Nakanishi Masaya, Niidome Tetsuhiro, Matsuda Satoru, Akaike Akinori, Kihara Takeshi, Sugimoto Hachiro
Department of Neuroscience for Drug Discovery, Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida-Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
Eur J Neurosci. 2007 Feb;25(3):649-58. doi: 10.1111/j.1460-9568.2007.05309.x.
Neural stem/progenitor cells (NSPCs) proliferate and differentiate depending on their intrinsic properties and local environment. It has been recognized that astrocytes promote neurogenic differentiation of NSPCs, suggesting the importance of cell-cell interactions between glial cells and NSPCs. Recent studies have demonstrated that microglia, one type of glial cells, play an important role in neurogenesis. However, little is known about how activated microglia control the proliferation and differentiation of NSPCs. In this study, we investigated the possibility that microglia-derived soluble factors regulate the behaviour of NSPCs. To this end, NSPCs and microglial cultures were obtained from rat embryonic day 16 subventricular zone (SVZ) and rat postnatal 1 day cortex, respectively, and the conditioned medium from microglia was prepared. Microglial-conditioned medium had no significant effect on the proliferation of NSPCs. In contrast, it increased the percentage of cells positive for a marker of astrocytes, glial fibrillary acidic protein (GFAP) during differentiation. The induction of astrocytic differentiation by microglial-conditioned medium was reduced by the inhibition of the Janus kinase/signal transducer and activation of transcription (JAK/STAT) and mitogen-activated protein kinase (MAPK) pathways. Furthermore, microglia-derived interleukin (IL)-6 and leukaemia inhibitory factor (LIF) were identified as essential molecules for this astrocytic differentiation using neutralizing antibodies and recombinant cytokines. Our results suggest that microglia as well as astrocytes contribute to the integrity of the local environment of NSPCs, and at least IL-6 and LIF released by activated microglia promote astrocytic differentiation of NSPCs via the activation of the JAK/STAT and MAPK pathways.
神经干/祖细胞（NSPCs）的增殖和分化取决于其内在特性和局部环境。人们已经认识到星形胶质细胞可促进NSPCs的神经源性分化，这表明神经胶质细胞与NSPCs之间细胞间相互作用的重要性。最近的研究表明，小胶质细胞作为一种神经胶质细胞，在神经发生中起重要作用。然而，关于活化的小胶质细胞如何控制NSPCs的增殖和分化知之甚少。在本研究中，我们探讨了小胶质细胞衍生的可溶性因子调节NSPCs行为的可能性。为此，分别从大鼠胚胎第16天的脑室下区（SVZ）和出生后第1天的皮质获得NSPCs和小胶质细胞培养物，并制备小胶质细胞条件培养基。小胶质细胞条件培养基对NSPCs的增殖没有显著影响。相反，它增加了分化过程中星形胶质细胞标志物胶质纤维酸性蛋白（GFAP）阳性细胞的百分比。抑制Janus激酶/信号转导子和转录激活因子（JAK/STAT）以及丝裂原活化蛋白激酶（MAPK）途径可降低小胶质细胞条件培养基对星形胶质细胞分化的诱导作用。此外，使用中和抗体和重组细胞因子确定小胶质细胞衍生的白细胞介素（IL）-6和白血病抑制因子（LIF）是这种星形胶质细胞分化的必需分子。我们的结果表明，小胶质细胞和星形胶质细胞都有助于NSPCs局部环境的完整性，并且至少活化的小胶质细胞释放的IL-6和LIF通过激活JAK/STAT和MAPK途径促进NSPCs的星形胶质细胞分化。
