CXCR2 antagonism promotes oligodendrocyte precursor cell differentiation and enhances remyelination in a mouse model of multiple sclerosis

Wang, Lu; Yang, Hanyu; Zang, Caixia; Dong, Yunhui; Shang, Junmei; Chen, Jiajing; Wang, Yue; Liu, Hui; Zhang, Zihong; Xu, Heng; Bao, Xiaoyong; Zhang, Dan

doi:10.1016/j.nbd.2019.104630

Cited by 16 publications

(16 citation statements)

References 39 publications

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“…Second, Moyon et al pointed out the role of IL1B and CCL2 production by premyelinating OPCs in modulating their motility capacities and eventually differentiation (Moyon et al, 2015). Third, CXCR2 counteracts adult OPC differentiation and myelination potential, in a model of multiple sclerosis, by interfering with the PI3K/AKT/mTOR pathway, thereby strongly reinforcing the possibility of a role of cytokines and chemokines in OPC maturation during development (Wang et al, 2020). One possible pathway for the counteracting effects of cytokines and chemokines on OPC differentiation is that their production could regulate the recruitment by OPCs of other cells that are known to influence OPC maturation (like microglia; (Jana and Pahan, 2005;Balabanov et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Epigenome priming dictates transcription response and white matter fate upon perinatal inflammation

Schang

Steenwinckel

Lipecki

et al. 2018

Preprint

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Research Council (UK) through the Midlands Integrative Biology Training Partnership (MIBTP). The supporting bodies played no role in any aspect of study design, analysis, interpretation or decision to publish this data. Schang et al. 2 Author's contributions ALS performed bioinformatics microarray and ATAC--seq dataset analyses, as well as wet experiments, including the MACS--isolation of O4+ OPCs and RT--qPCR experiments, in association with JvS (experimental design, mouse treatment and cell sorting) and TLC (cell culture, cytokine quantification by luminex). BF contributed to the design of the project, and brought very helpful suggestions along the experimental process and writing of manuscript. SO, DSD, PG and VM codirected the work. SO supervised JL, CRG, KWA and ND in their input ATAC--seq analyses and developed bioinformatic tools for testing for enrichment of paired motifs of transcription binding sites, and also proposed and performed the bioinformatic comparison between the epigenomic landscapes of OPCs and inflamed HAECs. PS co--supervised JL and CRG. DSD played a major role in suggesting the use of ATAC--Seq, animated the collaboration with SO, and performed the MACs--isolation of OPCs and ATAC--Seq data experiments with ALS whom she co--supervised with VM and PG. PG scientifically co--directed with VM the project. In particular, he was at the origin of the MACS--isolation of the OPCs and produced OPC transcriptomic datasets and initiated their analyses. VM drove the study by proposing to analyze and intersect epigenomic data and transcriptomic data, for which she supervised DSD and co--supervised ALS; she wrote the paper with input from ALS, BF, SO, DSD, and PG. Schang et al. 3 AbstractPremature birth is the commonest cause of death and disability in young children. Diffuse white matter injury (DWMI), provoked by inflammatory insults accompanying prematurity, is associated with increased risk of neurodevelopmental disorders -such as autism spectrum disorders -and is due to maturation arrest in oligodendrocyte precursors (OPCs). The lack of therapeutic solutions is a strong impetus to unveil the molecular mechanisms underlying neuroinflammation impact on OPC cell fate. We used a validated mouse model of DWMI, induced by systemic--and neuro--inflammation -as observed in preterm infants -and based on interleukin--1B administration from postnatal day P1 to P5. Using integrated genome--wide approaches we showed that neuroinflammation induced limited epigenomic disturbances in OPCs, but marked transcriptomic alterations of genes of the immune/inflammatory pathways. We found that these genes were expressed in control OPCs and physiologically downregulated between P3--P10, as part of the OPC normal developmental trajectory. We observed that transcription factors of the inflammatory pathways occupied DNA both in unstressed and inflamed OPCs. Thus, rather than altering genome--wide chromatin accessibility, neuroinflammation takes advantage of open chromatin regions and deeply counteracts the stage--depen...

