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Trends in Neurosciences Apr 2019Myelin is a multilayer lipid membrane structure that wraps and insulates axons, allowing for the efficient propagation of action potentials. During developmental... (Review)
Review
Myelin is a multilayer lipid membrane structure that wraps and insulates axons, allowing for the efficient propagation of action potentials. During developmental myelination of the central nervous system (CNS), oligodendrocyte progenitor cells (OPCs) proliferate and migrate to their final destination, where they terminally differentiate into mature oligodendrocytes and myelinate axons. Lineage progression and terminal differentiation of oligodendrocyte lineage cells are under tight transcriptional and post-transcriptional control. The characterization of several recently identified regulatory factors that govern these processes, which are the focus of this review, has greatly increased our understanding of oligodendrocyte development and function. These insights are critical to facilitate efforts to enhance OPC differentiation in neurological disorders that disrupt CNS myelin.
Topics: Animals; Cell Differentiation; Humans; Oligodendroglia
PubMed: 30770136
DOI: 10.1016/j.tins.2019.01.002 -
Cold Spring Harbor Perspectives in... Jun 2015Myelinated nerve fibers have evolved to enable fast and efficient transduction of electrical signals in the nervous system. To act as an electric insulator, the myelin... (Review)
Review
Myelinated nerve fibers have evolved to enable fast and efficient transduction of electrical signals in the nervous system. To act as an electric insulator, the myelin sheath is formed as a multilamellar membrane structure by the spiral wrapping and subsequent compaction of the oligodendroglial plasma membrane around central nervous system (CNS) axons. Current evidence indicates that the myelin sheath is more than an inert insulating membrane structure. Oligodendrocytes are metabolically active and functionally connected to the subjacent axon via cytoplasmic-rich myelinic channels for movement of macromolecules to and from the internodal periaxonal space under the myelin sheath. This review summarizes our current understanding of how myelin is generated and also the role of oligodendrocytes in supporting the long-term integrity of myelinated axons.
Topics: Axons; Glycolysis; Models, Biological; Myelin Sheath; Oligodendroglia; Synaptic Transmission
PubMed: 26101081
DOI: 10.1101/cshperspect.a020479 -
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 -
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 -
Nature Neuroscience Mar 2019Investigating human oligodendrogenesis and the interaction of oligodendrocytes with neurons and astrocytes would accelerate our understanding of the mechanisms...
Investigating human oligodendrogenesis and the interaction of oligodendrocytes with neurons and astrocytes would accelerate our understanding of the mechanisms underlying white matter disorders. However, this is challenging because of the limited accessibility of functional human brain tissue. Here, we developed a new differentiation method of human induced pluripotent stem cells to generate three-dimensional brain organoids that contain oligodendrocytes as well as neurons and astrocytes, called human oligodendrocyte spheroids. We found that oligodendrocyte lineage cells derived in human oligodendrocyte spheroids transitioned through developmental stages similar to primary human oligodendrocytes and that the migration of oligodendrocyte lineage cells and their susceptibility to lysolecithin exposure could be captured by live imaging. Moreover, their morphology changed as they matured over time in vitro and started myelinating neurons. We anticipate that this method can be used to study oligodendrocyte development, myelination, and interactions with other major cell types in the CNS.
Topics: Astrocytes; Cell Culture Techniques; Cell Differentiation; Cell Line; Cell Lineage; Humans; Induced Pluripotent Stem Cells; Neurons; Oligodendroglia; Spheroids, Cellular; Transcriptome
PubMed: 30692691
DOI: 10.1038/s41593-018-0316-9 -
Nature Feb 2019Oligodendrocytes wrap nerve fibres in the central nervous system with layers of specialized cell membrane to form myelin sheaths. Myelin is destroyed by the immune...
Oligodendrocytes wrap nerve fibres in the central nervous system with layers of specialized cell membrane to form myelin sheaths. Myelin is destroyed by the immune system in multiple sclerosis, but myelin is thought to regenerate and neurological function can be recovered. In animal models of demyelinating disease, myelin is regenerated by newly generated oligodendrocytes, and remaining mature oligodendrocytes do not seem to contribute to this process. Given the major differences in the dynamics of oligodendrocyte generation and adaptive myelination between rodents and humans, it is not clear how well experimental animal models reflect the situation in multiple sclerosis. Here, by measuring the integration of C derived from nuclear testing in genomic DNA, we assess the dynamics of oligodendrocyte generation in patients with multiple sclerosis. The generation of new oligodendrocytes was increased several-fold in normal-appearing white matter in a subset of individuals with very aggressive multiple sclerosis, but not in most subjects with the disease, demonstrating an inherent potential to substantially increase oligodendrocyte generation that fails in most patients. Oligodendrocytes in shadow plaques-thinly myelinated lesions that are thought to represent remyelinated areas-were old in patients with multiple sclerosis. The absence of new oligodendrocytes in shadow plaques suggests that remyelination of lesions occurs transiently or not at all, or that myelin is regenerated by pre-existing, and not new, oligodendrocytes in multiple sclerosis. We report unexpected oligodendrocyte generation dynamics in multiple sclerosis, and this should guide the use of current, and the development of new, therapies.
