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Dicer deficient adult microglia negatively impacts the process of demyelination and remyelination

ABSTRACT: Microglia, the resident immune cells of the central nervous system (CNS), are important regulators of normal brain activities. In CNS demyelinating diseases like multiple sclerosis (MS), the functions of these cells are of particular interest. Based on the observation of diminished Dicer positive microglia/macrophages number in demyelinating white matter lesions (WMLs) of human MS brains, here we probed the impact of impaired microRNA (miRNA)-mediated post-transcriptional gene regulation in a mouse model lacking microglia/macrophage-specific Dicer1 expression during demyelination and remyelination. Conditional Dicer1 ablation and loss of miRNAs expression in adult microglia led to extensive demyelination and impaired myelin processing. Interestingly, demyelination was accompanied by increased apoptosis of mature oligodendrocytes (OLs) and arresting oligodendrocyte progenitor cells (OPCs) in the precursor stage. At the transcriptional level, Dicer1-deficient microglia led to downregulation of microglial homeostatic genes, increased cell proliferation, and a shift towards a disease-associated phenotype. Loss of remyelination efficiency in these mice was accompanied by stalling of OPCs in the precursor stage. Collectively, finding from this study highlight a new role of microglial miRNAs in promoting a pro-regenerative phenotype in addition to promoting OPC maturation and differentiation during demyelination and remyelination.

ORGANISM(S): Mus musculus

PROVIDER: GSE263765 | GEO | 2025/04/10

REPOSITORIES: GEO

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Project description:In multiple sclerosis (MS) and experimental models of demyelination, myelin repair is mostly achieved by oligodendrocyte precursor cells (OPCs). To gain insight into the biological specificity of these adult precursors, in the perspective to better understand why remyelination often fails in MS, we performed a micro-array analysis on purified populations of murine OPCs and oligodendrocytes. We demonstrated that, in a control environment, M-bM-^@M-^\quiescentM-bM-^@M-^] adult OPCs are more mature than neonatal OPCs, with a mRNA profile closer to oligodendrocytes. However, when demyelination occurs, adult OPCs revert to an immature gene expression profile, acquiring higher migration and faster differentiation capacities. Among the many genes differentially regulated by these M-bM-^@M-^\activatedM-bM-^@M-^] adult OPCs, genes of the innate immune response, IL1M-NM-2 and CCL2 were strongly upregulated after demyelination, with increased protein expression in experimental demyelinating lesions and within MS plaques. We first showed in vitro that both IL1M-NM-2 and CCL2 M-bM-^@M-^\accountM-bM-^@M-^] for increased migration capacities of adult OPCs, an effect that is suppressed by corresponding receptor blockade. Focusing on Ccl2, we then demonstrated that lentiviral over-expression of Ccl2 increases motility of M-bM-^@M-^\quiescentM-bM-^@M-^] adult OPCs, which become as mobile as M-bM-^@M-^\activatedM-bM-^@M-^] adult OPCs. This in vitro gain of function was further confirmed in vivo, by showing an increased migration of grafted CG4 oligodendroglial cells over-expressing-Ccl2. These results, demonstrating that M-bM-^@M-^\activatedM-bM-^@M-^] adult OPCs upregulate immune cues favouring their migration, open new perspective of demyelination-induced immune-glial interactions, which might influence both oligodendroglial and inflammatory cells, therefore play a key role in lesion fate in multiple sclerosis. In this study, we loaded purified population of progenitors of oligodendrocytes (OPCs) (from neonatal, 2-month-old, 2-month-old and cuprizone-treated brains) and of mature oligodendrocytes (OLs) (2-month-old brains) and compared their gene expression. We compared gene expression of neonatal OPCs, adult OPCs, adult OLs and adult OPCs from control conditions and from demyelinating conditions, using 3 to 4 independant replicates in each group.

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Dicer deficient adult microglia negatively impacts the process of demyelination and remyelination

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