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Neurobiology of Disease Aug 2023Oligodendrocytes (OLs), the myelin-forming cells of the central nervous system, are integral to axonal integrity and function. Hypoxia-ischemia episodes can cause severe... (Review)
Review
Oligodendrocytes (OLs), the myelin-forming cells of the central nervous system, are integral to axonal integrity and function. Hypoxia-ischemia episodes can cause severe damage to these vulnerable cells through excitotoxicity, oxidative stress, inflammation, and mitochondrial dysfunction, leading to axonal dystrophy, neuronal dysfunction, and neurological impairments. OLs damage can result in demyelination and myelination disorders, severely impacting axonal function, structure, metabolism, and survival. Adult-onset stroke, periventricular leukomalacia, and post-stroke cognitive impairment primarily target OLs, making them a critical therapeutic target. Therapeutic strategies targeting OLs, myelin, and their receptors should be given more emphasis to attenuate ischemia injury and establish functional recovery after stroke. This review summarizes recent advances on the function of OLs in ischemic injury, as well as the present and emerging principles that serve as the foundation for protective strategies against OLs deaths.
Topics: Humans; Ischemic Stroke; Oligodendroglia; Myelin Sheath; Central Nervous System; Stroke
PubMed: 37321419
DOI: 10.1016/j.nbd.2023.106200 -
Redox Biology Feb 2024Accumulation of reactive oxygen species (ROS), especially on lipids, induces massive cell death in neurons and oligodendrocyte progenitor cells (OPCs) and causes severe...
Accumulation of reactive oxygen species (ROS), especially on lipids, induces massive cell death in neurons and oligodendrocyte progenitor cells (OPCs) and causes severe neurologic deficits post stroke. While small compounds, such as deferoxamine, lipostatin-1, and ferrostatin-1, have been shown to be effective in reducing lipid ROS, the mechanisms by which endogenously protective molecules act against lipid ROS accumulation and subsequent cell death are still unclear, especially in OPCs, which are critical for maintaining white matter integrity and improving long-term outcomes after stroke. Here, using mouse primary OPC cultures, we demonstrate that interleukin-10 (IL-10), a cytokine playing roles in reducing neuroinflammation and promoting hematoma clearance, significantly reduced hemorrhage-induced lipid ROS accumulation and subsequent ferroptosis in OPCs. Mechanistically, IL-10 activated the IL-10R/STAT3 signaling pathway and upregulated the DLK1/AMPK/ACC axis. Subsequently, IL-10 reprogrammed lipid metabolism and reduced lipid ROS accumulation. In addition, in an autologous blood injection intracerebral hemorrhagic stroke (ICH) mouse model, deficiency of the endogenous Il-10, specific knocking out Il10r or Dlk1 in OPCs, or administration of ACC inhibitor was associated with increased OPC cell death, demyelination, axonal sprouting, and the cognitive deficits during the chronic phase of ICH and vice versa. These data suggest that IL-10 protects against OPC loss and white matter injury by reducing lipid ROS, supporting further development of potential clinical applications to benefit patients with stroke and related disorders.
Topics: Animals; Humans; Mice; Ferroptosis; Interleukin-10; Lipids; Oligodendroglia; Reactive Oxygen Species; Stroke
PubMed: 38070317
DOI: 10.1016/j.redox.2023.102982 -
Nature Reviews. Neuroscience Aug 2023Extracellular vesicles (EVs) have recently emerged as versatile elements of cell communication in the nervous system, mediating tissue homeostasis. EVs influence the... (Review)
Review
Extracellular vesicles (EVs) have recently emerged as versatile elements of cell communication in the nervous system, mediating tissue homeostasis. EVs influence the physiology of their target cells via horizontal transfer of molecular cargo between cells and by triggering signalling pathways. In this Review, we discuss recent work revealing that EVs mediate interactions between oligodendrocytes and neurons, which are relevant for maintaining the structural integrity of axons. In response to neuronal activity, myelinating oligodendrocytes release EVs, which are internalized by neurons and provide axons with key factors that improve axonal transport, stress resistance and energy homeostasis. Glia-to-neuron transfer of EVs is thus a crucial facet of axonal preservation. When glial support is impaired, axonal integrity is progressively lost, as observed in myelin-related disorders, other neurodegenerative diseases and with normal ageing. We highlight the mechanisms that oligodendroglial EVs use to sustain axonal integrity and function.
Topics: Axons; Oligodendroglia; Myelin Sheath; Neuroglia; Extracellular Vesicles
PubMed: 37258632
DOI: 10.1038/s41583-023-00711-y -
Cell Feb 2024Myelin, the insulating sheath that surrounds neuronal axons, is produced by oligodendrocytes in the central nervous system (CNS). This evolutionary innovation, which...
