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Cells Nov 2019Oligodendrocytes are the myelinating cells of the central nervous system (CNS) that are generated from oligodendrocyte progenitor cells (OPC). OPC are distributed... (Review)
Review
Oligodendrocytes are the myelinating cells of the central nervous system (CNS) that are generated from oligodendrocyte progenitor cells (OPC). OPC are distributed throughout the CNS and represent a pool of migratory and proliferative adult progenitor cells that can differentiate into oligodendrocytes. The central function of oligodendrocytes is to generate myelin, which is an extended membrane from the cell that wraps tightly around axons. Due to this energy consuming process and the associated high metabolic turnover oligodendrocytes are vulnerable to cytotoxic and excitotoxic factors. Oligodendrocyte pathology is therefore evident in a range of disorders including multiple sclerosis, schizophrenia and Alzheimer's disease. Deceased oligodendrocytes can be replenished from the adult OPC pool and lost myelin can be regenerated during remyelination, which can prevent axonal degeneration and can restore function. Cell population studies have recently identified novel immunomodulatory functions of oligodendrocytes, the implications of which, e.g., for diseases with primary oligodendrocyte pathology, are not yet clear. Here, we review the journey of oligodendrocytes from the embryonic stage to their role in homeostasis and their fate in disease. We will also discuss the most common models used to study oligodendrocytes and describe newly discovered functions of oligodendrocytes.
Topics: Alzheimer Disease; Animals; Humans; Multiple Sclerosis; Myelin Sheath; Oligodendrocyte Precursor Cells; Oligodendroglia; Remyelination; Schizophrenia
PubMed: 31726662
DOI: 10.3390/cells8111424 -
Nature Jan 2023Myelin is required for the function of neuronal axons in the central nervous system, but the mechanisms that support myelin health are unclear. Although macrophages in...
Myelin is required for the function of neuronal axons in the central nervous system, but the mechanisms that support myelin health are unclear. Although macrophages in the central nervous system have been implicated in myelin health, it is unknown which macrophage populations are involved and which aspects they influence. Here we show that resident microglia are crucial for the maintenance of myelin health in adulthood in both mice and humans. We demonstrate that microglia are dispensable for developmental myelin ensheathment. However, they are required for subsequent regulation of myelin growth and associated cognitive function, and for preservation of myelin integrity by preventing its degeneration. We show that loss of myelin health due to the absence of microglia is associated with the appearance of a myelinating oligodendrocyte state with altered lipid metabolism. Moreover, this mechanism is regulated through disruption of the TGFβ1-TGFβR1 axis. Our findings highlight microglia as promising therapeutic targets for conditions in which myelin growth and integrity are dysregulated, such as in ageing and neurodegenerative disease.
Topics: Adult; Animals; Humans; Mice; Axons; Central Nervous System; Microglia; Myelin Sheath; Neurodegenerative Diseases; Oligodendroglia; Cognition; Transforming Growth Factor beta1; Receptor, Transforming Growth Factor-beta Type I; Lipid Metabolism; Aging
PubMed: 36517604
DOI: 10.1038/s41586-022-05534-y -
Molecular Psychiatry Jan 2021Depression is a common mental illness, affecting more than 300 million people worldwide. Decades of investigation have yielded symptomatic therapies for this disabling... (Review)
Review
Depression is a common mental illness, affecting more than 300 million people worldwide. Decades of investigation have yielded symptomatic therapies for this disabling condition but have not led to a consensus about its pathogenesis. There are data to support several different theories of causation, including the monoamine hypothesis, hypothalamic-pituitary-adrenal axis changes, inflammation and immune system alterations, abnormalities of neurogenesis and a conducive environmental milieu. Research in these areas and others has greatly advanced the current understanding of depression; however, there are other, less widely known theories of pathogenesis. Oligodendrocyte lineage cells, including oligodendrocyte progenitor cells and mature oligodendrocytes, have numerous important functions, which include forming myelin sheaths that enwrap central nervous system axons, supporting axons metabolically, and mediating certain forms of neuroplasticity. These specialized glial cells have been implicated in psychiatric disorders such as depression. In this review, we summarize recent findings that shed light on how oligodendrocyte lineage cells might participate in the pathogenesis of depression, and we discuss new approaches for targeting these cells as a novel strategy to treat depression.
Topics: Cell Lineage; Depression; Humans; Myelin Sheath; Oligodendroglia
PubMed: 33144710
DOI: 10.1038/s41380-020-00930-0 -
Nature Reviews. Neuroscience Dec 2020Throughout our lifespan, new sensory experiences and learning continually shape our neuronal circuits to form new memories. Plasticity at the level of synapses has been... (Review)
Review
Throughout our lifespan, new sensory experiences and learning continually shape our neuronal circuits to form new memories. Plasticity at the level of synapses has been recognized and studied for decades, but recent work has revealed an additional form of plasticity - affecting oligodendrocytes and the myelin sheaths they produce - that plays a crucial role in learning and memory. In this Review, we summarize recent work characterizing plasticity in the oligodendrocyte lineage following sensory experience and learning, the physiological and behavioural consequences of manipulating that plasticity, and the evidence for oligodendrocyte and myelin dysfunction in neurodevelopmental disorders with cognitive symptoms. We also discuss the limitations of existing approaches and the conceptual and technical advances that are needed to move forward this rapidly developing field.
