RNA-Sequencing reveals mechanisms by which human glial progenitor cells (hGPCs) initiate remyelination
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE112557 | GEO | 2020/05/09
REPOSITORIES: GEO
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Project description:Mouse cuprizone (CPZ ) model of experimental de- and remyelination was applied to mimic demyelination pathology of multiple sclerosis. In order to identify differentially expressed microRNAs involved in de- and remyelination, the affected areas of corpus callosum were isolated from mice exposed to CPZ and conducted an Agilent microarray analysis. To induce demyelination, CPZ was administrated for four weeks. Spontaneous remyelination occurs as mice returned to the regular diet after four weeks feeding with CPZ (DEM_4w). Remyelination was examined at two time points: acute remyelination induced by four weeks CPZ feeding followed by two days of regular diet (two days remyelination: REM_2d), and full remyelination induced by four weeks CPZ feeding followed by two weeks of regular diet (two weeks remyelination: REM_2w). Control mice (C) were kept on a normal diet. The following groups representing de- and remyelinisation pathology in corpus callosum of CPZ-treated mice were compared: Demyelination: 4weeks CPZ: DEM_4w; Acute remyelination: 4 weeks CPZ +2 days UNTREATED: REM_2d; Full remyelination: 4 weeks CPZ +2 weeks UNTREATED: REM_2w; and UNTREATED control (C). The experiments were performed using 2-4 animals per groups.
2018-04-11 | GSE100662 | GEO
Project description:Purpose: The central nervous system (CNS) possesses intrinsic remyelination capabilities in response to demyelinating injury. However, this remyelination potential is diminished as demyelinating disease such as multiple sclerosis progresses overtime. To better understand myelin repair processes, the goal of this study was to determine temporal transcriptomic changes in cerebral white matter (corpus callosum) and gray matter (cortex and hippocampus) after acute and chronic demyelinating injury. The cuprizone mouse model of de- and remyelination was used for this investigation. Methods: Adult C57BL/6 mice were exposed to cuprizone diet (0.2%) for 3, 5 or 12 weeks followed by returning to normal diet for up to 12 weeks for recovery. Brain regions were dissected for bulk RNA-seq. Conclusion: RNA-seq analyses suggest common and distinct spatiotemporal transcriptional alterations during CNS demyelination and remyelination. Dataset for this study represents the first that covers gene expression landscapes of three brain regions over extended regenerative periods after chronic CNS demyelination.
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Project description:RNA-Sequencing reveals mechanisms by which human glial progenitor cells (hGPCs) initiate remyelination
| PRJNA448175 | ENA
Project description:Remyelinating substances could be an essential supplement to immunomodulatory medications, optimizing the treatment of multiple sclerosis (MS) patients. Fingolimod is a sphingosine-1-phosphate receptor (S1PR) modulator and crosses the blood-brain barrier. Central nervous system (CNS) cells express S1PRs, and Fingolimod could theoretically improve CNS remyelination and be neuroprotective per se, but data are inconsistent. We used the cuprizone model for investigating the effect of fingolimod on remyelination and axonal damage by Immunohistochemistry and quantitative mass spectrometry. After three weeks of remyelination, fingolimod-treated mice had more mature oligodendrocytes in the secondary motor cortex than the placebo group. However, fingolimod did not at any time point affect remyelination or axonal damage. We conclude that fingolimod does not promote remyelination or protect against axonal injury or loss after cuprizone exposure.
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Project description:We employed a cuprizone-induced demyelinating model to identify the role of AhR in remyelination with microglial AhR-deficient mice and wild type mice. RNA-seq was performed to compare gene transcriptional profile in wild type mice and microglial AhR-deficient mice of cuprizone model to gain insight into the effects of AhR on microglia function.
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Project description:Microglia are considered both pathogenic and protective during recovery from demyelination, but their precise role remains ill-defined. Here, using an inhibitor of colony stimulating factor 1 receptor (CSF1R), PLX5622, and mice infected with a neurotropic coronavirus (mouse hepatitis virus, strain JHMV), we show that depletion of microglia after clearance of virus infection resulted in impaired myelin repair and prolonged clinical disease. Microglia were required only during the early stages of remyelination. Notably, large deposits of extracellular vesiculated myelin and cellular debris were detected in the spinal cords of PLX5622-treated and not control mice, which correlated with decreased numbers of oligodendrocytes in demyelinating lesions in drug-treated mice. Further, gene expression analyses demonstrated differential expression of genes involved in myelin debris clearance, lipid and cholesterol recycling, and promotion of oligodendrocyte function. The results also demonstrate that microglial function could not be compensated by infiltrating macrophages. Together, these results demonstrate key roles for microglia in debris clearance and the initiation of remyelination following infection with a neurotropic coronavirus but are not necessary during later stages of remyelination.
