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.
Astrocyte maldevelopment is implicated in various neuropsychiatric diseases associated with early life stress. However, the underlying astrocytopathy mechanism, which can result in the psychiatric ...symptoms, remains unclear. In this study, it is shown that a reduced oligodendrocyte precursor cell (OPC) population accompanies hindered hippocampal astrocytic development in an improved parental isolation mouse model, and that the loss of OPCs suppresses astrocytic network formation and activity. It is further demonstrated that OPC‐derived Wnt ligands, in particular Wnt7b, are required for Wnt/β‐catenin pathway‐mediated astrocytic development and subsequent effects related to neuronal function. In addition, focal replenishment of Wnt7a/b is sufficient to rescue astrocytic maldevelopment. These results elucidate a Wnt‐paracrine‐dependent but myelin‐independent role of OPCs in regulating astrocytic development, which provides a unique insight into the astrocytopathy mechanism in early life stress, and can be implicated in the pathogenesis of human early life stress‐related neuropsychiatric disorders.
Astrocyte maldevelopment, including defective astrocytic network formation, is implicated in neuropsychiatric diseases induced by early life stress. It is shown that reduced oligodendrocyte precursor cell (OPC) number occurred in early life stress causes astrocyte maldevelopment through decreased level of OPC‐derived Wnt ligands, which subsequently elicits neuronal dysfunction and neuropsychiatric symptoms.
Epigenetic alterations and impaired oligodendroglial myelination in the prefrontal cortex have been shown to correlate with behavioral and cognitive dysfunctions in social deprivation. Our previous ...study demonstrated that quetiapine, an atypical antipsychotic, could promote oligodendroglial differentiation and myelination. However, whether and how quetiapine could be beneficial in modulating aberrant epigenetic alterations in oligodendroglial cells and relieving behavioral alterations from social isolation is unknown. In this study, quetiapine was orally administered in adolescent mice undergoing mild stress of social isolation. We firstly confirmed that social isolation during a novel adolescent period could impair sociability, but not locomotive behaviors in mice. Moreover, quetiapine alleviated myelin deficits, and increased levels of histone methylation (H3K9me3) in mature oligodendroglia in the prefrontal cortex of socially isolated mice. Strikingly, quetiapine treatment significantly increased locomotive activity, and successfully reversed social avoidance behavior of the socially isolated mice. Taken together, our data suggest that quetiapine may rescue behavioral changes from social isolation through modulating epigenetic status toward the beneficial direction for oligodendroglial maturation, providing new insights into the pharmacological mechanism of quetiapine for mental illnesses.
Astrocytes (ASTs) and oligodendroglial lineage cells (OLGs) are major macroglial cells in the central nervous system. ASTs communicate with each other through connexin (Cx) and Cx-based network ...structures, both of which allow for quick transport of nutrients and signals. Moreover, ASTs interact with OLGs through connexin (Cx)-mediated networks to modulate various physiological processes in the brain. In this article, following a brief description of the infrastructural basis of the glial networks and exocrine factors by which ASTs and OLGs may crosstalk, we focus on recapitulating how the interactions between these two types of glial cells modulate myelination, and how the AST-OLG interactions are involved in protecting the integrity of the blood-brain barrier (BBB) and regulating synaptogenesis and neural activity. Recent studies further suggest that AST-OLG interactions are associated with myelin-related diseases, such as multiple sclerosis. A better understanding of the regulatory mechanisms underlying AST-OLG interactions may inspire the development of novel therapeutic strategies for related brain diseases.