Topics: Animals; Demyelinating Diseases; Humans; Learning; Memory; Myelin Sheath; Neuronal Plasticity; Oligodendroglia; Synapses
PubMed: 33046886
DOI: 10.1038/s41583-020-00379-8 -
Neuron Nov 2022Remyelination, the myelin regenerative response that follows demyelination, restores saltatory conduction and function and sustains axon health. Its declining efficiency... (Review)
Review
Remyelination, the myelin regenerative response that follows demyelination, restores saltatory conduction and function and sustains axon health. Its declining efficiency with disease progression in the chronic autoimmune disease multiple sclerosis (MS) contributes to the currently untreatable progressive phase of the disease. Although some of the bona fide myelin regenerative medicine clinical trials have succeeded in demonstrating proof-of-principle, none of these compounds have yet proceeded toward approval. There therefore remains a need to increase our understanding of the fundamental biology of remyelination so that existing targets can be refined and new ones discovered. Here, we review the role of inflammation, in particular innate immunity, in remyelination, describing its many and complex facets and discussing how our evolving understanding can be harnessed to translational goals.
Topics: Humans; Remyelination; Oligodendroglia; Myelin Sheath; Multiple Sclerosis; Inflammation
PubMed: 36228613
DOI: 10.1016/j.neuron.2022.09.023 -
Neuron Jan 2023Oligodendrocyte precursor cells (OPCs) undergo an extensive and coordinated migration in the developing CNS, using the pre-formed scaffold of developed blood vessels as...
Oligodendrocyte precursor cells (OPCs) undergo an extensive and coordinated migration in the developing CNS, using the pre-formed scaffold of developed blood vessels as their physical substrate for migration. While OPC association with vasculature is critical for dispersal, equally important for permitting differentiation and proper myelination of target axons is their appropriate and timely detachment, but regulation of this process remains unclear. Here we demonstrate a correlation between the developmental formation of astrocytic endfeet on vessels and the termination of OPC perivascular migration. Ex vivo and in vivo live imaging shows that astrocyte endfeet physically displace OPCs from vasculature, and genetic abrogation of endfoot formation hinders both OPC detachment from vessels and subsequent differentiation. Astrocyte-derived semaphorins 3a and 6a act to repel OPCs from blood vessels at the cessation of their perivascular migration and, in so doing, permit subsequent OPC differentiation by insulating them from a maturation inhibitory endothelial niche.
Topics: Oligodendrocyte Precursor Cells; Astrocytes; Oligodendroglia; Cell Differentiation; Cell Movement
PubMed: 36384142
DOI: 10.1016/j.neuron.2022.10.032 -
Nature Neuroscience Sep 2020During development, oligodendrocytes contact and wrap neuronal axons with myelin. Similarly to neurons and synapses, excess myelin sheaths are produced and selectively...
During development, oligodendrocytes contact and wrap neuronal axons with myelin. Similarly to neurons and synapses, excess myelin sheaths are produced and selectively eliminated, but how elimination occurs is unknown. Microglia, the resident immune cells of the central nervous system, engulf surplus neurons and synapses. To determine whether microglia also prune myelin sheaths, we used zebrafish to visualize and manipulate interactions between microglia, oligodendrocytes, and neurons during development. We found that microglia closely associate with oligodendrocytes and specifically phagocytose myelin sheaths. By using a combination of optical, genetic, chemogenetic, and behavioral approaches, we reveal that neuronal activity bidirectionally balances microglial association with neuronal cell bodies and myelin phagocytosis in the optic tectum. Furthermore, multiple strategies to deplete microglia resulted in oligodendrocytes maintaining excessive and ectopic myelin. Our work reveals a neuronal activity-regulated role for microglia in modifying developmental myelin targeting by oligodendrocytes.
Topics: Animals; Animals, Genetically Modified; Microglia; Myelin Sheath; Neurogenesis; Neurons; Oligodendroglia; Phagocytosis; Spinal Cord; Superior Colliculi; Zebrafish
PubMed: 32632287
DOI: 10.1038/s41593-020-0654-2 -
The Journal of Clinical Investigation Apr 2022Dysfunction of protein trafficking has been intensively associated with neurological diseases, including neurodegeneration, but whether and how protein transport...
