Proliferation is a requirement for differentiation of oligodendrocyte progenitor cells during CNS remyelination

Abstract

SummaryOligodendrocytes that generate new myelin sheaths around demyelinated axons in the regenerative process of remyelination are generally derived from oligodendrocyte progenitor cells (OPCs). During this process, OPCs become activated, populate the area of myelin loss, and finally differentiate. Although much is known about the individual stages of remyelination, the exact sequence of events and whether a dependency of each individual stage on each other exists is unknown. Understanding the biology behind these questions is important for the development of remyelination therapies to overcome the age-related decline in remyelination efficiency observed in the chronic phase of multiple sclerosis (MS). Here we show that, following toxin-induced demyelination, all re-populating OPCs first migrate into the site of damage, undergo relatively few rounds of division and eventually differentiate. We further show that OPC proliferation is a requirement for differentiation. Together, our results reveal an unexpected link between OPC proliferation and differentiation, and opens up the possibility of novel regenerative strategies in MS focussing on stimulating OPC proliferation.

Clemastine Ameliorates Myelin Deficits via Preventing Senescence of Oligodendrocytes Precursor Cells in Alzheimer’s Disease Model Mouse

“…The discrepancy could be attributed to the different models used in the studies, as they used mice that underwent 2 weeks of social isolation, which does not induce the loss of OPCs ( Liu et al, 2016 ). Moreover, a recent study found that in toxin-induced focal demyelination, the proliferation of the migrated OPCs is a requirement for them to differentiate at the lesion site ( Foerster et al, 2020 ). Blocking the cell cycle of OPCs in vitro resulted in a significant compromise of the differentiation of the cells ( Foerster et al, 2020 ).…”

“…Moreover, a recent study found that in toxin-induced focal demyelination, the proliferation of the migrated OPCs is a requirement for them to differentiate at the lesion site ( Foerster et al, 2020 ). Blocking the cell cycle of OPCs in vitro resulted in a significant compromise of the differentiation of the cells ( Foerster et al, 2020 ). Therefore, it is possible that clemastine supports the normal cellular activities of OPCs, including proliferation and differentiation, preventing the loss of the cells rather than enhancing the cellular activities under the neurodegeneration conditions.…”

Multicolor strategies for investigating clonal expansion and tissue plasticity

“…Robin Franklin’s laboratory used Confetti; Sox10-iCre mice to investigate the individual response of peri-lesional OPC to focal toxin-induced demyelination. After identification of clones with hierarchical clustering analysis, the authors determined that the number and size of clones progressively increase from 3–21 days after the lesion, suggesting that many surrounding cells are responding to the lesion by repopulating it and undergoing few cycles of division [ 150 ].…”

Neuroprotective effects of Sonic hedgehog agonist SAG in a rat model of neonatal stroke

“…There was a proliferative oligodendroglial response with SAG treatment in both models. Recent work has shown that increased proliferation is a prerequisite for the oligodendroglial differentiation( 31 ) and that newly generated oligodendrocytes exhibit enhanced and accurate axonal myelination( 32 ). Although we did not see a significant increase in mature CC1+ cells at these early time points, further studies are needed to determine whether SAG-induced oligodendroglial proliferation might benefit myelin generation in the long term.…”