Although the link of white matter to pathophysiology of schizophrenia is documented, loss of myelin is not detected in patients at the early stages of the disease, suggesting that pathological ...evolution of schizophrenia may occur before significant myelin loss. Disrupted-in-schizophrenia-1 (DISC1) protein is highly expressed in oligodendrocyte precursor cells (OPCs) and regulates their maturation. Recently, DISC1-Δ3, a major DISC1 variant that lacks exon 3, has been identified in schizophrenia patients, although its pathological significance remains unknown. In this study, we detected in schizophrenia patients a previously unidentified pathological phenotype of OPCs exhibiting excessive branching. We replicated this phenotype by generating a mouse strain expressing DISC1-Δ3 gene in OPCs. We further demonstrated that pathological OPCs, rather than myelin defects, drive the onset of schizophrenic phenotype by hyperactivating OPCs' Wnt/β-catenin pathway, which consequently upregulates Wnt Inhibitory Factor 1 (Wif1), leading to the aberrant synaptic formation and neuronal activity. Suppressing Wif1 in OPCs rescues synaptic loss and behavioral disorders in DISC1-Δ3 mice. Our findings reveal the pathogenetic role of OPC-specific DISC1-Δ3 variant in the onset of schizophrenia and highlight the therapeutic potential of Wif1 as an alternative target for the treatment of this disease.
Oligodendrocyte (OL) maturation arrest in human white matter injury contributes significantly to the failure of endogenous remyelination in multiple sclerosis (MS) and newborn brain injuries such as ...hypoxic ischemic encephalopathy (HIE) that cause cerebral palsy. In this study, we identify an oligodendroglial-intrinsic factor that controls OL maturation specifically in the setting of injury. We find a requirement for the ring finger protein Rnf43 not in normal development but in neonatal hypoxic injury and remyelination in the adult mammalian CNS. Rnf43, but not the related Znrf3, is potently activated by Wnt signaling in OL progenitor cells (OPCs) and marks activated OPCs in human MS and HIE. Rnf43 is required in an injury-specific context, and it promotes OPC differentiation through negative regulation of Wnt signal strength in OPCs at the level of Fzd1 receptor presentation on the cell surface. Inhibition of Fzd1 using UM206 promotes remyelination following ex vivo and in vivo demyelinating injury.
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•RNF43 marks activated OPCs in human white matter injury•Rnf43 is required for OPC differentiation in injury, not in development•Rnf43 inhibits the Wnt pathway by regulating Fzd1 surface presentation on OPCs•Pharmacological inhibition of Fzd1 promotes OPC differentiation during remyelination
Niu et al. identify a factor, Rnf43, that marks activated oligodendrocyte progenitor cells (OPCs) in human white matter injury, which is required in an injury-specific context for their maturation and successful remyelination, and acts by regulating Wnt signal strength at the level of OPC surface presentation of the Wnt receptor Fzd1.
Oligodendroglial lineage cells go through a series of morphological changes before myelination. Prior to myelination, cell processes and membrane structures enlarge by approximately 7,000 times, ...which is required to support axonal wrapping and myelin segment formation. Failure of these processes leads to maldevelopment and impaired myelination. Quetiapine, an atypical antipsychotic drug, was proved to promote oligodendroglial differentiation and (re)myelination, pending detailed effects and regulatory mechanism. In this study, we showed that quetiapine promotes morphological maturation of oligodendroglial lineage cells and myelin segment formation, and a short‐term quetiapine treatment is sufficient to induce these changes. To uncover the underlying mechanism, we examined the effect of quetiapine on the Oligodendrocyte transcription factor 1 (Olig1). We found that quetiapine upregulates Olig1 expression level and promotes nuclear Olig1 translocation to the cytosol, where it functions not as a transcription modulator, but in a way that highly correlates with oligodendrocyte morphological transformation. In addition, quetiapine treatment reverses the negative regulatory effect of the Olig1‐regulated G protein‐coupled receptor 17 (GPR17) on oligodendroglial morphological maturation. Our results demonstrate that quetiapine enhances oligodendroglial differentiation and myelination by promoting cell morphological transformation. This would shed light on the orchestration of oligodendroglia developmental mechanisms, and provides new targets for further therapeutic research.
Main Points
QUE promotes morphological maturation of oligodendroglia in vivo and in vitro.
QUE upregulates Olig1 expression level and prompts its nuclear–cytoplasmic translocation.
QUE prevents over‐expressed GPR17 from negatively regulating oligodendroglial morphological maturation.