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Section: Discussionmentioning

confidence: 99%

Epigenome priming dictates transcription response and white matter fate upon perinatal inflammation

Schang

Steenwinckel

Lipecki

et al. 2018

Preprint

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“…The mechanisms by which overall recruitment of OPC and subsequent generation of oligodendrocytes remain unclear and are likely complex due to the number of signaling pathways that may be influenced by sulfatase activity. As proof of concept, we assayed OPC migration in vitro following treatment with CXCL1, a known inhibitor of OPC migration and remyelination 45,46 . We found that CXCL1 treatment was able to reduce hOPC migration and, consistent with the role of HSPGs in CXCL1 signaling 47 , we found that SULF2 KD rescued the effect of CXCL1 on hOPC migration.…”

Section: Discussionmentioning

confidence: 99%

Overcoming the inhibitory microenvironment surrounding oligodendrocyte progenitor cells following experimental demyelination

et al. 2021

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Chronic demyelination in the human CNS is characterized by an inhibitory microenvironment that impairs recruitment and differentiation of oligodendrocyte progenitor cells (OPCs) leading to failed remyelination and axonal atrophy. By network-based transcriptomics, we identified sulfatase 2 (Sulf2) mRNA in activated human primary OPCs. Sulf2, an extracellular endosulfatase, modulates the signaling microenvironment by editing the pattern of sulfation on heparan sulfate proteoglycans. We found that Sulf2 was increased in demyelinating lesions in multiple sclerosis and was actively secreted by human OPCs. In experimental demyelination, elevated OPC Sulf1/2 expression directly impaired progenitor recruitment and subsequent generation of oligodendrocytes thereby limiting remyelination. Sulf1/2 potentiates the inhibitory microenvironment by promoting BMP and WNT signaling in OPCs. Importantly, pharmacological sulfatase inhibition using PI-88 accelerated oligodendrocyte recruitment and remyelination by blocking OPC-expressed sulfatases. Our findings define an important inhibitory role of Sulf1/2 and highlight the potential for modulation of the heparanome in the treatment of chronic demyelinating disease.

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“…The direct effect of CXCL1 on oligodendrocytes was studied in transgenic mice, in which knocking out its receptor CXCR2 led to a reduced number of mature oligodendrocytes and consequent hypomyelination, but an increased population of OPCs (Padovani‐Claudio, Liu, Ransohoff, & Miller, 2006). In a study by Wang et al (2020), it was shown that a CXCR2 antagonist was effective in stimulating OPC proliferation and differentiation in a cuprizone‐induced mouse model of MS. Only a small subpopulation of oligodendrocytes expresses CXCR2 in human fetal and adult MS tissue (Filipovic, Jakovcevski, & Zecevic, 2003; Filipovic & Zecevic, 2008), therefore CXCL1 acts mainly on human oligodendrocytes through other cell types such as astrocytes (Bradl & Lassmann, 2010).…”

Section: The Role Of Growth Factors and Cytokines In Oligodendrocyte mentioning

confidence: 99%

The impact of trophic and immunomodulatory factors on oligodendrocyte maturation: Potential treatments for encephalopathy of prematurity

Vaes

Brandt

Wanders

et al. 2020

Glia

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Encephalopathy of prematurity (EoP) is a major cause of morbidity in preterm neonates, causing neurodevelopmental adversities that can lead to lifelong impairments. Preterm birth‐related insults, such as cerebral oxygen fluctuations and perinatal inflammation, are believed to negatively impact brain development, leading to a range of brain abnormalities. Diffuse white matter injury is a major hallmark of EoP and characterized by widespread hypomyelination, the result of disturbances in oligodendrocyte lineage development. At present, there are no treatment options available, despite the enormous burden of EoP on patients, their families, and society. Over the years, research in the field of neonatal brain injury and other white matter pathologies has led to the identification of several promising trophic factors and cytokines that contribute to the survival and maturation of oligodendrocytes, and/or dampening neuroinflammation. In this review, we discuss the current literature on selected factors and their therapeutic potential to combat EoP, covering a wide range of in vitro, preclinical and clinical studies. Furthermore, we offer a future perspective on the translatability of these factors into clinical practice.

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CXCR2 antagonism promotes oligodendrocyte precursor cell differentiation and enhances remyelination in a mouse model of multiple sclerosis

Cited by 16 publications

References 39 publications

Epigenome priming dictates transcription response and white matter fate upon perinatal inflammation

Epigenome priming dictates transcription response and white matter fate upon perinatal inflammation

Overcoming the inhibitory microenvironment surrounding oligodendrocyte progenitor cells following experimental demyelination

The impact of trophic and immunomodulatory factors on oligodendrocyte maturation: Potential treatments for encephalopathy of prematurity

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