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Project description:The molecular basis of CNS myelin regeneration (remyelination) is poorly understood. Here we generate a comprehensive transcriptional profile of the separate stages of spontaneous remyelination following focal demyelination in the rat CNS. White matter tracts in the rat caudal cerebellar peduncles were focally demyelinated using 0.1% ethidium bromide, the lesions were isolated using laser capture microdissection at 5, 14 and 28 days postlesion, followed by RNA extraction and Illumina beadarray analysis of differentially expressed transcripts. We found transcripts encoding retinoid acid receptor RXR-gamma is highly differentially expressed during remyelination, and that oligodendrocyte lineage cells express RXR-gamma in rat tissues undergoing remyelination and in active and remyelinated MS lesions. RXR-gamma knockdown by RNA interference or RXR-specific antagonists severely inhibit oligodendrocyte differentiation in culture. In RXR-gamma deficient mice, adult oligodendrocyte precursor cells efficiently repopulate lesions following demyelination, but display delayed differentiation into mature oligodendrocytes. Administration of the RXR agonist 9-cis-retinoic acid to demyelinated cerebellar slice cultures and to aged rats following demyelination results in more remyelinated axons. RXR-gamma is therefore a positive regulator of endogenous oligodendrocyte precursor cell differentiation and remyelination, and may be a pharmacological target for CNS regenerative therapy. 9 Samples analysed, 3 different time points each with 3 biological replicates.
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2023-05-17 | E-MTAB-9270 | biostudies-arrayexpress
Project description:In the adult mammalian brain, Gli1 expressing neural stem cells reside in the subventricular zone and their progeny are recruited to sites of demyelination in the white matter where they regenerate oligodendrocytes, the myelin forming cells. Remarkably, genetic and pharmacologic inhibition of Gli1 enhances remyelination in the adult brain. To understand the molecular mechanisms involved, we performed a transcriptomic analysis to compare the expression of genes in Gli1 neural stem cells with either intact Gli1 expression or genetic loss of Gli1 from adult mice on control diet or cuprizone diet, which induces demyelination. These data will be a valuable resource for identifying therapeutic targets for enhancing remyelination in demyelinating diseases like multiple sclerosis.
2021-03-31 | GSE162683 | GEO
Project description:We have recently described sustained clinical recovery associated with dampened neuroinflammation and remyelination following transplantation of neural precursor cells (NPCs) derived from human embryonic stem cells (hESCs) in a viral model of the human demyelinating disease multiple sclerosis. In order to test the general applicability of NPC transplantation, we developed a new method for the differentiation and purification of NPCs from pluripotent stem cells (PSCs). Herein, we investigated the therapeutic potential of NPCs generated from human induced pluripotent stem cells (iPSCs) in mice infected with the neurotropic JHM strain of mouse hepatitis virus (JHMV) that induces an immune-mediated demyelinating disease sharing clinical and histologic similarities to the human demyelinating disease multiple sclerosis (MS). JHMV-infected mice intraspinally transplanted with EB (embryoid body)-derived NPCs (EB-NPCs) exhibited decreased accumulation of CD4+ T cells in the central nervous system that was concomitant with reduced demyelination at the site of injection. Dampened neuroinflammation and remyelination was correlated with a transient increase in CD4+FOXP3+ regulatory T cells (Tregs) concentrated within the peripheral lymphatics. Importantly, pathological improvements were limited in comparison to our previous report on hESC-derived NPCs and did not result in significant clinical recovery. Further examination of EB-NPCs by whole genome expression analysis showed them to be significantly different than our previously published cells. These findings highlight an intrinsic disparity in the therapeutic potential of NPCs generated from pluripotent stem cells. Pluripotent stem cells were differentiated to neural precursor cells (NPCs) by two separate methods to study the differences in final cell type. The first method was a 4 factor 9 day directed differentiation. This was applied to WA09 embryonic stem cells (ESCs) as well as two lines of induced pluripotent stem cells (iPSCs) that were developed in our lab HDF51iPSC and HDF69iPSC. The other method was a multistep process that included transition through an embryoid body (EB) stage. This was done with the used on the HDF51iPCS line. For controls we used the original pluripotent stem cell lines (WA09, HDF51iPSC and HDF69iPSC) as well as HDF417 which is a human dermal fibroblast line collected by our lab.
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