Myelin, the insulating sheath that surrounds neuronal axons, is produced by oligodendrocytes in the central nervous system (CNS). This evolutionary innovation, which first appears in jawed vertebrates, enabled rapid transmission of nerve impulses, more complex brains, and greater morphological diversity. Here, we report that RNA-level expression of RNLTR12-int, a retrotransposon of retroviral origin, is essential for myelination. We show that RNLTR12-int-encoded RNA binds to the transcription factor SOX10 to regulate transcription of myelin basic protein (Mbp, the major constituent of myelin) in rodents. RNLTR12-int-like sequences (which we name RetroMyelin) are found in all jawed vertebrates, and we further demonstrate their function in regulating myelination in two different vertebrate classes (zebrafish and frogs). Our study therefore suggests that retroviral endogenization played a prominent role in the emergence of vertebrate myelin.
Topics: Animals; Gene Expression; Myelin Sheath; Oligodendroglia; Retroelements; RNA; Zebrafish; Anura
PubMed: 38364788
DOI: 10.1016/j.cell.2024.01.011 -
Current Opinion in Cell Biology Feb 2024Multiple Sclerosis (MS) is a common cause of impairment in working-aged adults. MS is characterized by neuroinflammation and infiltration of peripheral immune cells to... (Review)
Review
Multiple Sclerosis (MS) is a common cause of impairment in working-aged adults. MS is characterized by neuroinflammation and infiltration of peripheral immune cells to the brain, which cause myelin loss and death of oligodendrocytes and neurons. Many studies on MS have focused on the peripheral immune sources of demyelination and repair. However, recent studies revealed that a glial cell type, the astrocytes, undergo robust morphological and transcriptomic changes that contribute significantly to demyelination and myelin repair. Here, we discuss recent findings elucidating signaling modalities that astrocytes acquire or lose in MS and how these changes alter the interactions of astrocytes with other nervous system cell types.
Topics: Humans; Multiple Sclerosis; Astrocytes; Myelin Sheath; Oligodendroglia; Neurons
PubMed: 38145604
DOI: 10.1016/j.ceb.2023.102307 -
Nature Neuroscience Dec 2023
Topics: Humans; Alzheimer Disease; Myelin Sheath; Brain
PubMed: 38040972
DOI: 10.1038/s41593-023-01524-z -
International Journal of Molecular... Nov 2023A diverse array of neurological and psychiatric disorders, including multiple sclerosis, Alzheimer's disease, and schizophrenia, exhibit distinct myelin abnormalities at... (Review)
Review
A diverse array of neurological and psychiatric disorders, including multiple sclerosis, Alzheimer's disease, and schizophrenia, exhibit distinct myelin abnormalities at both the molecular and histological levels. These aberrations are closely linked to dysfunction of oligodendrocytes and alterations in myelin structure, which may be pivotal factors contributing to the disconnection of brain regions and the resulting characteristic clinical impairments observed in these conditions. Astrocytes, which significantly outnumber neurons in the central nervous system by a five-to-one ratio, play indispensable roles in the development, maintenance, and overall well-being of neurons and oligodendrocytes. Consequently, they emerge as potential key players in the onset and progression of a myriad of neurological and psychiatric disorders. Furthermore, targeting astrocytes represents a promising avenue for therapeutic intervention in such disorders. To gain deeper insights into the functions of astrocytes in the context of myelin-related disorders, it is imperative to employ appropriate in vivo models that faithfully recapitulate specific aspects of complex human diseases in a reliable and reproducible manner. One such model is the cuprizone model, wherein metabolic dysfunction in oligodendrocytes initiates an early response involving microglia and astrocyte activation, culminating in multifocal demyelination. Remarkably, following the cessation of cuprizone intoxication, a spontaneous process of endogenous remyelination occurs. In this review article, we provide a historical overview of studies investigating the responses and putative functions of astrocytes in the cuprizone model. Following that, we list previously published works that illuminate various aspects of the biology and function of astrocytes in this multiple sclerosis model. Some of the studies are discussed in more detail in the context of astrocyte biology and pathology. Our objective is twofold: to provide an invaluable overview of this burgeoning field, and, more importantly, to inspire fellow researchers to embark on experimental investigations to elucidate the multifaceted functions of this pivotal glial cell subpopulation.
