Disruption of the blood-brain barrier (BBB) is critical to initiation and perpetuation of disease in multiple sclerosis (MS). We report an interaction between oligodendroglia and vasculature in MS ...that distinguishes human white matter injury from normal rodent demyelinating injury. We find perivascular clustering of oligodendrocyte precursor cells (OPCs) in certain active MS lesions, representing an inability to properly detach from vessels following perivascular migration. Perivascular OPCs can themselves disrupt the BBB, interfering with astrocyte endfeet and endothelial tight junction integrity, resulting in altered vascular permeability and an associated CNS inflammation. Aberrant Wnt tone in OPCs mediates their dysfunctional vascular detachment and also leads to OPC secretion of Wif1, which interferes with Wnt ligand function on endothelial tight junction integrity. Evidence for this defective oligodendroglial-vascular interaction in MS suggests that aberrant OPC perivascular migration not only impairs their lesion recruitment but can also act as a disease perpetuator via disruption of the BBB.
Aging affects almost all the aspects of brain functions, but the mechanisms remain largely undefined. Increasing number of literatures have manifested the important role of glial cells in regulating ...the aging process. Oligodendroglial lineage cell is a major type of glia in central nervous system (CNS), composed of mature oligodendrocytes (OLs), and oligodendroglia precursor cells (OPCs). OLs produce myelin sheaths that insulate axons and provide metabolic support to meet the energy demand. OPCs maintain the population throughout lifetime with the abilities to proliferate and differentiate into OLs. Increasing evidence has shown that oligodendroglial cells display active dynamics in adult and aging CNS, which is extensively involved in age-related brain function decline in the elderly. In this review, we summarized present knowledge about dynamic changes of oligodendroglial lineage cells during normal aging and discussed their potential roles in age-related functional decline. Especially, focused on declined myelinogenesis during aging and underlying mechanisms. Clarifying those oligodendroglial changes and their effects on neurofunctional decline may provide new insights in understanding aging associated brain function declines.
Oligodendrocyte precursor cells (OPCs) undergo a series of energy-consuming developmental events; however, the uptake and trafficking pathways for their energy metabolites remain unknown. In the ...present study, we found that 2-NBDG, a fluorescent glucose analog, can be delivered between astrocytes and oligodendrocytes through connexin-based gap junction channels but cannot be transferred between astrocytes and OPCs. Instead, connexin hemichannel-mediated glucose uptake supports OPC proliferation, and ethidium bromide uptake or increase of 2-NBDG uptake rate is correlated with intracellular Ca(2+) elevation in OPCs, indicating a Ca(2+)-dependent activation of connexin hemichannels. Interestingly, deletion of connexin 43 (Cx43, also known as GJA1) in astrocytes inhibits OPC proliferation by decreasing matrix glucose levels without impacting on OPC hemichannel properties, a process that also occurs in corpus callosum from acute brain slices. Thus, dual functions of connexin-based channels contribute to glucose supply in oligodendroglial lineage, which might pave a new way for energy-metabolism-directed oligodendroglial-targeted therapies.
Autism spectrum disorder (ASD) is the most commonly diagnosed neurodevelopmental disorder. Independent of neuronal dysfunction, ASD and its associated comorbidities have been linked to ...hypomyelination and oligodendroglial dysfunction. Additionally, the neuromodulator adenosine has been shown to affect certain ASD comorbidities and symptoms, such as epilepsy, impairment of cognitive function, and anxiety. Adenosine is both directly and indirectly responsible for regulating the development of oligodendroglia and myelination through its interaction with, and modulation of, several neurotransmitters, including glutamate, dopamine, and serotonin. In this review, we will focus on the recent discoveries in adenosine interaction with physiological and pathophysiological activities of oligodendroglia and myelination, as well as ASD-related aspects of adenosine actions on neuroprotection and neuroinflammation. Moreover, we will discuss the potential therapeutic value and clinical approaches of adenosine manipulation against hypomyelination in ASD.
By using keywords crawled by big data as a survey reference, this research applied latent category clustering method and binary logistic regression model analysis method to analyze the differences in ...community group buying behaviors of residents from different city scale and summarize the shopping behavior and features of different types of residents, for the purpose of offering advice on different marketing methods for different types of urban residents, so as to realize the precise marketing of community e-commerce and promote the further development of the industry.
As one of the top causes of blindness worldwide, glaucoma leads to diverse optic neuropathies such as degeneration of retinal ganglion cells (RGCs). It is widely accepted that the level of ...intraocular pressure (IOP) is a major risk factor in human glaucoma, and reduction of IOP level is the principally most well-known method to prevent cell death of RGCs. However, clinical studies show that lowering IOP fails to prevent RGC degeneration in the progression of glaucoma. Thus, a comprehensive understanding of glaucoma pathological process is required for developing new therapeutic strategies. In this study, we provide functional and histological evidence showing that optic nerve defects occurred before retina damage in an ocular hypertension glaucoma mouse model, in which oligodendroglial lineage cells were responsible for the subsequent neuropathology. By treatment with clemastine, an Food and Drug Administration (FDA)-approved first-generation antihistamine medicine, we demonstrate that the optic nerve and retina damages were attenuated via promoting oligodendrocyte precursor cell (OPC) differentiation and enhancing remyelination. Taken together, our results reveal the timeline of the optic neuropathies in glaucoma and highlight the potential role of oligodendroglial lineage cells playing in its treatment. Clemastine may be used in future clinical applications for demyelination-associated glaucoma.
