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Tag: Stem Cells

  • Magnesium’s pivotal role in slowing aging’s impact

    Magnesium’s pivotal role in slowing aging’s impact

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    Aging is associated with many biological, physiological, and psychological changes, some of which include a decline in cognitive function, greying of hair, frailty, and increased risk of contracting certain diseases. Aging also increases the risk of chronic diseases such as diabetes, hypertension, and cardiovascular events.

    Most older adults experience chronic magnesium deficiency or hypomagnesemia, which may be due to low dietary magnesium content, reduced intestinal absorption, and increased urination. In a recent review published in the journal Nutrients, researchers discuss the role of magnesium in aging.

    Study: Magnesium and the Hallmarks of Aging. Image Credit: monticello / Shutterstock.comStudy: Magnesium and the Hallmarks of Aging. Image Credit: monticello / Shutterstock.com

    The role of magnesium in telomere attrition

    Telomeres are present at both ends of chromosomes, thereby protecting them from degradation and fusion with other chromosomes to preserve genetic information. Between 50-100 base pairs of telomeric DNA are lost after each cell division; therefore, telomeres shorten as age advances.

    When a telomere attains a critical short length, cells recognize it, and replication is attenuated, which results in cell senescence. Previous studies have indicated that magnesium maintains telomeric chromatin structure and integrity, as well as supports telomerase regulation.

    Genomic instability

    Genomic instability, which involves DNA damage, chromosomal abnormalities, and mutations, is a key driver of aging. Genomic instability occurs due to oxidative stress, epigenetic alterations, inadequate DNA repair, and telomere maintenance.

    Throughout the cell cycle, magnesium is essential for stabilizing chromatin assembly. Furthermore, DNA grooves have specific binding sites for magnesium, thereby demonstrating its role in DNA conformation.

    Insufficient magnesium levels cause DNA instability through oxidation stress, as various enzymes involved in DNA repair are activated by magnesium. Thus, magnesium plays a crucial role in the DNA replication process and preservation of genome stability.

    Epigenetic alterations

    Epigenetic alterations refer to the modification of genomic expression without alterations in DNA sequence. The epigenome can be altered through lifestyle factors, diets, and pharmaceutics. Additionally, the age-related inflammatory environment and inhibitory molecules released from stressed cells may lead to epigenetic alterations, which can modify cellular function.

    Several studies have highlighted the association of magnesium with epigenetics. For example, hypomagnesemia causes down-regulation of hepatic 11β-hydroxysteroid dehydrogenase-2 (Hsd11b2) promoters, which affect the metabolism of neonatal offspring.

    Loss of proteostasis

    Proteostasis alterations are associated with weak protein stability and misfolded proteins. Several age-related chronic diseases, such as Alzheimer’s and Parkinson’s disease, have been attributed to the dysregulation of proteostasis. Importantly, low magnesium levels in the brain may lead to many neurological disorders, including epilepsy, Alzheimer’s disease, Parkinson’s disease, and migraines. 

    Magnesium downregulates tumor-necrosis factor α (TNF-α) and interleukin 1β (IL-1β) production, in addition to supporting the clearance of amyloid β (Aβ) precursor molecules by proteasomal degradation pathways. Magnesium also inhibits the N-methyl-D-aspartate (NMDA) receptor and increases excitatory neurotransmission.

    Mitochondrial dysfunction

    The mitochondria is involved in multiple cell signaling processes that determine cell fate, including cellular survival and death by apoptosis. Dysfunctional mitochondria can lead to the persistent reduction in cellular adenosine triphosphate (ATP) levels for prolonged periods, which may lead to chronic inflammation, cellular damage, and oxidative stress. These conditions are also linked with age-associated diseases, such as Alzheimer’s disease and Parkinson’s disease. 

    Magnesium binds with ATP to form the Mg-ATP complex. The presence of intracellular free magnesium has been associated with the development of hypertension and diabetes, both of which are conditions that are more prevalent in older adults. Low magnesium levels are also associated with oxidative stress damage through reduced lipid peroxidation and antioxidant enzyme activity.

    Cellular senescence

    Cellular senescence is associated with cellular stress and irreversible DNA damage. Additional features of aging include senescence-associated mitochondrial dysfunction, altered nutrient and stress signaling, and autophagy/mitophagy dysfunction.