Topics: Humans; Animals; Mice; Cuprizone; Demyelinating Diseases; Astrocytes; Myelin Sheath; Oligodendroglia; Multiple Sclerosis; Microglia; Mice, Inbred C57BL; Disease Models, Animal
PubMed: 38003609
DOI: 10.3390/ijms242216420 -
Developmental Cell Jul 2023Acute brain injuries evoke various response cascades directing the formation of the glial scar. Here, we report that acute lesions associated with hemorrhagic injuries...
Acute brain injuries evoke various response cascades directing the formation of the glial scar. Here, we report that acute lesions associated with hemorrhagic injuries trigger a re-programming of oligodendrocytes. Single-cell RNA sequencing highlighted a subpopulation of oligodendrocytes activating astroglial genes after acute brain injuries. By using PLP-DsRed1/GFAP-EGFP and PLP-EGFP/GFAP-mRFP1 transgenic mice, we visualized this population of oligodendrocytes that we termed AO cells based on their concomitant activity of astro- and oligodendroglial genes. By fate mapping using PLP- and GFAP-split Cre complementation and repeated chronic in vivo imaging with two-photon laser-scanning microscopy, we observed the conversion of oligodendrocytes into astrocytes via the AO cell stage. Such conversion was promoted by local injection of IL-6 and was diminished by IL-6 receptor-neutralizing antibody as well as by inhibiting microglial activation with minocycline. In summary, our findings highlight the plastic potential of oligodendrocytes in acute brain trauma due to microglia-derived IL-6.
Topics: Mice; Animals; Astrocytes; Interleukin-6; Glial Fibrillary Acidic Protein; Oligodendroglia; Mice, Transgenic; Brain Injuries
PubMed: 37220747
DOI: 10.1016/j.devcel.2023.04.016 -
Nature Neuroscience May 2024Exposure to environmental chemicals can impair neurodevelopment, and oligodendrocytes may be particularly vulnerable, as their development extends from gestation into...
Exposure to environmental chemicals can impair neurodevelopment, and oligodendrocytes may be particularly vulnerable, as their development extends from gestation into adulthood. However, few environmental chemicals have been assessed for potential risks to oligodendrocytes. Here, using a high-throughput developmental screen in cultured cells, we identified environmental chemicals in two classes that disrupt oligodendrocyte development through distinct mechanisms. Quaternary compounds, ubiquitous in disinfecting agents and personal care products, were potently and selectively cytotoxic to developing oligodendrocytes, whereas organophosphate flame retardants, commonly found in household items such as furniture and electronics, prematurely arrested oligodendrocyte maturation. Chemicals from each class impaired oligodendrocyte development postnatally in mice and in a human 3D organoid model of prenatal cortical development. Analysis of epidemiological data showed that adverse neurodevelopmental outcomes were associated with childhood exposure to the top organophosphate flame retardant identified by our screen. This work identifies toxicological vulnerabilities for oligodendrocyte development and highlights the need for deeper scrutiny of these compounds' impacts on human health.
Topics: Oligodendroglia; Animals; Mice; Humans; Flame Retardants; Female; Cells, Cultured; Cell Differentiation; Mice, Inbred C57BL; Environmental Pollutants
PubMed: 38528201
DOI: 10.1038/s41593-024-01599-2 -
Nature Neuroscience Oct 2023Oligodendrocytes, the myelinating cells of the central nervous system (CNS), are generated from oligodendrocyte precursor cells (OPCs) that express neurotransmitter...
Oligodendrocytes, the myelinating cells of the central nervous system (CNS), are generated from oligodendrocyte precursor cells (OPCs) that express neurotransmitter receptors. However, the mechanisms that affect OPC activity in vivo and the physiological roles of neurotransmitter signaling in OPCs are unclear. In this study, we generated a transgenic mouse line that expresses membrane-anchored GCaMP6s in OPCs and used longitudinal two-photon microscopy to monitor OPC calcium (Ca) dynamics in the cerebral cortex. OPCs exhibit focal and transient Ca increases within their processes that are enhanced during locomotion-induced increases in arousal. The Ca transients occur independently of excitatory neuron activity, rapidly decline when OPCs differentiate and are inhibited by anesthesia, sedative agents or noradrenergic receptor antagonists. Conditional knockout of α1A adrenergic receptors in OPCs suppresses spontaneous and locomotion-induced Ca increases and reduces OPC proliferation. Our results demonstrate that OPCs are directly modulated by norepinephrine in vivo to enhance Ca dynamics and promote population homeostasis.
Topics: Mice; Animals; Oligodendrocyte Precursor Cells; Calcium; Norepinephrine; Mice, Transgenic; Oligodendroglia; Cerebral Cortex; Cell Proliferation; Arousal; Cell Differentiation
PubMed: 37697112
DOI: 10.1038/s41593-023-01426-0