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Single-cell profiling of remyelination in the LPC model

ABSTRACT: Remyelination is reparative process by which axons that have lost their supportive insulation are re-encased in myelin. Multiple cell types are known to participate in this process, but their transcriptional dynamics from initial injury to full repair remain poorly characterized. Here, we combined high-throughput single-nucleus RNA-seq with Slide-seq, a high-resolution spatial transcriptomics technology, to densely reconstruct the cellular processes that coordinate remyelination after lysolecithin injection. First, we found extensive transcriptional diversity of glia and monocyte-derived macrophages from damage to repair. Second, we identified a population of infiltrating peripheral immune cells-- mostly CD8 T-cells and natural killer cells--that are enriched specifically during remyelination. Thirdly, we identified a concerted Interferon-response signature that is shared across several glial cell types--microglia, astrocytes, and oligodendrocyte lineage--just prior to reestablishment of myelin

ORGANISM(S): Mus musculus

PROVIDER: GSE276570 | GEO | 2024/09/09

REPOSITORIES: GEO

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Project description:The progressive loss of CNS myelin in patients with multiple sclerosis (MS) has been proposed to result from the combined effects of damage to oligodendrocytes and failure of remyelination. A common feature of demyelinated lesions is the presence of oligodendrocyte precursors (OLPs) blocked at a premyelinating stage. However, the mechanistic basis for inhibition of myelin repair is incompletely understood. To identify novel regulators of OLP differentiation, potentially dysregulated during repair, we performed a genome-wide screen of 1040 transcription factor-encoding genes expressed in remyelinating rodent lesions. We report that M-bM-^HM-<50 transcription factor-encoding genes show dynamic expression during repair and that expression of the Wnt pathway mediator Tcf4 (aka Tcf7l2) within OLPs is specific to lesionedM-bM-^@M-^Tbut not normalM-bM-^@M-^Tadult white matter. We report that M-NM-2-catenin signaling is active during oligodendrocyte development and remyelination in vivo. Moreover, we observed similar regulation of Tcf4 in the developing human CNS and lesions of MS. Data mining revealed elevated levels of Wnt pathway mRNA transcripts and proteins within MS lesions, indicating activation of the pathway in this pathological context. We show that dysregulation of WntM-bM-^@M-^SM-NM-2-catenin signaling in OLPs results in profound delay of both developmental myelination and remyelination, based on (1) conditional activation of M-NM-2-catenin in the oligodendrocyte lineage in vivo and (2) findings from APCMin mice, which lack one functional copy of the endogenous Wnt pathway inhibitor APC. Together, our findings indicate that dysregulated WntM-bM-^@M-^SM-NM-2-catenin signaling inhibits myelination/remyelination in the mammalian CNS. Evidence of Wnt pathway activity in human MS lesions suggests that its dysregulation might contribute to inefficient myelin repair in human neurological disorders. 12 samples total. Two variables in the experiment: genotype (wild type or Olig2cre/DA-Cat) and Developmental stage (Day 4 or Day 15). 4 phenotypes in total with 3 biological replicates for each phenotype.

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Single-cell profiling of remyelination in the LPC model

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