Regulation of neural stem cells during development and regeneration of the central nervous system

Abstract

Three principal cell types in the central nervous system, i.e., neurons, astrocytes and oligodendrocytes, arise from neural stem cells. Recent studies have revealed that such stem cells are present in the adult brain as well as in the developing brain. Recent advances enabled us to understand molecular regulation of neural stem cells, raising a possibility that they can be used for therapeutic treatment of neurodegenerative diseases. Differentiation of neural stem cells into the three neural cell types is known to be regulated in part by cell-external cues. For example, cytokines in the interleukin-6 (IL-6) family and the transforming growth factor β (TGF β) family promote astrocytogenesis. In the nucleus of cytokine-treated cells, multiple physical interactions among transcription factors and transcriptional co-activators occur and contribute to the neuroglial differentiation. Upon injury, cytokines secreted from injured tissues affect cell fates of neighboring stem cells during nerve regeneration in the adult. In this case, undesired gliosis is often observed, which is most likely induced by such cytokines. In addition to cell-external cues, cell fate determination process is also regulated by cell-intrinsic programs, which include epigenetic regulation. Spationtemporally regulated expression of lineage specific genes are important for fate determination of neural stem cells, which in some cases is associated with DNA methylation and histone modification within their promoters. From these viewpoints, we here discuss molecular regulation of neural stem cells during development and regeneration. Efforts to apply our findings to therapeutic treatment of neurodegenerative disorders are also discussed.