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Cell Metabolism Dec 2023The peripheral nervous system harbors a remarkable potential to regenerate after acute nerve trauma. Full functional recovery, however, is rare and critically depends on...
The peripheral nervous system harbors a remarkable potential to regenerate after acute nerve trauma. Full functional recovery, however, is rare and critically depends on peripheral nerve Schwann cells that orchestrate breakdown and resynthesis of myelin and, at the same time, support axonal regrowth. How Schwann cells meet the high metabolic demand required for nerve repair remains poorly understood. We here report that nerve injury induces adipocyte to glial signaling and identify the adipokine leptin as an upstream regulator of glial metabolic adaptation in regeneration. Signal integration by leptin receptors in Schwann cells ensures efficient peripheral nerve repair by adjusting injury-specific catabolic processes in regenerating nerves, including myelin autophagy and mitochondrial respiration. Our findings propose a model according to which acute nerve injury triggers a therapeutically targetable intercellular crosstalk that modulates glial metabolism to provide sufficient energy for successful nerve repair.
Topics: Peripheral Nerves; Myelin Sheath; Neuroglia; Schwann Cells; Nerve Regeneration
PubMed: 37989315
DOI: 10.1016/j.cmet.2023.10.017 -
Nature Reviews. Immunology Jan 2024Microglia are resident macrophages of the central nervous system that have key functions in its development, homeostasis and response to damage and infection. Although... (Review)
Review
Microglia are resident macrophages of the central nervous system that have key functions in its development, homeostasis and response to damage and infection. Although microglia have been increasingly implicated in contributing to the pathology that underpins neurological dysfunction and disease, they also have crucial roles in neurological homeostasis and regeneration. This includes regulation of the maintenance and regeneration of myelin, the membrane that surrounds neuronal axons, which is required for axonal health and function. Myelin is damaged with normal ageing and in several neurodegenerative diseases, such as multiple sclerosis and Alzheimer disease. Given the lack of approved therapies targeting myelin maintenance or regeneration, it is imperative to understand the mechanisms by which microglia support and restore myelin health to identify potential therapeutic approaches. However, the mechanisms by which microglia regulate myelin loss or integrity are still being uncovered. In this Review, we discuss recent work that reveals the changes in white matter with ageing and neurodegenerative disease, how this relates to microglia dynamics during myelin damage and regeneration, and factors that influence the regenerative functions of microglia.
Topics: Humans; Microglia; Myelin Sheath; Neurodegenerative Diseases; Central Nervous System; Macrophages
PubMed: 37452201
DOI: 10.1038/s41577-023-00907-4 -
Science (New York, N.Y.) May 2024To fully understand how the human brain works, knowledge of its structure at high resolution is needed. Presented here is a computationally intensive reconstruction of...
To fully understand how the human brain works, knowledge of its structure at high resolution is needed. Presented here is a computationally intensive reconstruction of the ultrastructure of a cubic millimeter of human temporal cortex that was surgically removed to gain access to an underlying epileptic focus. It contains about 57,000 cells, about 230 millimeters of blood vessels, and about 150 million synapses and comprises 1.4 petabytes. Our analysis showed that glia outnumber neurons 2:1, oligodendrocytes were the most common cell, deep layer excitatory neurons could be classified on the basis of dendritic orientation, and among thousands of weak connections to each neuron, there exist rare powerful axonal inputs of up to 50 synapses. Further studies using this resource may bring valuable insights into the mysteries of the human brain.
Topics: Humans; Axons; Cerebral Cortex; Dendrites; Neurons; Oligodendroglia; Synapses; Temporal Lobe; Microscopy
PubMed: 38723085
DOI: 10.1126/science.adk4858 -
Trends in Neurosciences Jul 2023Adult oligodendrocyte precursor cells (aOPCs), transformed from fetal OPCs, are idiosyncratic neuroglia of the central nervous system (CNS) that are distinct in many... (Review)
Review
Adult oligodendrocyte precursor cells (aOPCs), transformed from fetal OPCs, are idiosyncratic neuroglia of the central nervous system (CNS) that are distinct in many ways from other glial cells. OPCs have been classically studied in the context of their remyelinating capacity. Recent studies, however, revealed that aOPCs not only contribute to post-lesional remyelination but also play diverse crucial roles in multiple neurological diseases. In this review we briefly present the physiology of aOPCs and summarize current knowledge of the beneficial and detrimental roles of aOPCs in different CNS diseases. We discuss unique features of aOPC death, reactivity, and changes during senescence, as well as aOPC interactions with other glial cells and pathological remodeling during disease. Finally, we outline future perspectives for the study of aOPCs in brain pathologies which may instigate the development of aOPC-targeting therapeutic strategies.