Oligodendroglial Development Huang, Nanxin; Niu, Jianqin; Feng, Yue ...
The Neuroscientist (Baltimore, Md.),
12/2015, Letnik:
21, Številka:
6
Journal Article
Recenzirano
In the central nervous system, the generation of mature oligodendrocytes from their progenitors is a critical step in myelination, which is essential for normal nervous system function. Thus, ...understanding the regulatory mechanism underlying oligodendroglial development is of great importance, especially for the development of new therapeutic strategies that promote remyelination in demyelinating diseases, such as multiple sclerosis. Previous studies have focused on genetic patterns and revealed a network of cell signaling pathways and related transcription factors involved in oligodendroglial lineage development. Recently, epigenetic regulation, which refers to regulation of gene expression by adjusting the environment of the genes has been shown to play a profound role during oligodendroglial development. In this review, we summarize the recent data demonstrating the effects of chromatin modification and remodeling in regulating oligodendroglial development and discuss the use of high-throughput analysis and bio-informatics in future studies.
Myelinating glial cells (MGCs), oligodendrocytes (OLs) in the central nervous system (CNS) and Schwann cells (SCs) in the peripheral nervous system (PNS), generate myelin sheaths that insulate axons. ...After myelination is completed in adulthood, MGC functions independent from myelin are required to support axon survival, but the underlying mechanisms are still unclear. Dicer is a key enzyme that is responsible for generating functional micro‐RNAs (miRNAs). Despite the importance of Dicer in initiating myelination, the role of Dicer in mature MGCs is still unclear. Here, Dicer was specifically deleted in mature MGCs in 2‐month old mice (PLP‐CreERT; Dicer fl/fl) by tamoxifen administration. Progressive motor dysfunction was observed in the Dicer conditional knockout mice, which displayed hind limb ataxia at 3 months post recombination that deteriorated into paralysis within 5 months. Massive axonal degeneration/atrophy in peripheral nerves was responsible for this phenomenon, but overt demyelination was not observed in either the CNS or PNS. In contrast to the PNS, signs of axonal degeneration were not observed in the CNS of these animals. We induced a Dicer deletion in oligodendroglia at postnatal day 5 in NG2‐CreERT; Dicer fl/fl mice to evaluate whether Dicer expression in OLs is essential for axonal survival. Dicer deletion in oligodendroglia did not cause motor dysfunction at the age of 7 months. Neither axonal atrophy nor demyelination was observed in the CNS. Based on our results, Dicer expression in SCs is required to maintain axon integrity in adult PNS, and Dicer is dispensable for maintaining myelin sheaths in MGCs.
Main Points
Dicer deletion in mature myelinating glial cells induces late and progressive motor dysfunction in adult mice.
Dicer functions in Schwann Cells are essentially required for maintaining axon integrity but dispensable for maintaining myelin sheaths.
Oligodendrocyte (OL) and myelin development are crucial for network integration and are associated with higher brain functions. Accumulating evidence has demonstrated structural and functional ...impairment of OLs and myelin in serious mental illnesses. However, whether these deficits contribute to the brain dysfunction or pathogenesis of such diseases still lacks direct evidence. In this study, we conditionally deleted
Olig2
in oligodendroglial lineage cells (
Olig2
cKO) and screened the behavioral changes in adult mice. We found that
Olig2
ablation impaired myelin development, which further resulted in severe hypomyelination in the anterior cingulate cortex. Strikingly,
Olig2
cKO mice exhibited an anxious phenotype, aberrant responses to stress, and cognitive deficits. Moreover,
Olig2
cKO mice showed increased vulnerability to social avoidance under the mild stress of social isolation. Together, these results indicate that developmental deficits in OL and myelin lead to cognitive impairment and increase the risk of phenotypes reminiscent of mental illnesses.
As a major contributor of chemotherapy resistance and malignant recurrence, glioma stem cells (GSCs) have been proposed as a target for the treatment of gliomas. To evaluate the therapeutic potential ...of quetiapine (QUE), an atypical antipsychotic, for the treatment of malignant glioma, we established mouse models with GSCs-initiated orthotopic xenograft gliomas and subcutaneous xenograft tumors, using GSCs purified from glioblastoma cell line GL261. We investigated antitumor effects of QUE on xenograft gliomas and its underlying mechanisms on GSCs. Our data demonstrated that (i) QUE monotherapy can effectively suppress GSCs-initiated tumor growth; (ii) QUE has synergistic effects with temozolomide (TMZ) on glioma suppression, and importantly, QUE can effectively suppress TMZ-resistant (or -escaped) tumors generated from GSCs; (iii) mechanistically, the anti-glioma effect of QUE was due to its actions of promoting the differentiation of GSCs into oligodendrocyte (OL)-like cells and its inhibitory effect on the Wnt/β-catenin signaling pathway. Together, our findings suggest an effective approach for anti-gliomagenic treatment via targeting OL-oriented differentiation of GSCs. This also opens a door for repurposing QUE, an FDA approved drug, for the treatment of malignant glioma.
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