Multiple O2aopc Populations With Different Properties

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The initial proposal that the differences between perinatal and adult O-2A/OPCs indicates that the specific physiologic requirements of a particular tissue are reflected in the intrinsic properties of the precursor cells resident in that tissue has recently been extended to consider different CNS regions of animals of the same age. In these studies, striking differences between the properties of O-2A/OPCs isolated from different regions of the CNS of 7-d-old rat pups have been found, differences that once again appear to be highly relevant to the understanding of development.

One of the striking aspects of CNS development is that different regions of this tissue develop according to different schedules, with great variations seen in the timing of both neurogenesis and gliogenesis. For example, neuron production in the rat spinal cord is largely complete by the time of birth, is still ongoing in the rat cerebellum for at least several days after birth, and continues in the olfactory system and in some regions of the hippocampus of multiple species throughout life. Similarly, myelination has long been known to progress in a rostral-caudal direction, beginning in the spinal cord significantly earlier than in the brain (e.g., refs. 127-129). Even within a single CNS region, myelination is not synchronous. In the rat optic nerve, for example, myelino-genesis occurs with a retinal-to-chiasmal gradient, with regions of the nerve nearest the retina becoming myelinated first (127,130). The cortex itself shows the widest range of timing for myelination, both initiating later than many other CNS regions (e.g., refs. 127-129) and exhibiting an ongoing myelinogenesis that can extend over long periods of time. This latter characteristic is seen perhaps most dramatically in the human brain, for which it has been suggested that myelination may not be complete until after several decades of life (131,132).

Variant time courses of development in different CNS regions could be due to two fundamentally different reasons. One possibility is precursor cells are sufficiently plastic in their developmental programs that local differences in exposure to modulators of division and differentiation may account for these variances. Alternatively, it may be that the precursor cells resident in particular tissues express differing biological properties related to the timing of development in the tissue to which they contribute.

As has been discussed earlier, there is ample evidence for extensive plasticity in the behavior of O-2A/OPCs, which appear to be the direct ancestor of oligodendrocytes. O-2A/OPCs obtained from the optic nerves of 7-d-old (P7) rat pups and grown in the presence of saturating levels of PDGF exhibit an approximately equal probability of undergoing a self-renewing division or exiting the cell cycle and differentiating into an oligodendrocyte (81). The tendency of dividing O-2A/OPCs to generate oligodendrocytes is enhanced if cells are coexposed to such signaling molecules as thyroid hormone, ciliary neurotrophic factor or retinoic acid (e.g., refs. 32,47, and 48). In contrast, coexposure to NT-3 or basic fibroblast growth factor inhibits differentiation and is associated with increased precursor cell division and self-renewal (30,47,56). The balance between self-renewal and differentiation in dividing O-2A/OPCs can also be modified by the concentrations of the signaling molecules to which they are exposed, as well as by intracellular redox state (35). Thus, the effects of the microenvironment could theoretically have considerable effects on the timing and extent of oligodendro-cyte generation.

Recent experiments have raised the possibility that the differing timing of oligo-endrocyte generation and myelination in different CNS regions is associated with the existence of regionally specialized O-2A/OPCs (133). Characterization of O-2A/OPCs isolated from different regions indicates these developmental patterns are consistent with properties of the specific O-2A/OPCs resident in each region. In particular, cells isolated from optic nerve, optic chiasm and cortex of identically aged rats show marked differences in their tendency to undergo self-renewing division and in their sensitivity to known inducers of oligodendrocyte generation. Precursor cells isolated from the cortex, a CNS region where myelination is a more protracted process than in the optic nerve, appear to be intrinsically more likely to begin generating oligodendrocytes at a later stage and over a longer time period than cells isolated from the optic nerve. For example, in conditions where optic nerve-derived O-2A/OPCs generated oligo-dendrocytes within 2 d, oligodendrocytes arose from chiasm-derived cells after 5 d and from cortical O-2A/OPCs only after 7-10 d. These differences, which appear to be cell-intrinsic, were manifested both in reduced percentages of clones producing oli-godendrocytes and in a lesser representation of oligodendrocytes in individual clones. In addition, responsiveness of optic nerve-, chiasm- and cortex-derived O-2A/OPCs to TH and CNTF, well-characterized inducers of oligodendrocyte generation, was inversely related to the extent of self-renewal observed in basal division conditions.

The preceding results indicate that the O-2A/OPC population may be more complex than initially envisaged, with the properties of the precursor cells resident in any particular region being reflective of differing physiological requirements of the tissues to which these cell contribute. For example, as discussed earlier, a variety of experiments have indicated that the O-2A/OPC population of the optic nerve arises from a germinal zone located in or near the optic chiasm and enters the nerve by migration (44,134). Thus, it would not be surprising if the progenitor cells of the optic chiasm expressed properties expected of cells at a potentially earlier developmental stage than those cells that are isolated from optic nerve of the same physiological age. Such properties would be expected to include the capacity to undergo a greater extent of self-renewal, much as has been seen when the properties of O-2A/OPCs from optic nerves of embryonic rats and postnatal rats have been compared (58). In respect to the properties of cortical progenitor cells, physiological considerations also appear to be consistent with our observations. The cortex is one of the last regions of the CNS in which myelination is initiated, and the process of myelination also can continue for extended periods in this region (127-129). If the biology of a precursor cell population is reflective of the developmental characteristics of the tissue in which it resides, then one might expect that O-2A/OPCs isolated from this tissue would not initiate oligodendrocyte generation until a later time than occurs with O-2A/OPCs isolated from structures in which myelination occurs earlier. In addition, cortical O-2A/OPCs might be physiologically required to make oligodendrocytes for a longer time owing to the long period of continued development in this tissue, at least as this has been defined in the human CNS (e.g., refs. 131,132).

The observation that O-2A/OPCs from different CNS regions express different levels of responsiveness to inducers of differentiation adds a new level of complexity to attempts to understand how different signaling molecules contribute to the generation of oligodendrocytes. This observation also raises questions about whether cells from different regions also express differing responses to cytotoxic agents, and whether such differences can be biologically dissected so as to yield a better understanding of this currently mysterious form of biological variability.

If there are multiple biologically distinct populations of O-2A/OPCs, it is important to consider whether similar heterogeneity exists among oligodendrocytes themselves. Evidence for morphological heterogeneity among oligodendrocytes is well established. Early silver impregnation studies identified four distinct morphologies of myelinating oligodendrocytes and this was largely confirmed by ultrastructural analyses in a variety of species (135-137). Oligodendrocyte morphology is closely correlated with diameter of the axons with which the cell associates (138,139). Type I and II oligodendro-cytes arise late in development, myelinate many internodes on predominantly small diameter axons while type III and IV oligodendrocyte arise later and myelinate mainly large diameter axons. Such morphological and functional differences between oligodendrocytes are associated with different biochemical characteristics. Oligodendrocytes that myelinate small diameter fibers (type 1 and 11) express higher levels of carbonic anhydrase II (CAII) (138,140), while those myelinating larger axons (type III and IV) express a specific small isoform of the myelin-associated glycoprotein (MAG) (138). Whether such differences represent the response of homogenous cells to different environments or distinct cell lineages is unclear. Transplant studies demonstrated that presumptive type I and II cells have the capacity to myelinate both small and large diameter axons suggesting that the morphological differences are environmentally induced (141). By contrast, some developmental studies have been interpreted to suggest that the different classes of oligodendrocytes may be derived from biochemically distinct precursors (142) that differ in expression of PDGFR-a and PLP/Dm20, although more recent studies are not necessarily supportive of this hypothesis (143).

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