face

    The signaling pathway, known as mTOR, controls several cell functions, including cell division and cell survival, and is known to be the target of an immunosuppressive medicinal product, rapamycin, which is administered during organ transplantation to avoid rejection.

    The mTOR signaling pathway acts as an intracellular nutritional sensor specifically tailored to amino acids, the building blocks of proteins. The researchers found that the mTOR pathway modulates the formation of facial skeletal structures in humans, mice, and zebrafish. This led researchers to investigate whether the protein content of the pregnancy diet affects mTOR and plays a role in the formation of the facial bone structure.

    Pregnant mice were given diets with high and low protein levels. As expected, the protein levels in the female’s diet were consistent with the activity level of mTOR in the developing face. In newborn offspring, the differences in the face were noticeable, albeit subtle.

    It is difficult to describe the exact effects, which can be caused by protein content in the diet during human pregnancy. But our data suggest that the mechanism is evolutionarily conserved and, from this perspective, likely serves to increase variability in the feeding apparatus, thus, allowing animals to adapt to various feeding sources in the wild. In mice, we see, for example, an enlarged nasal cavity in the offspring of mice fed a protein-enriched diet and a slightly elongated jaw in mice where the mother has eaten a low-protein diet.”

    Andrei Chagin, Professor of Molecular Medicine

    Good nutrition and clinical practices

    This international study was led by researchers at Sahlgrenska Academy at the University of Gothenburg in collaboration with colleagues at Karolinska Institutet, Belgium, Japan, China, Russia, the Czech Republic, and Austria.

    The aim has been to contribute to the future development of more effective clinical methods for the prevention and treatment of different types of facial congenital malformations and to increase knowledge of what a good pregnancy diet should contain.

    “The findings emphasize the importance of maintaining a well-balanced diet during pregnancy, with particular attention to protein intake. The insights open new avenues for understanding the intricate interplay between genetics, lifestyle, and the formation of our unique facial features,” concludes Andrei Chagin.

    Source:

    Journal reference:

    Xie, M., et al. (2024). The level of protein in the maternal murine diet modulates the facial appearance of the offspring via mTORC1 signaling. Nature Communications. doi.org/10.1038/s41467-024-46030-3.

    [ad_2]

    Source link

  • Therapeutic potential of CD20 x CD3 bispecific antibodies

    Therapeutic potential of CD20 x CD3 bispecific antibodies

    [ad_1]

    On Monday, March 25th, 2024, the U.S. FDA declined approval for Regeneron’s Odronextamab for two forms of lymphoma due to concerns over the progress of ongoing confirmatory trials. Cancer immunotherapy with CD3 bispecific antibodies (BsAbs) is a fast-developing field. As of March 2024, the FDA has approved three CD20 × CD3 BsAbs: mosunetuzumab (Lunsumio) for relapsed or refractory follicular lymphoma (R/R FL), glofitamab (Columvi) for relapsed or refractory diffuse B cell lymphoma (R/R DLBCL) or large B cell lymphoma (LBCL) with two or more prior therapies, and Epcoritamab (DuoBody®) for adult patients with relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) after two or more systemic therapies. Progress in CD20 × CD3 bispecific antibody therapy underscores the need for ongoing research and advancement.

    Bispecific antibody. Image Credit: Sino Biological

    Bispecific antibodies mechanism of action

    CD20 × CD3 bispecific antibodies bind to both CD20 on malignant B cells and CD3 on T cells, bringing them into close proximity, which triggers T cell-mediated killing of the targeted B cells.

    • CD20 × CD3: Bridging T cells to CD20+ B-cell lymphomas

    CD20 × CD3 bispecific antibodies (bsAbs) have shown effectiveness in treating various lymphomas including non-Hodgkin lymphoma (NHL), by activating T cells to attack CD20-positive B-cell lymphomas. CD20, highly expressed in B-cell lymphomas but absent in normal tissues, makes anti-CD20 drugs the main treatment for these conditions. These drugs work through various mechanisms like antibody-dependent cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and direct CD20 binding. The CD3/TCR complex facilitates the infiltration of cytotoxic T lymphocytes into cancerous cells, leading to cell death. Bispecific antibodies, targeting CD3, activate T cells to eliminate lymphoma cells by recognizing CD20. CD20 × CD3 bsAbs, engineered extensively, offer advantages like high specificity, moderate affinity, and minimal side effects. Their unique binding site allows them to effectively target CD20-positive cells, including those resistant to rituximab. 