As the most abundant gap junction protein in the central nervous system (CNS), astrocytic connexin 43 (Cx43) maintains astrocyte network homeostasis, affects oligodendroglial development and ...participates in CNS pathologies as well as injury progression. However, its role in remyelination is not yet fully understood. To address this issue, we used astrocyte‐specific Cx43 conditional knockout (Cx43 cKO) mice generated through the use of a hGFAP‐cre promoter, in combination with mice carrying a floxed Cx43 allele that were subjected to lysolecithin so as to induce demyelination. We found no significant difference in the demyelination of the corpus callosum between Cx43 cKO mice and their non‐cre littermate controls, while the remyelination process in Cx43 cKO mice was accelerated. Moreover, an increased number of mature oligodendrocytes and an unaltered number of oligodendroglial lineage cells were found in Cx43 cKO mouse lesions. This indicates that oligodendrocyte precursor cell (OPC) differentiation was facilitated by astroglial Cx43 depletion as remyelination progressed. Underlying the latter, there was a down‐regulated glial activation and modulated local inflammation as well as a reduction of myelin debris in Cx43 cKO mice. Importantly, 2 weeks of orally administrating boldine, a natural alkaloid that blocks Cx hemichannel activity in astrocytes without affecting gap junctional communication, obviously modulated local inflammation and promoted remyelination. Together, the data suggest that the astrocytic Cx43 hemichannel is negatively involved in the remyelination process by favoring local inflammation. Consequently, inhibiting Cx43 hemichannel functionality may be a potential therapeutic approach for demyelinating diseases in the CNS.
Connexin 43 deletion in astrocytes accelerates OPC differentiation and remyelination in a mouse model of lysolecithin‐induced demyelination.
During remyelination, astrocytic Cx43 deletion modulates local inflammation and reduces myelin debris.
Chronic treatment with the natural compound boldine, a selective antagonist for connexin hemichannels, modulates local inflammation and favors remyelination.
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.
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•Astrocyte endfoot placement terminates developmental OPC perivascular migration•Astrocyte-derived semaphorins 3a and 6a act to repel OPCs from blood vessels•OPC detachment from endothelium permits their subsequent differentiation
Su et al. find that the developmental placement of astrocyte endfeet on vessels controls the termination of widespread OPC perivascular migration. Astrocytes produce semaphorins 3a and 6a, which repel OPCs from the vasculature and permit their subsequent differentiation by releasing them from a maturation inhibitory endothelial niche.
Background and objective: Plasma concentrations of brain natriuretic peptide (BNP) are elevated in patients with chronic obstructive pulmonary disease (COPD), and high plasma BNP levels are ...associated with a poor prognosis. We aimed to evaluate the effects of a diuretic and a vasodilator on plasma BNP levels and health‐related quality of life (HRQOL) in patients with acute exacerbations of COPD (AECOPD).
Methods: Forty patients with an AECOPD and high plasma BNP levels, but without any clinical evidence of cor pulmonale, were selected. The patients were randomly divided into two groups of 20 patients. In addition to standard treatment for AECOPD, the patients in group I were treated with a mild diuretic, and those in group II were treated with the diuretic and a vasodilator. Twenty patients with stable COPD were selected as a control group. Plasma BNP concentrations were measured on admission and on the third and sixth days. The patients' HRQOL was evaluated using the short‐form 36‐item (SF‐36) questionnaire before and after treatment.
Results: Plasma BNP concentrations in patients with AECOPD were significantly decreased after treatment, and this decrease was more striking in group II than in group I. There were no significant differences in SF‐36 domain scores between patients with stable COPD and those with acute exacerbations who were treated with a diuretic and a vasodilator.
Conclusions: Plasma BNP levels decreased rapidly in patients with an AECOPD after therapy with a diuretic and a vasodilator, and the treatment did not impair their health status.
Plasma brain natriuretic peptide levels decreased rapidly in patients with acute exacerbations of chronic obstructive pulmonary disease after intravenous therapy with a diuretic and a vasodilator, and the treatment did not impair the health status of these patients.
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