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.
Oligodendrocytes myelinate axons in the central nervous system and develop from oligodndrocyte precursor cells (OPCs) that must first migrate extensively during brain and spinal cord development. We ...show that OPCs require the vasculature as a physical substrate for migration. We observed that OPCs of the embryonic mouse brain and spinal cord, as well as the human cortex, emerge from progenitor domains and associate with the abluminal endothelial surface of nearby blood vessels. Migrating OPCs crawl along and jump between vessels. OPC migration in vivo was disrupted in mice with defective vascular architecture but was normal in mice lacking pericytes. Thus, physical interactions with the vascular endothelium are required for OPC migration. We identify Wnt-Cxcr4 (chemokine receptor 4) signaling in regulation of OPC-endothelial interactions and propose that this signaling coordinates OPC migration with differentiation.
Functional screening for compounds that promote remyelination represents a major hurdle in the development of rational therapeutics for multiple sclerosis. Screening for remyelination is problematic, ...as myelination requires the presence of axons. Standard methods do not resolve cell-autonomous effects and are not suited for high-throughput formats. Here we describe a binary indicant for myelination using micropillar arrays (BIMA). Engineered with conical dimensions, micropillars permit resolution of the extent and length of membrane wrapping from a single two-dimensional image. Confocal imaging acquired from the base to the tip of the pillars allows for detection of concentric wrapping observed as 'rings' of myelin. The platform is formatted in 96-well plates, amenable to semiautomated random acquisition and automated detection and quantification. Upon screening 1,000 bioactive molecules, we identified a cluster of antimuscarinic compounds that enhance oligodendrocyte differentiation and remyelination. Our findings demonstrate a new high-throughput screening platform for potential regenerative therapeutics in multiple sclerosis.
Air pollution remains one of the major health threats around the world. Compared to adults, foetuses and infants are more vulnerable to the effects of environmental toxins. Maternal exposure to air ...pollution causes several adverse birth outcomes and may lead to life-long health consequences. Given that a healthy intrauterine environment is a critical factor for supporting normal foetal brain development, there is a need to understand how prenatal exposure to air pollution affects brain health and results in neurological dysfunction. This review summarised the current knowledge on the adverse effects of prenatal air pollution exposure on early life neurodevelopment and subsequent impairment of cognition and behaviour in childhood, as well as the potential of early-onset neurodegeneration. While inflammation, oxidative stress, and endoplasmic reticulum are closely involved in the physiological response, sex differences also occur. In general, males are more susceptible than females to the adverse effect of in-utero air pollution exposure. Considering the evidence provided in this review and the rising concerns of global air pollution, any efforts to reduce pollutant emission or exposure will be protective for the next generation.
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•Prenatal exposure to air pollution impacts foetal brain development and cognition.•Males have a greater susceptibility to prenatal air pollution exposure than females.•Oxidative stress, ER stress and neuroinflammation interactions lead to abnormal brain functions.
The temporal and spatial patterning involved in the specification, differentiation, and myelination by oligodendroglia is coordinated in part by the activation and repression of various ...transcriptional programs. Olig2 is a basic helix-loop-helix transcription factor necessary for oligodendroglial development and expressed continuously throughout the lineage. Despite evidence for the critical role of Olig2 in oligodendroglial specification and differentiation, the function for Olig2 during later stages of oligodendroglial development, namely, the transition into mature oligodendrocytes (OLs) and the formation of the myelin sheath, remains unclear. To address the possibility for a stage-specific role, we deleted Olig2 in oligodendrocyte precursor cells (OPCs) under the control of the CNPase-promoter or in immature OLs under the inducible proteolipid protein promoter. As expected, ablation of Olig2 in OPCs significantly inhibits differentiation, resulting in hypomyelination. However, deletion of the Olig2 gene in immature OLs significantly enhances the maturation process and accelerates the kinetics of myelination/remyelination. Underlying the stage-specific roles for Olig2 is the compensatory expression and function of Olig1, a transcription factor that promotes OL maturation and (re)myelination. Olig1 expression is significantly reduced upon Olig2 deletion in OPCs but is dramatically increased by nearly threefold when deleted in immature OLs. By enforcing expression of Olig1 into OPCs in a null Olig2 background, we demonstrate that overexpression of Olig1 is sufficient to rescue the differentiation phenotype and partially compensates for the Olig2 deletion in vitro. Our results suggest a stage-specific regulatory role for Olig2, mediated by Olig1 that conveys opposing functions on the differentiation and maturation of oligodendrocytes.
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.
Astrocytes play a crucial role in the maintenance of the normal functions of the Central Nervous System (CNS). During the pathogenesis of neurodegenerative diseases, astrocytes undergo morphological ...and functional remodeling, a process called reactive astrogliosis, in response to the insults to the CNS. One of the key aspects of the reactive astrocytes is the change in the expression and function of connexins. Connexins are channel proteins that highly expressed in astrocytes, forming gap junction channels and hemichannels, allowing diffusional trafficking of small molecules. Alterations of astrocytic connexin expression and function found in neurodegenerative diseases have been shown to affect the disease progression by changing neuronal function and survival. In this review, we will summarize the role of astroglial connexins in neurodegenerative diseases including Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Also, we will discuss why targeting connexins can be a plausible therapeutic strategy to manage these neurodegenerative diseases.
Porcine epidemic diarrhea virus (PEDV) is a highly infectious and pathogenic virus causing high morbidity and mortality, especially in newborn piglets. There remain problems with contemporary PEDV ...vaccines, in part because of the rapid variation of PEDV, poor conferred immunity, and numerous side effects. The ability to produce PEDV-neutralizing antibodies suggests that we may be able to increase the success rate of PEDV prevention in piglets using these antibodies. In this study, we produced an anti-PEDV S protein monoclonal antibody (anti-PEDV mAb-2) that neutralized PEDV-CV777 (a G1 strain), PEDV-SDSX16 and PEDV-Aj1102 (two G2 strains). In vivo challenge experiments demonstrated that anti-PEDV mAb-2 inhibited the PEDV infection in piglets. We also produced three HEK293 cell lines that expressed anti-PEDV mAb-2. Overall, our study showed that anti-PEDV mAb-2 produced from hybridoma supernatants effectively inhibited PEDV infection in piglets, and the recombinant HEK293 cell lines expressed anti-PEDV mAb-2 genes.
Oligodendrocyte progenitor cells (OPC) undergo asymmetric cell division (ACD) to generate one OPC and one differentiating oligodendrocyte (OL) progeny. Loss of pro-mitotic proteoglycan and OPC marker ...NG2 in the OL progeny is the earliest immunophenotypic change of unknown mechanism that indicates differentiation commitment. Here, we report that expression of the mouse homolog of Drosophila tumor suppressor Lethal giant larvae 1 (Lgl1) is induced during OL differentiation. Lgl1 conditional knockout OPC progeny retain NG2 and show reduced OL differentiation, while undergoing more symmetric self-renewing divisions at the expense of asymmetric divisions. Moreover, Lgl1 and hemizygous Ink4a/Arf knockouts in OPC synergistically induce gliomagenesis. Time lapse and total internal reflection microscopy reveals a critical role for Lgl1 in NG2 endocytic routing and links aberrant NG2 recycling to failed differentiation. These data establish Lgl1 as a suppressor of gliomagenesis and positive regulator of asymmetric division and differentiation in the healthy and demyelinated murine brain.
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