Topics: Oligodendrocyte Precursor Cells; Central Nervous System; Neuroglia; Remyelination; Oligodendroglia; Cell Differentiation; Myelin Sheath
PubMed: 37183154
DOI: 10.1016/j.tins.2023.04.003 -
Nature Reviews. Neuroscience Dec 2023Experience sculpts brain structure and function. Activity-dependent modulation of the myelinated infrastructure of the nervous system has emerged as a dimension of... (Review)
Review
Experience sculpts brain structure and function. Activity-dependent modulation of the myelinated infrastructure of the nervous system has emerged as a dimension of adaptive change during childhood development and in adulthood. Myelination is a richly dynamic process, with neuronal activity regulating oligodendrocyte precursor cell proliferation, oligodendrogenesis and myelin structural changes in some axonal subtypes and in some regions of the nervous system. This myelin plasticity and consequent changes to conduction velocity and circuit dynamics can powerfully influence neurological functions, including learning and memory. Conversely, disruption of the mechanisms mediating adaptive myelination can contribute to cognitive impairment. The robust effects of neuronal activity on normal oligodendroglial precursor cells, a putative cellular origin for many forms of glioma, indicates that dysregulated or 'hijacked' mechanisms of myelin plasticity could similarly promote growth in this devastating group of brain cancers. Indeed, neuronal activity promotes the pathogenesis of many forms of glioma in preclinical models through activity-regulated paracrine factors and direct neuron-to-glioma synapses. This synaptic integration of glioma into neural circuits is central to tumour growth and invasion. Thus, not only do neuron-oligodendroglial interactions modulate neural circuit structure and function in the healthy brain, but neuron-glioma interactions also have important roles in the pathogenesis of glial malignancies.
Topics: Humans; Neurons; Oligodendroglia; Myelin Sheath; Neuroglia; Glioma
PubMed: 37857838
DOI: 10.1038/s41583-023-00744-3 -
The Journal of Clinical Investigation Oct 2023B cell clonal expansion and cerebrospinal fluid (CSF) oligoclonal IgG bands are established features of the immune response in multiple sclerosis (MS). Clone-specific...
B cell clonal expansion and cerebrospinal fluid (CSF) oligoclonal IgG bands are established features of the immune response in multiple sclerosis (MS). Clone-specific recombinant monoclonal IgG1 Abs (rAbs) derived from MS patient CSF plasmablasts bound to conformational proteolipid protein 1 (PLP1) membrane complexes and, when injected into mouse brain with human complement, recapitulated histologic features of MS pathology: oligodendrocyte cell loss, complement deposition, and CD68+ phagocyte infiltration. Conformational PLP1 membrane epitopes were complex and governed by the local cholesterol and glycolipid microenvironment. Abs against conformational PLP1 membrane complexes targeted multiple surface epitopes, were enriched within the CSF compartment, and were detected in most MS patients, but not in inflammatory and noninflammatory neurologic controls. CSF PLP1 complex Abs provide a pathogenic autoantibody biomarker specific for MS.
Topics: Mice; Animals; Humans; Multiple Sclerosis; Myelin Sheath; Immunoglobulin G; Epitopes; Proteolipids
PubMed: 37561592
DOI: 10.1172/JCI162731 -
Nature Neuroscience Oct 2023Oligodendrocyte precursor cells (OPCs) are a population of tissue-resident glial cells found throughout the CNS, constituting approximately 5% of all CNS cells and... (Review)
Review
Oligodendrocyte precursor cells (OPCs) are a population of tissue-resident glial cells found throughout the CNS, constituting approximately 5% of all CNS cells and persisting from development to adulthood and aging. The canonical role of OPCs is to give rise to myelinating oligodendrocytes. However, additional functions of OPCs beyond this traditional role as precursors have been suggested for a long time. In this Perspective, we provide an overview of the multiple myelination-independent functions that have been described for OPCs in the context of neuron development, angiogenesis, inflammatory response, axon regeneration and their recently discovered roles in neural circuit remodeling.
Topics: Myelin Sheath; Oligodendrocyte Precursor Cells; Axons; Nerve Regeneration; Oligodendroglia; Cell Differentiation
PubMed: 37653126
DOI: 10.1038/s41593-023-01423-3 -
Neuron Nov 2023Myelination depends on the maintenance of oligodendrocytes that arise from oligodendrocyte precursor cells (OPCs). We show that OPC-specific proliferation, morphology,...
