Age-dependent effects of metformin on human oligodendrocyte lineage cell ensheathment capacity.
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1036538 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26700900_1.fastq.gz | Fastqsanger.gz | |||
| SRR26700900_2.fastq.gz | Fastqsanger.gz | |||
| SRR26700901_1.fastq.gz | Fastqsanger.gz | |||
| SRR26700901_2.fastq.gz | Fastqsanger.gz | |||
| SRR26700902_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 58 |
Similar Datasets
Project description:Metformin restores myelination potential of aged rat A2B5+ oligodendroglia (OL) progenitor cells and may enhance recovery in children with post-radiation brain injury. Human late progenitor cells (O4+A2B5+) have superior capacity to ensheath nanofibers compared to mature OLs, with cells from pediatric sources exceeding adults. In this study we assessed effects of metformin on ensheathment capacity of human adult and pediatric progenitors and mature OLs and relate differences to transcriptional changes. A2B5+ progenitors and mature OLs, derived from surgical tissues by immune-magnetic separation, were assessed for ensheathment capacity in nanofiber plates over 2 weeks. Metformin (10µM every other day) was added to selected cultures. RNA was extracted from treated and control cultures after 2 days. For all ages, ensheathment by progenitors exceeded mature OLs. Metformin enhanced ensheathment by adult donor cells but reduced ensheathment by pediatric cells. Metformin marginally increased cell death in pediatric progenitors. Metformin induced changes in gene expression distinct for each cell type. Adult progenitors showed up-regulation of pathways involved in process outgrowth and promoting lipid biosynthesis. Pediatric progenitors showed a relatively greater proportion of down- versus up-regulated pathways, these involved cell morphology, development, and synaptic transmission. Metformin induced AMPK activation in all cell types; AMPK inhibitor BML-275 reduced functional metformin effects only with adult cells. Our results indicate age and differentiation stage related differences of human OL lineage cells in response to metformin. Clinical trials for demyelinating conditions will indicate how these differences translate in vivo.
2023-11-11 | GSE247159 | GEO
Project description:Metformin restores the myelination potential of aged rat A2B5+ oligodendrocyte progenitor cells and may enhance recovery in children with post-radiation brain injury. Human late progenitor cells (O4+A2B5+) have a superior capacity to ensheath nanofibres compared to mature oligodendrocytes, with cells from paediatric sources exceeding adults. In this study, we assessed the effects of metformin on ensheathment capacity of human adult and paediatric progenitors and mature oligodendrocytes and related differences to transcriptional changes. A2B5+ progenitors and mature cells, derived from surgical tissues by immune-magnetic separation, were assessed for ensheathment capacity in nanofibre plates over 2 weeks. Metformin (10 µM every other day) was added to selected cultures. RNA was extracted from treated and control cultures after 2 days. For all ages, ensheathment by progenitors exceeded mature oligodendrocytes. Metformin enhanced ensheathment by adult donor cells but reduced ensheathment by paediatric cells. Metformin marginally increased cell death in paediatric progenitors. Metformin-induced changes in gene expression are distinct for each cell type. Adult progenitors showed up-regulation of pathways involved in the process of outgrowth and promoting lipid biosynthesis. Paediatric progenitors showed a relatively greater proportion of down- versus up-regulated pathways, these involved cell morphology, development and synaptic transmission. Metformin-induced AMP-activated protein kinase activation in all cell types; AMP-activated protein kinase inhibitor BML-275 reduced functional metformin effects only with adult cells. Our results indicate age and differentiation stage-related differences in human oligodendroglia lineage cells in response to metformin. Clinical trials for demyelinating conditions will indicate how these differences translate in vivo.