    Sino Biological’s offering to support CD20 × CD3 bispecific antibody research

    Sino Biological partners with customers to accelerate drug discovery and development. As an international reagent supplier and service provider, Sino Biological is proud to provide a comprehensive suite of recombinant bispecific antibody production services and best-in class drug target reagents, with the ultimate goal of facilitating bispecific antibody development and screening.

    [ad_2]

    Source link

  • Asthma attacks cause airway damage beyond inflammation, research shows

    Asthma attacks cause airway damage beyond inflammation, research shows

    [ad_1]

    In asthma, the tightening of muscles around the bronchi causes damage to the airway by squeezing and destroying epithelial cells, which promotes the airway inflammation and mucus production often associated with an asthma attack, researchers report. The findings suggest that preventing the mechanical damage caused by an asthma attack, rather than treating only its downstream symptoms, could pave the way for therapies that stop the whole asthma inflammatory cycle.

    Asthma is a common airway disorder affecting more than 300 million people worldwide. Although it is primarily considered an inflammatory disease, a diagnostic feature of asthma is mechanical bronchoconstriction – the constriction of the smooth muscle that surrounds the airway – which can result in severe breathing difficulty and increased airway mucus production. Airway immune activation and inflammation are thought to drive bronchoconstriction during asthma exacerbations (acute episodes of worsening asthma symptoms). As such, the gold standard therapy for asthma exacerbations is albuterol, a short-acting bronchodilator, and inhaled corticosteroids, which treat the underlying inflammation.

    However, these treatments are not always effective, and a mechanistic understanding of asthma exacerbations remains incomplete. Building on previous research, Dustin Bagley and colleagues investigated the underlying root causes of asthma pathobiology. Using mouse models of asthma and human lung tissue samples, Bagley et al. discovered that bronchoconstriction causes a pathological overcrowding of cells in the airway epithelium, triggering a process called cell extrusion that leads to airway tissue damage. This mechanism resulted in inflammation and mucus secretion in both mice and humans. This damage results in a breakdown of epithelial barrier function and could provide a pathway for further bronchoconstrictive attacks and inflammation. Although the authors show that albuterol treatment does not prevent airway epithelia damage or its resultant inflammation after an asthma attack, they found that inhibitors that stopped the cell extrusion pathway counteracted mechanical damage to the airway and substantially reduced the inflammatory response.

    “These findings not only establish that bronchoconstriction is a pro-inflammatory stimulus but also point toward the potential for new research avenues that seek to inhibit a ‘mechano-inflammatory’ vicious cycle,” write Jeffery Drazen and Jeffery Fredberg in a related Perspective.

    Source:

    American Association for the Advancement of Science (AAAS)

    Journal reference:

    Bagley, D. C., et al. (2024) Bronchoconstriction damages airway epithelia by crowding-induced excess cell extrusion. Science. doi.org/10.1126/science.adk2758.

    [ad_2]

    Source link

  • Unlocking the secrets of long-lived RNAs in brain cells

    Unlocking the secrets of long-lived RNAs in brain cells

    [ad_1]

    After two decades in the United States, Martin Hetzer returned home to Austria in 2023 to become the 2nd President of the Institute of Science and Technology Austria (ISTA). A year into his new role, the molecular biologist remains engaged in the realm of aging research.

    Hetzer is fascinated by the biological puzzles surrounding the aging processes in organs like the brain, heart, and pancreas. Most cells comprising these organs are not renewed throughout a human’s entire life span. Nerve cells (neurons) in the human brain, for instance, can be as old as the organism, even up to more than a century, and must function for a lifetime. This remarkable age of neurons might be a major risk factor for neurodegenerative disorders such as Alzheimer’s disease. Crucial to comprehending these kinds of ailments is a deeper understanding of how nerve cells function over time and maintain control. This potentially opens doors to therapeutically counteract the aging processes of these specific cells.

