Heterogeneity and balance between proliferation and maturation in the oligodendrocyte progenitor pool
Oligodendrocyte progenitor cells (OPCs) persist in the adult Central Nervous System (CNS) and guarantee oligodendrocyte turnover and myelin repair throughout life. It remains obscure how OPCs avoid exhaustion during adulthood and whether, similar to neural stem cells, they include distinct populations or functional stages intrinsically committed to self-maintain or to produce a differentiating progeny. To address these issues, by in vivo fate-mapping approaches we examined the phenotype of OPCs during mitosis and the fate of their daughter cells at distinct time points after cell birth. We found that distinct transcription factors are expressed in segregated subsets of dividing OPCs in the mouse adult and juvenile cerebral cortex. Such subsets produce cell progenies with different fates. Further, we showed that a fraction of dividing OPCs gives rise to asymmetric daughter cell pairs including sister OPCs with diverse early immunophenotypic profiles and fates (i.e. acquisition of premyelinating markers or maintenance of progenitor features, including the expression of NG2, PDGFRa and the ability to undergo re-proliferation). Sister OPC heterogeneity appears as early as cells exit cytokinesis, suggesting that, similar to stem cells, a subset of the dividing OPCs can undergo asymmetric division. Interestingly, although molecules such as NG2 and PDGFRa expressed in the mother cells do not segregate asymmetrically during OPC mitosis, OPCs express a repertoire of classical molecular regulators of the cell division modality operating in neural stem cells, including cell fate determinants and polarity machineries. Our data point to the existence of mechanisms that finely tune the OPC turn-over to preserve the progenitor pool while assuring the production of new oligodendrocytes in the intact adult brain. Alteration of these mechanisms may contribute to the hamper oligodendrogenesis and myelin repair in the aged CNS.