Myelination depends on the maintenance of oligodendrocytes that arise from oligodendrocyte precursor cells (OPCs). We show that OPC-specific proliferation, morphology, and BMAL1 are time-of-day dependent. Knockout of Bmal1 in mouse OPCs during development disrupts the expression of genes associated with circadian rhythms, proliferation, density, morphology, and migration, leading to changes in OPC dynamics in a spatiotemporal manner. Furthermore, these deficits translate into thinner myelin, dysregulated cognitive and motor functions, and sleep fragmentation. OPC-specific Bmal1 loss in adulthood does not alter OPC density at baseline but impairs the remyelination of a demyelinated lesion driven by changes in OPC morphology and migration. Lastly, we show that sleep fragmentation is associated with increased prevalence of the demyelinating disorder multiple sclerosis (MS), suggesting a link between MS and sleep that requires further investigation. These findings have broad mechanistic and therapeutic implications for brain disorders that include both myelin and sleep phenotypes.
Topics: Mice; Animals; ARNTL Transcription Factors; Sleep Deprivation; Mice, Knockout; Oligodendroglia; Myelin Sheath; Multiple Sclerosis; Sleep; Cell Differentiation
PubMed: 37657440
DOI: 10.1016/j.neuron.2023.08.002 -
Nature Aug 2023Human-specific genomic changes contribute to the unique functionalities of the human brain. The cellular heterogeneity of the human brain and the complex regulation of...
Human-specific genomic changes contribute to the unique functionalities of the human brain. The cellular heterogeneity of the human brain and the complex regulation of gene expression highlight the need to characterize human-specific molecular features at cellular resolution. Here we analysed single-nucleus RNA-sequencing and single-nucleus assay for transposase-accessible chromatin with sequencing datasets for human, chimpanzee and rhesus macaque brain tissue from posterior cingulate cortex. We show a human-specific increase of oligodendrocyte progenitor cells and a decrease of mature oligodendrocytes across cortical tissues. Human-specific regulatory changes were accelerated in oligodendrocyte progenitor cells, and we highlight key biological pathways that may be associated with the proportional changes. We also identify human-specific regulatory changes in neuronal subtypes, which reveal human-specific upregulation of FOXP2 in only two of the neuronal subtypes. We additionally identify hundreds of new human accelerated genomic regions associated with human-specific chromatin accessibility changes. Our data also reveal that FOS::JUN and FOX motifs are enriched in the human-specifically accessible chromatin regions of excitatory neuronal subtypes. Together, our results reveal several new mechanisms underlying the evolutionary innovation of human brain at cell-type resolution.
Topics: Animals; Humans; Cell Nucleus; Chromatin; Datasets as Topic; Evolution, Molecular; Genome, Human; Genomics; Gyrus Cinguli; Macaca mulatta; Neurons; Oligodendroglia; Pan troglodytes; Single-Cell Gene Expression Analysis; Stem Cells; Transposases; Chromatin Assembly and Disassembly
PubMed: 37468639
DOI: 10.1038/s41586-023-06338-4 -
Cell May 2024Remyelination failure in diseases like multiple sclerosis (MS) was thought to involve suppressed maturation of oligodendrocyte precursors; however, oligodendrocytes are...
Remyelination failure in diseases like multiple sclerosis (MS) was thought to involve suppressed maturation of oligodendrocyte precursors; however, oligodendrocytes are present in MS lesions yet lack myelin production. We found that oligodendrocytes in the lesions are epigenetically silenced. Developing a transgenic reporter labeling differentiated oligodendrocytes for phenotypic screening, we identified a small-molecule epigenetic-silencing-inhibitor (ESI1) that enhances myelin production and ensheathment. ESI1 promotes remyelination in animal models of demyelination and enables de novo myelinogenesis on regenerated CNS axons. ESI1 treatment lengthened myelin sheaths in human iPSC-derived organoids and augmented (re)myelination in aged mice while reversing age-related cognitive decline. Multi-omics revealed that ESI1 induces an active chromatin landscape that activates myelinogenic pathways and reprograms metabolism. Notably, ESI1 triggered nuclear condensate formation of master lipid-metabolic regulators SREBP1/2, concentrating transcriptional co-activators to drive lipid/cholesterol biosynthesis. Our study highlights the potential of targeting epigenetic silencing to enable CNS myelin regeneration in demyelinating diseases and aging.
Topics: Animals; Myelin Sheath; Humans; Epigenesis, Genetic; Mice; Remyelination; Oligodendroglia; Central Nervous System; Mice, Inbred C57BL; Rejuvenation; Induced Pluripotent Stem Cells; Sterol Regulatory Element Binding Protein 1; Organoids; Demyelinating Diseases; Cell Differentiation; Small Molecule Libraries; Male; Regeneration; Multiple Sclerosis
PubMed: 38701782
DOI: 10.1016/j.cell.2024.04.005