Astroglial control of oligodendrocyte survival mediated by PDGF and leukemia inhibitory factor-like protein

Programmed death and the identification of growth factors delaying this process in the oligodendrocyte lineage suggest that other cell types provide oligodendrogliotrophins. To determine their source, primary cultures of oligodendroblasts immunopurified from postnatal rat cerebrum 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 after undergoing terminal differentiation into oligodendrocytes, as defined by the onset of expression of galactocerebroside. In medium conditioned by astrocytes, unlike the other tested cell types, differentiated oligodendrocytes survived for weeks in a mature myelinogenic state. Survival was partially reduced by immunoabsorption of the medium with antibodies to platelet-derived growth factor and abolished by immunoabsorption with antibodies to leukemia inhibitory factor. By the same criterion, survival activity was not attributed to other astrocytic products, ciliary neurotrophic factor and basic fibroblast growth factor. Membrane ultrafiltration analysis indicated the activity corresponded to heat-labile protein smaller (M(r) = 10(-30) x 10(3)) than native rat leukemia inhibitory factor (M(r) = 43 x 10(3)). The astrocytic stimulus was > 4-fold more efficacious than other known oligodendrogliotrophic cytokines, including ciliary neurotrophic factor, neurotrophin-3 and leukemia inhibitory factor itself, tested singly or in combination, and promoted survival additively with these agents. These findings suggest that 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 cytokine related to leukemia inhibitory factor.