Redox state as a central modulator of precursor cell function

Abstract

In our attempts to understand how the balance between self-renewal and differentiation is regulated in dividing precursor cells, we have discovered that intracellular redox state appears to be a critical modulator of this balance in oligodendrocyte-type-2 astrocyte (O-2A) progenitor cells. The intracellular redox state of freshly isolated progenitor cells allows prospective isolation of cells with different self-renewal characteristics, which can be further modulated in opposite directions by prooxidants and antioxidants. Redox state is itself modulated by cell-extrinsic signaling molecules that alter the balance between self-renewal and differentiation: growth factors that promote self-renewal cause progenitors to become more reduced, while exposure to signaling molecules that promote differentiation causes progenitors to become more oxidized. Moreover, pharmacological antagonists of the redox effects of these cell-extrinsic signaling molecules antagonize their effects on self-renewal and differentiation, further suggesting that cell-extrinsic signaling molecules that modulate this balance converge on redox modulation as a critical component of their effector mechanism. A further example of the potential relevance of intracellular redox state to development processes emerges from our attempts to understand why different central nervous system (CNS) regions exhibit different temporal patterns of oligodendrocyte generation and myelinogenesis. Characterization of O-2A progenitor cells (O-2A/OPCs) isolated from different regions indicates that these developmental patterns are consistent with properties of the specific O-2A/OPCs resident in each region. Marked differences were seen in self-renewal and differentiation characteristics of O-2A/OPCs isolated from cortex, optic nerve, and optic chiasm. In conditions where optic nerve-derived O-2A/OPCs generated oligodendrocytes within 2 days, oligodendrocytes arose from chiasm-derived cells after 5 days and from cortical O-2A/OPCs after only 7-10 days. These differences, which appear to be cell intrinsic, were manifested both in reduced percentages of clones producing oligodendrocytes and in a lesser representation of oligodendrocytes in individual clones. In addition, responsiveness of optic nerve-, chiasm-, and cortex-derived O-2A/OPCs to thyroid hormone (TH) and ciliary neurotrophic factor (CNTF), well-characterized inducers of oligodendrocyte generation, was inversely related to the extent of self-renewal observed in basal division conditions. These results demonstrate hitherto unrecognized complexities among the precursor cells thought to be the immediate ancestors of oligodendrocytes and suggest that the properties of these different populations may contribute to the diverse time courses of myelination in different CNS regions. Strikingly, O-2A/OPCs isolated from cortex and analyzed immediately upon isolation were more reduced in their redox state than were optic nerve-derived cells, precisely as would be predicted from our analysis of the role of redox state in modulating the balance between self-renewal and differentiation. Chiasm-derived cells, which exhibited self-renewal properties intermediate between cortex- and optic nerve-derived cells, were more reduced than optic nerve cells but more oxidized that cortical O-2A/OPCs.