A ROLE FOR TGF-BETA IN OLIGODENDROCYTE DIFFERENTIATION

Oligodendrocyte-type-2 astrocyte (O-2A) glial progenitor cells undergo a limited number of mitotic divisions in response to PDGF before diff erentiating into oligodendrocytes, the myelin-forming cell of the CNS. We examined the mechanism limiting O-2A proliferation, and demonstrat e that these cells secrete an inhibitor of cell proliferation that can be neutralized with antibodies to TGF-beta. O-2A cells also secrete a n inhibitory activity that cannot be neutralized with TGF-beta antibod ies. O-2A progenitor cultures express TGF-beta1 isoform and its transc ript, while oligodendrocyte cultures express TGF-beta1, beta-2, and be ta-3 isoforms. Both recombinant TGF-beta1 and O-2A conditioned medium inhibit the proliferation of O-2A progenitor cells cultured in the pre sence of PDGF, and this inhibition can be partially neutralized with p olyclonal TGF-beta antibodies. Thus, TGF-beta produced by O-2A cells m ay limit PDGF-driven mitosis and promote oligodendrocyte development. TGF-beta is a less potent inhibitor of O-2A proliferation when these c ells are cultured in the presence of bFGF, suggesting that bFGF interf eres with TGF-beta signaling. Thus, the production of TGF-beta by cell s in the O-2A lineage may account for the distinct effects of PDGF and bFGF on O-2A progenitor cell proliferation. Moreover, our results sug gest that TGF-beta may be an important mediator of oligodendrocyte dif ferentiation.