Heterogeneity of mature oligodendrocytes in the central nervous system

Neural Regeneration Research, Год журнала: 2024, Номер 20(5), С. 1336 - 1349

Опубликована: Июнь 26, 2024

Mature oligodendrocytes form myelin sheaths that are crucial for the insulation of axons and efficient signal transmission in central nervous system. Recent evidence has challenged classical view functionally static mature oligodendrocyte revealed a gamut dynamic functions such as ability to modulate neuronal circuitry provide metabolic support axons. Despite recognition potential heterogeneity function, comprehensive summary diversity is lacking. We delve into early 20 th -century studies by Robertson Río-Hortega laid foundation modern identification regional morphological oligodendrocytes. Indeed, recent morphologic functional call question long-assumed homogeneity function through distinct subtypes with varying myelination preferences. Furthermore, molecular investigations, employing techniques single cell/nucleus RNA sequencing, consistently unveil at least six subpopulations human system highly transcriptomically diverse vary region. Age disease related variation denotes impact pathological conditions multiple sclerosis, Alzheimer’s disease, psychiatric disorders. Nevertheless, caution warranted when subclassifying because simplification needed make conclusions about cell identity from temporally confined investigations. Future leveraging advanced like spatial transcriptomics single-cell proteomics promise more nuanced understanding heterogeneity. Such research avenues precisely evaluate care understand mitigating influence species, sex, region, age, hold development therapeutic interventions targeting varied pathology.

Язык: Английский

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snRNA-seq stratifies multiple sclerosis patients into distinct white matter glial responses

Neuron, Год журнала: 2024, Номер unknown

Опубликована: Дек. 1, 2024

Язык: Английский

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Mapping the glial transcriptome in Huntington’s disease using snRNAseq: selective disruption of glial signatures across brain regions

Acta Neuropathologica Communications, Год журнала: 2024, Номер 12(1)

Опубликована: Окт. 21, 2024

Abstract Huntington’s disease (HD) is an autosomal dominant neurodegenerative with a fatal outcome. There accumulating evidence of prominent role glia in the pathology HD, and we investigated this by conducting single nuclear RNA sequencing (snRNAseq) human post mortem brain four differentially affected regions; caudate nucleus, frontal cortex, hippocampus cerebellum. Across 127,205 nuclei from donors HD age/sex matched controls, found heterogeneity which altered HD. We describe changes abundance certain subtypes astrocytes, microglia, oligodendrocyte precursor cells oligodendrocytes between control samples, these differences are widespread across regions. Furthermore, highlight possible mechanisms that characterise glial contribution to including depletion myelinating oligodendrocytes, oligodendrocyte-specific upregulation calmodulin-dependent 3’,5’-cyclic nucleotide phosphodiesterase 1 A ( PDE1A ) molecular chaperones as cross-glial signature potential adaptive response accumulation mutant huntingtin (mHTT). Our results support hypothesis have important show all types disease.

Язык: Английский

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Neural cell diversity in the light of single-cell transcriptomics

Transcription, Год журнала: 2023, Номер 14(3-5), С. 158 - 176

Опубликована: Окт. 20, 2023

The development of highly parallel and affordable high-throughput single-cell transcriptomics technologies has revolutionized our understanding brain complexity. These methods have been used to build cellular maps the brain, its different regions, catalog diversity cells in each them during development, aging even disease. Now we know that is way beyond what was previously thought. Single-cell analyses revealed cell types considered homogeneous based on imaging techniques differ depending several factors including sex, age location within brain. expression profiles these also exploited understand which are regulatory programs behind decipher transcriptional pathways driving them. In this review, summarize how changed view human it could impact study neurodegenerative diseases. Moreover, describe new computational approaches can be differentiation gain insight into functions individual populations under conditions their alterations

Язык: Английский

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BRG1 programs PRC2-complex repression and controls oligodendrocyte differentiation and remyelination

The Journal of Cell Biology, Год журнала: 2024, Номер 223(7)

Опубликована: Апрель 23, 2024

Chromatin-remodeling protein BRG1/SMARCA4 is pivotal for establishing oligodendrocyte (OL) lineage identity. However, its functions oligodendrocyte-precursor cell (OPC) differentiation within the postnatal brain and during remyelination remain elusive. Here, we demonstrate that Brg1 loss profoundly impairs OPC in with a comparatively lesser effect spinal cord. Moreover, BRG1 critical after injury. Integrative transcriptomic/genomic profiling reveals exhibits dual role by promoting networks while repressing OL-inhibitory cues proneuronal programs. Furthermore, find interacts EED/PRC2 polycomb-repressive-complexes to enhance H3K27me3-mediated repression at gene loci associated OL-differentiation inhibition neurogenesis. Notably, depletion decreases H3K27me3 deposition, leading upregulation of BMP/WNT signaling proneurogenic genes, which suppresses OL Thus, our findings reveal hitherto unexplored spatiotemporal-specific developing CNS underscore new insight into BRG1/PRC2-mediated epigenetic regulation promotes safeguards commitment differentiation.

