THE INHIBITION OF OLIGODENDROCYTIC DIFFERENTIATION OF O-2A PROGENITORS CAUSED BY BASIC FIBROBLAST GROWTH-FACTOR IS OVERRIDDEN BY ASTROCYTES

The inhibition of differentiation of oligodendrocyte-type-2 astrocyte (O-2A) progenitors into oligodendrocytes caused by basic fibroblast growth factor (bFGF) can be overcome by non-0-2A lineage cells present in the optic nerve and by astrocytes purified from cerebral cortices. Although purified 0-2A progenitors grown in the presence of bFGF for up to 6 days were inhibited from differentiating into oligodendrocytes, 0-2A progenitors growing in heterogeneous optic nerve cultures did not show a similar inhibition of differentiation. The factor(s) responsible for overriding the inhibitory effects of bFGF appeared to be secreted by astrocytes, as extensive generation of oligodendrocytes was seen in cultures of purified 0-2A progenitors exposed to bFGF+ medium conditioned by purified astrocytes (ACM). In addition, purified 0-2A progenitors displayed a remarkable sensitivity to bFGF, which extended at least down to concentrations of 0.03 ng/ml, a concentration of <2 x 10(-12) M. At a bFGF concentration of just 0.1 ng/ml, this mitogen still promoted DNA synthesis in as many 0-2A progenitors as in cultures exposed to 1-30 ng/ml of this growth factor, but exhibited a reduced ability to promote DNA synthesis in oligodendrocytes. In addition, although concentrations of bFGF as low as 0.03 ng/ml were a potent stimulator of DNA synthesis in 0-2A progenitors, application of this amount of bFGF no longer inhibited the differentiation of progenitors into oligodendrocytes as effectively as application of higher bFGF concentrations. Thus, the induction of DNA synthesis by bFGF can be uncoupled from the inhibition of differentiation. Our results demonstrate that exposure of 0-2A progenitors to bFGF is not necessarily associated with an inhibition of differentiation. This result may have relevance to understanding the paradox posed by the combined observations that bFGF, along with other members of the FGF family, appear to be abundantly expressed in the CNS during development, yet oligodendrocytes nonetheless are generated in vivo. In addition, the differing effects of exposure to bFGF we observed in heterogeneous optic nerve cultures vs. cultures of purified 0-2A progenitors underscore the importance of utilizing purified cell cultures to examine the direct effects of a particular factor on differentiation, in concert with the use of heterogeneous cultures to examine the complex situations which may more closely resemble the biology of the intact organism.