    The latest collaborative publication by Hetzer, Tomohisa Toda from the Friedrich-Alexander University Erlangen-Nürnberg (FAU), who is also associated with the Max Planck Center for Physics and Medicine, Erlangen, and colleagues, gives new insights into this underexplored field of intricate mechanisms. For the first time in mammals, the study shows that RNA-;an essential group of molecules important for various biological processes inside the cell-;can persist throughout life. The scientists identified specific RNAs with genome-protecting functions in the nuclei of nerve cells of mice that remain stable for two years, covering their entire lives. The findings, published in the journal Science, underpin the importance of long-lived key molecules for maintaining a cell’s function.

    Longevity of key molecules

    The inside of cells is a very dynamic place. Some components are constantly renewed and updated; others stay the same their whole lives. It is like a city in which the old buildings blend in with the new ones. DNA found in the nucleus-;the city’s heart-;for instance, is as old as the organism. “DNA in our nerve cells is identical to DNA within the developing nerve cells in our mother’s womb,” explains Hetzer.

    Unlike stable DNA, which is constantly being repaired, RNA, especially messenger RNA (mRNA), which forms proteins upon DNA’s information, is characterized by its transient nature. The cellular scope, however, extends beyond mRNA to a group of so-called non-coding RNAs. They do not turn into proteins; instead, they have specific duties to contribute to the overall organization and function of the cell. Intriguingly, their lifespan remained a mystery. Until now.

    RNAs that last the whole life

    Hetzer and Co. set out to decipher that secret. Therefore, RNAs were labeled, i.e. “marked”, in the brains of newborn mice. “For this labeling, we used RNA analogs-;structurally similar molecules-;with little chemical hooks that click fluorescent molecules on the actual RNAs,” explains Hetzer. This assured efficient tracking of the molecules and powerful microscopic snapshots at any given time point in the mice’s lives.

    Surprisingly, our initial images revealed the presence of long-lived RNAs, in various cell types within the brain. We had to further dissect the data to identify the ones in the nerve cells. Fruitful collaboration with Toda’s lab enabled us to make sense of that chaos during brain mapping.”


    Martin Hetzer, Institute of Science and Technology Austria

    Collaboratively, the researchers were able to focus solely on long-lived RNAs in neurons. They quantified the molecules’ concentration throughout a mouse’s life, examined their composition and analyzed their positions.

    While humans have an average life expectancy of around 70 years, the typical lifespan of a mouse is 2.5 years. After one year, the concentration of long-lived RNAs was slightly reduced compared to newborns. However, even after two years, they remained detectable indicating a lifelong persistence of these molecules.

    RNAs help protect the genome

    Additionally, the scientists proved long-lived RNAs’ prominent role in cellular longevity. They found out that long-lived RNAs in neurons consist of mRNAs and non-coding RNAs and accumulate near the heterochromatin-;the densely packed region of the genome, typically homing inactive genes. Next they further investigated the function of these long-lived RNAs.

    In molecular biology, the most effective approach to achieve this is by reducing the molecule of interest and observing its subsequent effects. “As their name and our previous experiments suggest, these long-lived RNAs are extremely stable,” says Hetzer. The scientists, therefore, employed an in vitro (outside a living organism) approach, using neuronal progenitor cells-;stem cells with the capacity to give rise to neural cells, including neurons. The model system allowed them to effectively intervene with these long-lived RNAs. A lower amount of long-lived RNAs caused problems in the heterochromatin architecture and stability of genetic material, eventually affecting the cells’ viability. Thus, the important role of long-lived RNAs’ in cellular longevity was clarified.

    The study highlights that long-lived RNAs may function in the lasting regulation of genome stability. “Lifelong cellular maintenance during aging involves an extended life span of key molecules like the long-lived RNAs, we just identified,” Hetzer adds. The precise mechanism, however, remains unclear. “Together with unidentified proteins, long-lived RNAs likely form a stable structure that somehow interacts with the heterochromatin.” Upcoming research projects in Hetzer’s lab are set on finding these missing links and understanding the biological characteristics of these long-lived RNAs.

    Source:

    Institute of Science and Technology Austria

    Journal reference:

    Zocher, S., et al. (2024) Lifelong persistence of nuclear RNAs in the mouse brain. Science. doi.org/10.1126/science.adf3481.