    Certain cellular alterations that occur during senescence are similar to those caused by hypomagnesemia, including reduced protection against oxidative stress damage, cellular viability, cell cycle progression, and enhanced risk of transcription factor expression.

    Stem cell exhaustion

    Human tissues are maintained by stem cells due to their self-renewing capacity. More specifically, stem cells can differentiate into progenitor cells, from which various tissues are developed.

    Previous studies have shown that a reduction in the hemopoietic cells’ regenerative potential due to aging is associated with the reduced production of adaptive immune cells, which is otherwise known as immunosenescence.

    Magnesium is strongly linked with immune responses. For example, magnesium is a cofactor for the production of immunoglobulins (Ig), antibody-dependent cytolysis, macrophage response to lymphokines, and immune cell adherence.

    Conclusions

    Since the aging trajectory is variable, it can be modulated through magnesium intake and lifestyle changes. The current review discusses the importance of suitable magnesium levels throughout life, which may contribute to healthy aging.

    Journal reference:

    • Dominguez, L. J., Veronese, N., & Barbagallo, M. (2024). Magnesium and the Hallmarks of Aging. Nutrients 16(4); 496. doi:10.3390/nu16040496

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  • CRISPR-Cas9 gene-editing tool repairs defective T cells to treat rare hereditary disease

    CRISPR-Cas9 gene-editing tool repairs defective T cells to treat rare hereditary disease

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    Some hereditary genetic defects cause an exaggerated immune response that can be fatal. Using the CRISPR-Cas9 gene-editing tool, such defects can be corrected, thus normalizing the immune response, as researchers led by Klaus Rajewsky from the Max Delbrück Center now report in “Science Immunology.”

    Familial hemophagocytic lymphohistiocytosis (FHL) is a rare disease of the immune system that usually occurs in infants and young children under the age of 18 months. The condition is severe and has a high mortality rate. It is caused by various gene mutations that prevent cytotoxic T cells from functioning normally. These are a group of immune cells that kill virus-infected cells or otherwise altered cells. If a child with FHL contracts a virus – such as the Epstein-Barr virus (EBV), but also other viruses – the cytotoxic T cells cannot eliminate the infected cells. Instead, the immune response gets out of control. This leads to a cytokine storm and an excessive inflammatory reaction that affects the entire organism.

    “Doctors treat FHL with a combination of chemotherapy, immunosuppression and bone marrow transplantation, but many children still die of the disease,” says Professor Klaus Rajewsky, who heads the Immune Regulation and Cancer Lab at the Max Delbrück Center. He and his team have therefore developed a new therapeutic strategy. Using the CRISPR-Cas9 gene-editing tool, the researchers succeeded in repairing defective T cells from mice and from two critically ill infants. The repaired cytotoxic T cells then functioned normally, with the mice recovering from hemophagocytic lymphohistiocytosis. Rajewsky and his team have now published their findings in the journal “Science Immunology.”

    Gene repair strategy works in mice

    The starting point for the study were mice in which the team could mimic EBV infections. In these animals, the researchers altered a gene called perforin so that its function was completely lost or severely compromised – a common genetic defect in patients with FHL. When they then elicited a condition resembling an EBV infection, the affected B cells multiplied uncontrollably because the defective cytotoxic T cells were unable to eliminate them. As a result, the immune response went into overdrive and the mice developed hemophagocytic lymphohistiocytosis.

    The team next collected T memory stem cells – that is, long-lived T cells from which active cytotoxic T cells can mature – from the blood of the mice. The researchers used the CRISPR-Cas9 gene-editing tool to repair the defective perforin gene in the memory T cells and then injected the corrected cells back into the mice. The immune response in the animals quieted down and their symptoms disappeared.

    How long protection lasts is uncertain

    The first author of the paper, Dr Xun Li, used blood samples from two sick infants to test whether the strategy also works in humans. One had a defective perforin gene, the other a different defective gene.

    Our gene repair technique is more precise than previous methods, and the T cells are virtually unchanged after undergoing gene editing. It was also fascinating to see how effectively the memory T cells could be multiplied and repaired from even a small amount of blood.”


    Dr Xun Li, First Author

    Cell culture experiments showed that the infants’ repaired T memory cells were capable of a normal cytotoxic T cell response.