| S-EPMC11005772 | biostudies-literature
Project description:Metformin rejuvenates adult rat oligodendrocyte progenitor cells (OPCs) allowing more efficient differentiation into oligodendrocytes and improved remyelination of CNS axons and therefore is of interest as a possible therapeutic in demyelinating diseases such as multiple sclerosis (MS). We set out to test whether metformin had a similar effect in human stem cell derived-OPCs. We assessed the suitability of human monoculture, organoid and transplantation into immunodeficient mice (chimera model) culture systems in simulating in vivo adult human oligodendrocytes, finding most close resemblance in the chimera model. Metformin increased myelin proteins and/or sheaths in all models even when human cells had fetal signatures. In the chimera model, metformin led to a marked increase in mitochondrial area both in the human transplanted cells and in the mouse axons with associated increase in transcripts related to mitochondrial function and metabolism. Human oligodendrocytes from MS brain donors treated pre-mortem with metformin also expressed similar transcripts suggesting that metformin’s brain effect is not cell-specific, altering metabolism in both oligodendrocytes and axons leading to more myelin production, in part through mitochondrial changes. This bodes well for ongoing clinical trials testing metformin for neuroprotection.
2024-12-10 | GSE282369 | GEO
Project description:Metformin enhances human oligodendrocyte function by altering metabolism
| PRJNA1188459 | ENA
Project description:The age-related failure to regenerate lost oligodendrocytes from oligodendrocyte progenitor cells (OPCs) is associated with irreversible neurodegeneration in multiple sclerosis. Consequently, regenerative therapies for chronic demyelinating diseases remain a long sought after but elusive goal. Here we show that adult OPCs lose their inherent differentiation potential with increasing age. Moreover, aged OPCs do not remain responsive to pro-differentiation signals, posing significant constraints on the effectiveness of remyelination therapies based on the enhancement of OPC differentiation. We show that this reduced regenerative capacity is associated with hallmarks of cellular ageing, including reduced metabolic function and increased DNA damage. We find that fasting or treatment with metformin can reverse these changes and restore the regenerative capacity of aged OPCs, improving remyelination in aged animals following white matter injury. Importantly, aged OPCs treated with metformin regain their responsiveness to pro-differentiation factors, suggesting a potential for synergistic effects of rejuvenation and pro-differentiation therapies. Our findings have direct implications for understanding oligodendrocyte regeneration failure with ageing and how it might be reversed therapeutically.
2019-11-01 | GSE134765 | GEO
Project description:Myelination in the CNS is modulated by interplay between transcription factors and recruitment of chromatin modifying enzymes. Using a network built from genome-wide DNA methylation and transcriptomic profiling of sorted oligodendrocyte lineage cells that integrates oligodendrocyte-specific ChIP-Seq data, we defined a crucial role of DNA methylation in coordinating the transition between progenitor cell cycle arrest and oligodendrocyte differentiation. We further identified DNA methyltransferase 1 (DNMT1) as key regulator of oligodendrocyte survival at this transition point, as we detected severe and extensive developmental hypomyelination only in Olig1cre/+;Dnmt1flox/flox but not in Olig1cre/+;Dnmt3aflox/flox mice or in Cnpcre/+;Dnmt1flox/flox. This phenotype was characterized by decreased expression of genes regulating myelination and lipid metabolism â despite the hypomethylation observed at these genetic loci  â and upregulation of cell cycle and DNA-damage pathways. Therefore DNMT1 is a nodal point regulating proliferation, survival, and differentiation in the oligodendrocyte lineage, and is critical for cell number regulation in the developing brain. mRNA profiles of FAC-sorted P2 Pdgfra::GFP and P18 Plp1-GFP purified cell samples from mouse brains were generated by RNA-sequencing, in triplicate, using Illumina HiSeq 2000.
