Myelin sheathing of the axons connecting neurons is essential to the correct function of the nervous system. It is maintained by oligodendrocyte cells, but as noted in this open access paper, the maintenance of myelin is disrupted by the growing inflammation that accompanies aging. In the brain, microglia are innate immune cells that are responsible for a great deal of this inflammation. Some become senescent while others are overactive, made aggressive and inflammatory by the presence of damage and molecular waste in brain tissue. Removing senescent cells in the brain is a promising strategy to reduce the scope of age-related neuroinflammation, but other approaches will be needed as well to reduce inflammatory activity to youthful levels.
Extensive brain atrophy is a characteristic manifestation of aged brain. White matter degeneration is accompanied by encephalatrophy, leading to irreversible neurological and cognitive impairments. Remyelination is a natural protective and regenerative process that will be initiated in response to the degeneration of white matter. It is a complex process involving oligodendrocyte precursor cell (OPC) activation, migration, differentiation, and maturation to be oligodendrocytes (OLGs). Accumulating evidence indicates that remyelination is disturbed in the aged brain. However, a clear understanding of the effect of brain aging on the process of remyelination is still lacking.
Brain aging heightened the neuroinflammatory profile of the cerebral microenvironment, which activated microglia by attributing it to aging-related changes in remyelination. Previous studies have reported that activated microglia secrete a heterogeneity array of signaling molecules, including nitric oxide, reactive oxygen species, Il-6, Il-1β, and tumor necrosis factor (TNF), contributing to myelin damage and hindering proliferation or differentiation of OPCs. However, other studies indicated that activated microglia could promote OLG survival or OPC differentiation by releasing several regenerative factors including Igf-1, Igf-2, galectin-3, activin-A, and Il-1β, and clearing myelin debris.
These diverse results may be driven by the heterogeneous subpopulation of microglia, OLGs, and OPCs. Specific subgroups of OLGs and OPCs in different states may respond inconsistently to the stimulus of activated microglia. In addition, our previous study revealed that there were six subgroups of microglia with divergent functions in aged brain. A unique type of highly activated microglia was observed in aged mice only, with functional implications in immuno-inflammatory response. It remains poorly understood how this specific age-related subgroup of microglia effect on remyelination in aged brain. The exact mechanism of aged microglia in regulation of distinct subgroups of OLGs and OPCs needs to be determined.
In the present study, we aimed to explore the subclusters of OLGs and OPCs by analyzing the single-cell RNA sequence (scRNAseq) data of both young and aged brains. Oligodendrocytes were observed to up-regulate several senescence associated genes in aged brain. Four clusters of oligodendrocyte precursor cells (OPCs) were identified in both young and aged brains. The number of those OPCs in basal state was significantly increased, while the OPCs in the procedure of differentiation were immensely decreased in aged brain. Furthermore, it was identified that activated microglia in the aged brain released inflammatory factors to suppress OPC differentiation. Stat1 might be a potential target to transform senescent microglia into tissue repair type to promote oligodendrocyte generation.