ASTROGLIAL CONTROL OF OLIGODENDROCYTE SURVIVAL MEDIATED BY PDGF AND LEUKEMIA INHIBITORY FACTOR-LIKE PROTEIN

Programmed death and the identification of growth factors delaying thi s process in the oligodendrocyte lineage suggest that other cell types provide oligodendrogliotrophins. To determine their source, primary c ultures of oligodendroblasts immunopurified from postnatal rat cerebru m were used to screen other cultured neural and non-neural cell types for the release of survival factors into a defined insulin-containing medium, In non-conditioned medium, oligodendroblasts died 1-2 days aft er undergoing terminal differentiation into oligodendrocytes, as defin ed by the onset of expression of galactocerebroside. In medium conditi oned by astrocytes, unlike the other tested cell types, differentiated oligodendrocytes survived for weeks in a mature myelinogenic state. S urvival was partially reduced by immunoabsorption of the medium with a ntibodies to platelet-derived growth factor and abolished by immunoabs orption with antibodies to leukemia inhibitory factor, By the same cri terion, survival activity was not attributed to other astrocytic produ cts, ciliary neurotrophic factor and basic fibroblast growth factor. M embrane ultrafiltration analysis indicated the activity corresponded t o heat-labile protein smaller (M(r) = 10-30x10(3)) than native rat leu kemia inhibitory factor (M(r) = 43x10(3)). The astrocytic stimulus was >4-fold more efficacious than other known oligodendrogliotrophic cyto kines, including ciliary neurotrophic factor, neurotrophin-3 and leuke mia inhibitory factor itself, tested singly or in combination, and pro moted survival additively with these agents, These findings suggest th at astrocytes function as paracrine regulators of oligodendroblast and oligodendrocyte survival and that their effect is mediated initially by platelet-derived growth factor and thereafter by a powerful cytokin e related to leukemia inhibitory factor.