    [ad_2]

    Source link

  • Gene therapy and glycoside drugs offer new hope for polycystic kidney disease treatment

    Gene therapy and glycoside drugs offer new hope for polycystic kidney disease treatment

    [ad_1]

    Researchers have shown that dangerous cysts, which form over time in polycystic kidney disease (PKD), can be prevented by a single normal copy of a defective gene. This means the potential exists that scientists could one day tailor a gene therapy to treat the disease. They also discovered that a type of drug, known as a glycoside, can sidestep the effects of the defective gene in PKD. The discoveries could set the stage for new therapeutic approaches to treating PKD, which affects millions worldwide. The study, partially funded by the National Institutes of Health (NIH), is published in Cell Stem Cell.

    Scientists used gene editing and 3-D human cell models known as organoids to study the genetics of PKD, which is a life-threatening, inherited kidney disorder in which a gene defect causes microscopic tubes in the kidneys to expand like water balloons, forming cysts over decades. The cysts can crowd out healthy tissue, leading to kidney function problems and kidney failure. Most people with PKD are born with one healthy gene copy and one defective gene copy in their cells.

    Human PKD has been so difficult to study because cysts take years and decades to form. This new platform finally gives us a model to study the genetics of the disease and hopefully start to provide answers to the millions affected by this disease.”


    Benjamin Freedman, Ph.D., senior study author at the University of Washington, Seattle

    To better understand the genetic reasons cysts form in PKD, Freedman and his colleagues sought to determine if 3-D human mini-kidney organoids with one normal gene copy and one defective copy would form cysts. They grew organoids, which can mimic features of an organ’s structure and function, from induced pluripotent stem cells, which can become any kind of cell in the body.

    To generate organoids containing clinically relevant mutations, the researchers used a gene editing technique called base editing to create mutations in certain locations on the PKD1 and PKD2 genes in human stem cells. They focused on four types of mutations in these genes that are known to cause PKD by disrupting the production of polycystin protein. Disruptions in two types of the protein – polycystin-1 and polycystin-2 – are associated with the most severe forms of PKD.

    They then compared cells with two gene copy mutations in organoids to cells with only one gene copy mutation. In some cases, they also used gene editing to correct mutations in one of the two gene copies to see how this affected cyst formation. They found organoids with two defective gene copies always produced cysts and those that carried one good gene copy and one bad copy did not form cysts. 

    “We didn’t know if having a gene mutation in only one gene copy is enough to cause PKD, or if a second factor, such as another mutation or acute kidney injury was necessary,” Freedman said. “It’s unclear what such a trigger would look like, and until now, we haven’t had a good experimental model for human PKD.”

    According to Freedman, the cells with one healthy gene copy make only half the normal amount of polycystin-1 or polycystin-2, but that was sufficient to prevent cysts from developing. He added that the results suggest the need for a second trigger and that preventing that second hit might be able to prevent the disease.

    The organoid models also provided the first opportunity to study the effectiveness of a class of drugs known as eukaryotic ribosomal selective glycoside on PKD cyst formation.

    “These compounds will only work on single base pair mutations, which are commonly seen in PKD patients,” explained Freedman. “They wouldn’t be expected to work on any mouse models and didn’t work in our previous organoid models of PKD. We needed to create that type of mutation in an experimental model to test the drugs.”

    Freedman’s team found that the drugs could restore the ability of genes to make polycystin, increasing the levels of polycystin-1 to 50% and preventing cysts from forming. Even after cysts had formed, adding the drugs slowed their growth.

    Freedman suggested that a next step would be to test existing glycoside drugs in patients. Researchers also could explore the use of gene therapy as a treatment for PKD.

    The research was supported by NIH’s Nation Center for Advancing Translational Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, and National Institute of General Medical Sciences through awards R01DK117914, UH3TR002158, UH3TR003288, U01DK127553, U01AI176460, U2CTR004867, UC2DK126006, P30DK089507, R21DK128638, and R35GM142902; an Eloxx Pharmaceuticals Award; the Lara Nowak-Macklin Research Fund; and a Washington Research Foundation fellowship.

    Source:

    NIH/National Center for Advancing Translational Sciences (NCATS)

    Journal reference:

    Vishy, C. E., et al. (2024) Genetics of cystogenesis in base-edited human organoids reveal therapeutic strategies for polycystic kidney disease. Cell Stem Cell. doi.org/10.1016/j.stem.2024.03.005.

    [ad_2]

    Source link