    This means the therapeutic mechanism works in principle. But before patients can benefit from this discovery, the team needs to first resolve open questions and test the treatment concept in clinical trials. “It is still uncertain how long the protective effect lasts,” says Dr Christine Kocks, a scientist in Rajewsky’s team. “Since the T memory stem cells remain in the body for a long time, we hope the therapy provides long-term or even permanent protection. It is also conceivable that patients could be treated with their repaired T cells over and over again.”

    The procedure is minimally invasive since only a small amount of blood is needed, and the mice did not require any preparatory treatment – unlike, for example, with a bone marrow transplant. “We very much hope that our mechanism of action is a breakthrough in treating FHL,” says Rajewsky, “either to gain more time for a successful bone marrow transplant or even as a treatment itself.”

    Source:

    Max Delbrück Center for Molecular Medicine in the Helmholtz Association

    Journal reference:

    Li, X., et al. (2024) Precise CRISPR-Cas9 gene repair in autologous memory T cells to treat familial hemophagocytic lymphohistiocytosis. Science Immunology. doi.org/10.1126/sciimmunol.adi0042.

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  • Researchers discover new class of compound that targets cancer stem cells

    Researchers discover new class of compound that targets cancer stem cells

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    Many cancer therapies, in addition to producing numerous side effects, fail to achieve complete tumour remission, partly due to the presence of cancer stem cells, which are difficult to eradicate. These cells can self-renew and play a key role in tumor recurrence and metastasis processes, so there is significant interest in developing therapies that target this subset of tumour cells. 

    A collaboration between chemists from the Center for Research in Biological Chemistry and Molecular Materials (CiQUS), led by Prof. JL Mascareñas, and cell biologists from the CSIC (Instituto de Investigaciones Biomédicas Sols-Morreale, IIBM CSIC-UAM, Madrid), led by Dr. Bruno Sainz, has led to the discovery of a new class of compound that targets cancer stem cells and reduces their potential to generate tumors. For some years, Prof. Mascareñas’ laboratory has been conducting basic research on certain molecules based on metal complexes that can interact very selectively with DNA. These findings have allowed Dr. Sainz’s group to conduct extensive studies with mice implanted with patients’ tumors, demonstrating a powerful antitumor effect of these complexes. The scientists have demonstrated anticancer effects in pancreatic, colorectal, and osteosarcoma tumors, with low secondary toxicity, and studies on other types of cancer are currently underway. 

    Cancer stem cells rely on mitochondrial respiration to survive and evade the immune system’s defenses, which represents a metabolic Achilles’ heel. Mechanistic studies carried out this time suggest that the new compound, called Ru1, promotes a decrease in the expression of genes necessary for this respiration, the main energy source for these cells, causing them to lose their cancerous potential. Dr. Sainz’s group has also demonstrated that combined therapies with other antitumor agents are possible, resulting in additive effects. 

    The preliminary results of the scientific work, which also includes contributions from the USC’s ACUIGEN group, have just been published in a leading cancer research journal. All these studies have been made possible thanks to the support of different entities, including the Ignicia program (Xunta de Galicia), the Spanish Association Against Cancer, or the CaixaImpulse program (“la Caixa” Foundation), and the project is currently in an advanced stage for its transfer and preclinical valorization. 

    Source:

    Center for Research in Biological Chemistry and Molecular Materials (CiQUS)

    Journal reference:

    Alcalá, S., et al. (2024). Targeting cancer stem cell OXPHOS with tailored ruthenium complexes as a new anti-cancer strategy. Journal of Experimental & Clinical Cancer Research. doi.org/10.1186/s13046-023-02931-7.

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  • Scientists uncover a way to “hack” neurons’ internal clocks to speed up brain cell development

    Scientists uncover a way to “hack” neurons’ internal clocks to speed up brain cell development

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    The neurons that make up our brains and nervous systems mature slowly over many months. And while this may be beneficial from an evolutionary standpoint, the slow pace makes growing cells to study neurodegenerative and neurodevelopmental diseases -; like Parkinson’s disease, Alzheimer’s disease, and autism -; in the laboratory quite challenging.

    Currently, nerve cells derived from human pluripotent stem cells take months to reach an adultlike state in the lab -; a timeline that mirrors the slow pace of human brain development. (“Pluripotent stem cells” have the potential to develop into many other kinds of cells.)

