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Harnessing microglia capacity to facilitate myelin regeneration in chronically demyelinated brain lesions

ABSTRACT: Failure in remyelination is a key feature of progressive multiple sclerosis (MS) that drive neurodegeneration and accumulation of disabilities. Microglia crucially facilitate oligodendrocyte remyelination in MS lesions through myelin phagocytosis, and subsequent cholesterol metabolism and release. However, microglia lose this capacity in chronic demyelinated lesions, as they acquire a dysfunctional phenotype characterized by intracellular accumulation of lipid droplets due to impaired cholesterol processing of myelin debris. Given the abundance of microglia in chronic MS lesions, revitalizing their pro-remyelination capacity represents a critical repair strategy for progressive MS. Here, we reveal that dysregulation of neuregulin-1 underlies impaired remyelination in chronically demyelinated brain lesions. Therapeutic restoration of neuregulin-1 supports remarkable myelin regeneration by augmenting microglia capacity for clearance of myelin debris, cholesterol metabolism and efflux. Altogether, we demonstrate the promise of neuregulin-1 as an endogenous target to facilitate microglia reparative functions in progressive MS in which there is an unmet critical need for new treatments.

ORGANISM(S): Mus musculus

PROVIDER: GSE282653 | GEO | 2026/03/09

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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Harnessing microglia capacity to facilitate myelin regeneration in chronically demyelinated brain lesions

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