Dysfunction of protein trafficking has been intensively associated with neurological diseases, including neurodegeneration, but whether and how protein transport contributes to oligodendrocyte (OL) maturation and myelin repair in white matter injury remains unclear. ER-to-Golgi trafficking of newly synthesized proteins is mediated by coat protein complex II (COPII). Here, we demonstrate that the COPII component Sec13 was essential for OL differentiation and postnatal myelination. Ablation of Sec13 in the OL lineage prevented OPC differentiation and inhibited myelination and remyelination after demyelinating injury in the central nervous system (CNS), while improving protein trafficking by tauroursodeoxycholic acid (TUDCA) or ectopic expression of COPII components accelerated myelination. COPII components were upregulated in OL lineage cells after demyelinating injury. Loss of Sec13 altered the secretome of OLs and inhibited the secretion of pleiotrophin (PTN), which was found to function as an autocrine factor to promote OL differentiation and myelin repair. These data suggest that Sec13-dependent protein transport is essential for OL differentiation and that Sec13-mediated PTN autocrine signaling is required for proper myelination and remyelination.
Topics: Autocrine Communication; Carrier Proteins; Cell Differentiation; Cytokines; Demyelinating Diseases; Humans; Myelin Sheath; Oligodendroglia
PubMed: 35143418
DOI: 10.1172/JCI155096 -
Cell Death & Disease Mar 2022Oligodendrocyte progenitor cells (OPCs) differentiate to myelin-producing mature oligodendrocytes and enwrap growing or demyelinated axons during development and post...
Oligodendrocyte progenitor cells (OPCs) differentiate to myelin-producing mature oligodendrocytes and enwrap growing or demyelinated axons during development and post central nervous diseases. Failure of remyelination owing to cell death or undifferentiation of OPCs contributes to severe neurologic deficits and motor dysfunction. However, how to prevent the cell death of OPCs is still poorly understood, especially in hemorrhagic diseases. In the current study, we injected autologous blood into the mouse lateral ventricular to study the hemorrhage-induced OPC cell death in vivo. The integrity of the myelin sheath of the corpus callosum was disrupted post intraventricular hemorrhage (IVH) assessed by using magnetic resonance imaging, immunostaining, and transmission electron microscopy. Consistent with the severe demethylation, we observed massive cell death of oligodendrocyte lineages in the periventricular area. In addition, we found that ferroptosis is the major cell death form in Hemin-induced OPC death by using RNA-seq analysis, and the mechanism was glutathione peroxidase 4 activity reduction-resulted lipid peroxide accumulation. Furthermore, inhibition of ferroptosis rescued OPC cell death in vitro, and in vivo attenuated IVH-induced white matter injury and promoted recovery of neurological function. These data demonstrate that ferroptosis is an essential form of OPC cell death in hemorrhagic stroke, and rescuing ferroptotic OPCs could serve as a therapeutic target for stroke and related diseases.
Topics: Animals; Cell Differentiation; Ferroptosis; Hemorrhage; Hemorrhagic Stroke; Mice; Myelin Sheath; Oligodendrocyte Precursor Cells; Oligodendroglia; White Matter
PubMed: 35318305
DOI: 10.1038/s41419-022-04712-0 -
The Journal of Clinical Investigation Jan 2021Oligodendrocytes express low-density lipoprotein receptor (LDLR) to endocytose cholesterol for the maintenance of adulthood myelination. However, the potential role of...
Oligodendrocytes express low-density lipoprotein receptor (LDLR) to endocytose cholesterol for the maintenance of adulthood myelination. However, the potential role of LDLR in chronic cerebral ischemia-related demyelination remains unclear. We used bilateral carotid artery stenosis (BCAS) to induce sustained cerebral ischemia in mice. This hypoxic-ischemic injury caused a remarkable decrease in oligodendroglial LDLR, with impaired oligodendroglial differentiation and survival. Oligodendroglial cholesterol levels, however, remained unchanged. Mouse miR-344e-3p and the human homolog miR-410-3p, 2 miRNAs directly targeting Ldlr, were identified in experimental and clinical leukoaraiosis and were thus implicated in the LDLR reduction. Lentiviral delivery of LDLR ameliorated demyelination following chronic cerebral ischemia. By contrast, Ldlr-/- mice displayed inadequate myelination in the corpus callosum. Ldlr-/- oligodendrocyte progenitor cells (OPCs) exhibited reduced ability to differentiate and myelinate axons in vitro. Transplantation with Ldlr-/- OPCs could not rescue the BCAS-induced demyelination. Such LDLR-dependent myelin restoration might involve a physical interaction of the Asn-Pro-Val-Tyr (NPVY) motif with the phosphotyrosine binding domain of Shc, which subsequently activated the MEK/ERK pathway. Together, our findings demonstrate that the aberrant oligodendroglial LDLR in chronic cerebral ischemia impairs myelination through intracellular signal transduction. Preservation of oligodendroglial LDLR may provide a promising approach to treat ischemic demyelination.
Topics: Animals; Brain Ischemia; Chronic Disease; Corpus Callosum; Demyelinating Diseases; Male; Mice; Mice, Knockout; Oligodendroglia; Receptors, LDL
PubMed: 33141760
DOI: 10.1172/JCI128114