Loss of miR-145 promotes remyelination and functional recovery in a model of chronic centrel demyelination
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1118778 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR29250800.fastq.gz | Fastqsanger.gz | |||
| SRR29250801.fastq.gz | Fastqsanger.gz | |||
| SRR29250802.fastq.gz | Fastqsanger.gz | |||
| SRR29250803.fastq.gz | Fastqsanger.gz | |||
| SRR29250804.fastq.gz | Fastqsanger.gz |
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Project description:Strategies for treating progressive multiple sclerosis (MS) remain limited. Here, we found that miR-145-5p is overabundant uniquely in chronic lesion tissues from secondary progressive MS patients. We induced both acute and chronic demyelination in miR-145 knockout mice to determine its contributions to remyelination failure. Following acute demyelination, no advantage to miR-145 loss could be detected. However, after chronic demyelination, animals with miR-145 loss demonstrated increased remyelination and functional recovery, coincident with altered presence of astrocytes and microglia within the corpus callosum relative to wild-type animals. This improved response in miR-145 knockout animals coincided with a pathological upregulation of miR-145-5p in wild-type animals with chronic cuprizone exposure, paralleling human chronic lesions. Furthermore, miR-145 overexpression specifically in oligodendrocytes (OLs) severely stunted differentiation and negatively impacted survival. RNAseq analysis showed altered transcriptome in these cells with downregulated major pathways involved in myelination. Our data suggest that pathological accumulation of miR-145-5p is a distinctive feature of chronic demyelination and is strongly implicated in the failure of remyelination, possibly due to the inhibition of OL differentiation together with alterations in other glial cells. This is mirrored in chronic MS lesions, and thus miR-145-5p serves as a potential relevant therapeutic target in progressive forms of MS.
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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.
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Project description: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.
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