2016-04-14 | E-GEOD-66029 | biostudies-arrayexpress
Project description:Myelination in the CNS is modulated by interplay between transcription factors and recruitment of chromatin modifying enzymes. Using a network built from genome-wide DNA methylation and transcriptomic profiling of sorted oligodendrocyte lineage cells that integrates oligodendrocyte-specific ChIP-Seq data, we defined a crucial role of DNA methylation in coordinating the transition between progenitor cell cycle arrest and oligodendrocyte differentiation. We further identified DNA methyltransferase 1 (DNMT1) as key regulator of oligodendrocyte survival at this transition point, as we detected severe and extensive developmental hypomyelination only in Olig1cre/+;Dnmt1flox/flox but not in Olig1cre/+;Dnmt3aflox/flox mice or in Cnpcre/+;Dnmt1flox/flox. This phenotype was characterized by decreased expression of genes regulating myelination and lipid metabolism â despite the hypomethylation observed at these genetic loci  â and upregulation of cell cycle and DNA-damage pathways. Therefore DNMT1 is a nodal point regulating proliferation, survival, and differentiation in the oligodendrocyte lineage, and is critical for cell number regulation in the developing brain. Genome wide DNA methylation profiles of FAC-sorted P2 Pdgfra::GFP and P18 Plp1-GFP purified cell samples from mouse brains were generated by ERRBS analysis, in duplicate, using Illumina HiSeq 2000.
2016-04-14 | E-GEOD-66028 | biostudies-arrayexpress
Project description:We used RNA sequencing to examine the transcriptional changes in differentiated oligodendrocytes, oligodendrocyte precursor cells, astroctytes, and microglia after blocking exocytosis from oligodendrocyte-lineage cells
2022-10-31 | GSE168569 | GEO
Project description:Ovarian fibrosis is a pathological condition associated with aging and is responsible for a variety of ovarian dysfunctions. Given the known contributions of tissue fibrosis to tumorigenesis, it is anticipated that ovarian fibrosis may contribute to ovarian cancer risk. We recently reported that diabetic postmenopausal women using metformin had ovarian collagen abundance and organization that were similar to premenopausal ovaries from non-diabetic women. In this study, we investigated the effects of aging and metformin on mouse ovarian fibrosis at a single-cell level. We discovered that metformin treatment prevents age-associated ovarian fibrosis by modulating the proportion of fibroblasts, myofibroblasts and immune cells. We identified the emergence of a metformin responsive subpopulation of macrophages, unique to the aged mice treated with metformin. Our results demonstrate that metformin can modulate specific populations of immune cells and fibroblasts to prevent age-associated ovarian fibrosis and offers a new strategy to prevent ovarian fibrosis
2022-07-01 | GSE199914 | GEO
Project description:Metformin is a type 2 diabetes medication which extends life span across species when given from young adulthood onwards; late life effects of metformin are not well understood. Here we used C. elegans to investigate the outcome of metformin treatment initiated late in life. We found that, contrary to young age administration, old age metformin treatment interferes with energy homeostasis and shortens life span by aggravating age-associated mitochondrial dysfunction. Nematode mutants defective in mitochondrial respiration, mitochondrial biogenesis and mitochondrial quality control were highly susceptible to metformin killing already at young age while insulin receptor deficient nematodes carrying healthier mitochondria were protected from late life metformin toxicity. In the mammalian cell culture model of replicative senescence metformin killing correlated with loss of mitochondrial membrane potential and strong reduction of systemic ATP levels. Reduced ATP levels and depletion of lipid stores consistent with energy deficit were observed also in nematodes following late life metformin treatment. At the molecular level young animals responded to metformin by inducing adaptive stress responses and longevity-assurance pathways while old nematodes demonstrated a protein expression signature consistent with lipid turnover and energy deficit. Ectopic ATP supplementation was sufficient to alleviate metformin toxicity in human skin fibroblasts highlighting the key contribution of energy deficit to the detrimental effect of metformin. Also, co-exposure with rapamycin, known to stabilize cellular ATP levels under conditions of mitochondrial failure, significantly reduced metformin-inflicted lethality in both cells and old animals. In summary we uncovered a novel negative synergism between metformin treatment and mitochondrial dysfunction which gains importance late in life and may limit therapeutic benefits of metformin for older patients; these side effects can partially be overcome by co-treatment with agents stabilizing cellular ATP levels such as rapamycin.
2020-09-21 | PXD011579 | Pride