Autocrine inhibition of mitotic activity in cultured oligodendrocyte‐type‐2 astrocyte (O‐2A) precursor cells

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Abstract
During development, oligodendrocytes are generated from a bipotential glial stem cell, the oligodendrocyte‐type‐2 astrocyte precursor (O‐2A). O‐2A cells are under the mitogenic influence of the platelet‐derived growth factor (PDGF) released from type‐1 astrocytes. In vitro experiments have shown that O‐2A cells stimulated by PDGF are limited to a set number of divisions and then differentiate to oligodendrocytes by becoming unresponsive to the growth factor. In the healthy adult central nervous system, oligodendrocyte proliferation remains generally quiescent and is possibly under negative growth control. The view that O‐2A lineage cells are capable of negatively regulating their own proliferation is supported by the demonstration that conditioned medium obtained from O‐2A cultures inhibits their DNA synthesis. In addition to O‐2A cells, the newly established CG4 cell line, a derivative of O‐2A cells, was found to inhibit O‐2A lineage cell proliferation. The antiproliferative activity was present in the media conditioned by CG4 cells that were expanded as undifferentiated O‐2A precursors, as well as by CG4 cells induced to differentiate to nonproliferating oligodendrocytes. Moreover, the inhibitory activity was produced by CG4 cells (source cells) propagated by various mitogens. The inhibition of mitotic activity was nearly complete, dose‐dependent, fully reversible, and exhibited when CG4 cells (test cells) were stimulated to divide by various mitogens, such as PDGF, basic fibroblast growth factor, or medium conditioned by the neuronal B104 cell line. The inhibition of proliferation was accompanied by the conversion of the phenotype of CG4 cells, from A2B5+/O4− precursors to A2B5−/O4+ prooligodendrocytes. This change of antigenic phenotype, like the inhibition of proliferation, was reversible. These results suggest that O‐2A cells secrete an autocrine inhibitory factor capable of reversibly withdrawing them from the cell cycle, which suggests that the commitment to the oligodendrocyte lineage might proceed through more than one discrete stage.

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