    New research led by Memorial Sloan Kettering Cancer Center (MSK), however, has uncovered a way to “hack” the cells’ internal clocks to speed up the process. And the work is shedding new light on how cells’ developmental timetables are regulated.

    “This slow pace of nerve cell development has been linked to humans’ unique and complex cognitive abilities,” says Lorenz Studer, MD, Director of MSK’s Center for Stem Cell Biology and the senior author of two recent studies published in Nature and Nature Biotechnology. “Previous research has suggested the presence of a ‘clock’ within cells that sets the pace of our neurons’ development, but its biological nature had largely remained unknown -; until now.”

    New insights into nerve cell development

    Researchers, led by study first author Gabriele Ciceri, PhD, identified an epigenetic “barrier” in the stem cells that give rise to neural cells. (“Epigenetic changes” are ones that don’t alter the DNA code.) This barrier acts as a brake on the development process and determines the rate at which the cells mature. By inhibiting the barrier, the scientists were able to speed up the neurons’ development, they reported January 31 in Nature.

    While studying brain development in mice, I was struck by how neurons progress through a series of steps in a very precise schedule. But this schedule creates a big practical challenge when working with human neurons -; what takes hours and days in the mouse requires weeks and months in human cells.”


    Dr. Gabriele Ciceri, a senior research scientist in the Studer Lab at MSK’s Sloan Kettering Institute

    Furthermore, the team showed that this rate-setting epigenetic barrier is built into neural stem cells well before they differentiate into different types of neurons. They also found higher levels of the barrier in human neurons compared with mouse neurons, which may help explain differences in the pace of cell maturation in different species.

    Uncovering foundational biology

    That such discoveries were made at a cancer center isn’t as surprising as it might seem at first blush. The Studer Lab has long focused on harnessing advances in stem cell biology to develop new therapies for degenerative diseases and cancer -; both of which are strongly associated with aging.

    Moreover, MSK has long been a leader in “basic science” research -; that is, science that seeks to build fundamental understanding of human biology.

    About half of the National Institutes of Health (NIH) budget goes to funding basic science research. And the vast majority of drugs approved by the Food and Drug Administration in recent years involved publicly funded basic research, according to the NIH.

    “All of the major advances in cancer treatment in recent years -; immune checkpoint inhibitor therapy, CAR T cell therapy, cancer vaccines -; they’re all rooted in basic research,” says Joan Massagué, PhD, Director of the Sloan Kettering Institute and MSK’s Chief Scientific Officer. “Sometimes it can take years for the medical relevance of a particular discovery to become clear.”

    ‘A valuable research tool’

    A second study, led by Studer Lab graduate students Emiliano Hergenreder and Andrew Minotti and published January 2 in Nature Biotechnology, identified a combination of four chemicals that together can promote neuronal maturation. Dubbed GENtoniK, the chemical cocktail both represses epigenetic factors that inhibit cell maturation and stimulates factors that promote it.

    Along with helping to bring neurons to an adultlike state faster in the lab, the approach holds promise for other cell types, the researchers note.

    Not only was GENtoniK shown to speed the maturation of cortical neurons (involved in cognitive functions) and spinal motor neurons (involved in movement), but the chemicals were also able to accelerate the development of several other types of cells derived from stem cells, including melanocytes (pigment cells) and pancreatic beta cells (endocrine cells).

    “The generation of human neurons in a dish from stem cells provides a unique inroad into the study of brain health and disease,” the journal editors note in a research briefing that accompanied the study. “A major obstacle in the field arises from the fact that human neurons require many months to mature during development, making it difficult to recapitulate the process in vitro. The authors provide a valuable research tool by developing a simple drug cocktail that speeds up the maturation timeframe.”

    The findings could be particularly helpful in modeling disorders like autism that involve problems with synaptic connectivity, Dr. Studer says.

    Still, he notes, additional research is needed to develop models of neurodegenerative disorders that don’t occur until very late in life, such as Parkinson’s disease, which has long been a focus of Studer’s research.

    “Typically, a person is 60 to 70 years old when the disease begins. No baby gets Parkinson’s,” he says. “So, for those diseases, we need to be able to put the cells not just into an adult state but into an aged-like state. That’s something we’re continuing to work on.”

    Source:

    Memorial Sloan Kettering Cancer Center

    Journal references:

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