Reactive Astrocytes Inhibit the Survival and Differentiation of Oligodendrocyte Precursor Cells by Secreted TNF-α

Axonal demyelination is a consistent pathological characteristic of spinal cord injury (SCI). Although an increased number of oligodendrocyte progenitor cells (OPCs) is observed in the injured spinal cord, they fail to convert into mature oligodendrocytes. However, little is known about the underlying mechanism. In our study, we identified a link between inhibition of OPC survival and differentiation and reactive astrocytes in glial scar that was mediated by tumor necrosis factor-alpha (TNF-alpha). Initially, both glial scar tissue and reactive astrocyte-conditioned medium were shown to inhibit OPC differentiation. Reverse transcriptase polymerase chain reaction (RT-PCR) and immunochemistry revealed that OPCs expressed type 1 TNF-alpha receptor (TNF-R1). When TNF-alpha or TNF-R1 was neutralized with antibody, the effect of reactive astrocyte-conditioned medium or recombinant TNF-alpha protein on OPC differentiation was markedly attenuated. In addition, reactive astrocyte-conditioned medium was also shown to induce OPC apoptosis. All these findings provide the first evidence that reactive astrocytes release TNF-alpha to inhibit OPC survival and prevent them from differentiating into mature oligodendrocytes, suggesting a mechanism for the failure of remyelination after SCI.