Язык: Английский

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Developmental maturation and regional heterogeneity but no sexual dimorphism of the murine CNS myelin proteome

Glia, Год журнала: 2024, Номер unknown

Опубликована: Сен. 30, 2024

Abstract The molecules that constitute myelin are critical for the integrity of axon/myelin‐units and thus speed precision impulse propagation. In CNS, protein composition oligodendrocyte‐derived has evolutionarily diverged differs from in PNS. Here, we hypothesized CNS proteome also displays variations within same species. We used quantitative mass spectrometry to compare purified mouse brains at three developmental timepoints, male female mice, four regions. find most structural proteins approximately similar abundance across all tested conditions. However, multiple other markedly over time, implying matures between P18 P75 then remains relatively constant until least 6 months age. Myelin maturation involves a decrease cytoskeleton‐associated involved sheath growth wrapping, along with an increase subunits septin filament stabilizes mature myelin, which potentially exert protective functions. Among latter, quinoid dihydropteridine reductase (QDPR) emerges as highly specific marker oligodendrocytes myelin. Conversely, mice display essentially proteomes. Across regions analyzed, note spinal cord exhibits comparatively high HCN2‐channels, required particularly long sheaths. These findings show myelination composition, regional differences, but absence evidence sexual dimorphism.

Язык: Английский

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Multiple Sclerosis: Glial Cell Diversity in Time and Space

Glia, Год журнала: 2024, Номер unknown

Опубликована: Дек. 24, 2024

ABSTRACT Multiple sclerosis (MS) is the most prevalent human inflammatory disease of central nervous system with demyelination and glial scar formation as pathological hallmarks. Glial cells are key drivers lesion progression in MS roles both tissue damage repair depending on surrounding microenvironment functional state individual subtype. In this review, we describe recent developments context cell diversity summarizing findings respect to maladaptive functions related disease‐associated subtypes. A particular focus spatial temporal dynamics including subtypes microglia, oligodendrocytes, astrocytes. We contextualize high‐dimensional suggesting that dynamically change epigenomic, transcriptomic, metabolic features across inflamed rim during lesions. summary, detailed knowledge spatially restricted subtype critical for a better understanding pathology its pathogenesis well development novel therapies targeting specific types.

Язык: Английский

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Single-nuclei histone modification profiling of the adult human central nervous system unveils epigenetic memory of developmental programs

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Апрель 16, 2024

Abstract The adult human central nervous system (CNS) is remarkably complex, with neural cells displaying extensive transcriptional heterogeneity. However, how different layers of epigenetic regulation underpin this heterogeneity poorly understood. Here, we profile the CNS from distinct regions, for chromatin accessibility at single-nuclei level. In addition, simultaneously co-profiled histone modifications H3K27me3 and H3K27ac single nuclei-level, providing their first map in all major cell types. We unveil primed signatures HOX loci spinal cord-derived oligodendroglia (OLG) but not microglia. These were reminiscent developmental OLG decoupled robust gene expression. Moreover, using high-resolution Micro-C, show that induced pluripotent stem (iPS) derived OLGs exhibit a architecture compatible OLGs, bears strong resemblance only to architecture, also high-grade pontine gliomas. Thus, retain memory states, which might enable them promptly transcribe Hox genes, contexts regeneration, make susceptible gliomagenesis.

Язык: Английский

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Hyperglycemia selectively increases cerebral non-oxidative glucose consumption without affecting blood flow

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Сен. 10, 2024

Multiple studies have shown that hyperglycemia increases the cerebral metabolic rate of glucose (CMRglc) in subcortical white matter. This observation remains unexplained. Using positron emission tomography (PET) and euinsulinaemic clamps, we found, for first time, acute non-oxidative CMRglc (i.e., aerobic glycolysis (AG)) mater as well medial temporal lobe structures, cerebellum brainstem, all areas with low euglycemic CMRglc. Surprisingly, did not change regional blood flow (CBF), oxygen (CMRO

Язык: Английский

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R‐Ras1 and R‐Ras2 regulate mature oligodendrocyte subpopulations

Glia, Год журнала: 2024, Номер unknown

Опубликована: Ноя. 19, 2024

In the mammalian central nervous system, axonal myelination, executed by mature oligodendrocytes (MOLs), enables rapid neural transmission. Conversely, myelin deficiencies are hallmark features of multiple sclerosis, optic neuromyelitis, and some leukodystrophies. Recent studies have highlighted that MOLs heterogeneous; however, how MOL subpopulations specified balanced in physiological settings is poorly understood. Previous works demonstrated an essential role small GTPases R-Ras1 R-Ras2 survival myelination oligodendrocytes. this study, we aimed to determine contribute heterogeneity subpopulations. Our results evidence affect specification into distinct MOL1, MOL2, MOL5/6, which turn vary their dependence these GTPases. and/or mutant mice, observed increase MOL1 subpopulation a decrease MOL2 MOL5/6 We identified as key elements balancing MOLs. understanding molecular mechanisms underlying processes, crucial for innovating regenerative therapies system disorders.

Язык: Английский

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