Address for correspondence: Mark Noble, Department of Biomedical Genetics, University of Rochester School of Medicine, 601 Elmwood Avenue, Box 633, Rochester, New York 14642. Voice: 716-273-1448; fax: 716-273-1450.
mark_noble{at}urmc.rochester.edu
Ann. N.Y. Acad. Sci. 991: 251-271 (2003).
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.