Topics: Adult; Age of Onset; Aging; Case-Control Studies; Cell Differentiation; Cell Proliferation; Cell Separation; Female; Humans; Male; Multiple Sclerosis; Myelin Sheath; Oligodendroglia; Remyelination; White Matter
PubMed: 30675058
DOI: 10.1038/s41586-018-0842-3 -
Science (New York, N.Y.) Oct 2014Myelin-forming oligodendrocytes (OLs) are formed continuously in the healthy adult brain. In this work, we study the function of these late-forming cells and the myelin...
Myelin-forming oligodendrocytes (OLs) are formed continuously in the healthy adult brain. In this work, we study the function of these late-forming cells and the myelin they produce. Learning a new motor skill (such as juggling) alters the structure of the brain's white matter, which contains many OLs, suggesting that late-born OLs might contribute to motor learning. Consistent with this idea, we show that production of newly formed OLs is briefly accelerated in mice that learn a new skill (running on a "complex wheel" with irregularly spaced rungs). By genetically manipulating the transcription factor myelin regulatory factor in OL precursors, we blocked production of new OLs during adulthood without affecting preexisting OLs or myelin. This prevented the mice from mastering the complex wheel. Thus, generation of new OLs and myelin is important for learning motor skills.
Topics: Animals; Brain; Cell Proliferation; Gene Deletion; Humans; Learning; Male; Mental Recall; Mice; Mice, Transgenic; Motor Skills; Myelin Sheath; Oligodendroglia; Synaptic Transmission; Transcription Factors
PubMed: 25324381
DOI: 10.1126/science.1254960 -
Nature Biotechnology Apr 2021Human pluripotent stem cells (hPSCs) offer an unprecedented opportunity to model diverse cell types and tissues. To enable systematic exploration of the programming...
Human pluripotent stem cells (hPSCs) offer an unprecedented opportunity to model diverse cell types and tissues. To enable systematic exploration of the programming landscape mediated by transcription factors (TFs), we present the Human TFome, a comprehensive library containing 1,564 TF genes and 1,732 TF splice isoforms. By screening the library in three hPSC lines, we discovered 290 TFs, including 241 that were previously unreported, that induce differentiation in 4 days without alteration of external soluble or biomechanical cues. We used four of the hits to program hPSCs into neurons, fibroblasts, oligodendrocytes and vascular endothelial-like cells that have molecular and functional similarity to primary cells. Our cell-autonomous approach enabled parallel programming of hPSCs into multiple cell types simultaneously. We also demonstrated orthogonal programming by including oligodendrocyte-inducible hPSCs with unmodified hPSCs to generate cerebral organoids, which expedited in situ myelination. Large-scale combinatorial screening of the Human TFome will complement other strategies for cell engineering based on developmental biology and computational systems biology.
Topics: Alternative Splicing; Cell Differentiation; Cell Engineering; Cells, Cultured; Cellular Reprogramming Techniques; Coculture Techniques; Humans; Oligodendroglia; Pluripotent Stem Cells; Systems Biology; Transcription Factors
PubMed: 33257861
DOI: 10.1038/s41587-020-0742-6 -
CNS Neuroscience & Therapeutics Oct 2019Intracerebral hemorrhage (ICH) is a cerebrovascular disorder with high mortality and disability rates. Although a lot of effort has been put in ICH, there is still no... (Review)
Review
Intracerebral hemorrhage (ICH) is a cerebrovascular disorder with high mortality and disability rates. Although a lot of effort has been put in ICH, there is still no effective treatment for this devastating disease. Recent studies suggest that oligodendrocytes play an important role in brain repair after ICH and thus may be targeted for the therapies of ICH. Here in this review, we first introduce the origin, migration, proliferation, differentiation, and myelination of oligodendrocytes under physiological condition. Second, recent findings on how ICH affects oligodendrocyte biology and function are reviewed. Third, potential crosstalk between oligodendrocytes and other cells in the brain is also summarized. Last, we discuss the therapeutic potential of oligodendrocyte-based treatments in ICH. Our goal is to provide a comprehensive review on the biology and function of oligodendrocytes under both physiological and ICH conditions.
Topics: Brain; Cell Differentiation; Cell Movement; Cerebral Hemorrhage; Humans; Oligodendroglia
PubMed: 31410988
DOI: 10.1111/cns.13193 -
Molecular Neurobiology Jul 2016Oligodendrocytes, the myelinating cells of the central nervous system, mediate rapid action potential conduction and provide trophic support for axonal as well as... (Review)
Review
Oligodendrocytes, the myelinating cells of the central nervous system, mediate rapid action potential conduction and provide trophic support for axonal as well as neuronal maintenance. Their progenitor cell population is widely distributed in the adult brain and represents a permanent cellular reservoir for oligodendrocyte replacement and myelin plasticity. The recognition of oligodendrocytes, their progeny, and myelin as contributing factors for the pathogenesis and the progression of neurodegenerative disease has recently evolved shaping our understanding of these disorders. In the present review, we aim to highlight studies on oligodendrocytes and their progenitors in neurodegenerative diseases. We dissect oligodendroglial biology and illustrate evolutionary aspects in regard to their importance for neuronal functionality and maintenance of neuronal circuitries. After covering recent studies on oligodendroglia in different neurodegenerative diseases mainly in view of their function as myelinating cells, we focus on the alpha-synucleinopathy multiple system atrophy, a prototypical disorder with a well-defined oligodendroglial pathology.
Topics: Animals; Biological Evolution; Humans; Myelin Sheath; Neurodegenerative Diseases; Oligodendroglia
PubMed: 25966971
DOI: 10.1007/s12035-015-9205-3