Jiang Xue, Yi Saini, Liu Qin, Zhang Jinqiang
State Key Laboratory of Quality Research in Chinese Medicine & Institute of Chinese Medical Sciences, University of Macau, Macao, 999078 China.
Laboratory of neuropharmacology, Resource Institute for Chinese & Ethnic Materia Medica, Guizhou University of Traditional Chinese Medicine, Guiyang, 550025 China.
Cytotechnology. 2022 Jun;74(3):407-420. doi: 10.1007/s10616-022-00534-2. Epub 2022 Apr 24.
Microglia has been reported to be able to regulate the proliferation, differentiation and survival of adult neural stem/progenitor cells (NSPCs) by modulating the microenvironment, which results in different consequences of adult neurogenesis. However, whether the microglial activation is beneficial or harmful to NSPCs is still controversial because of the complexity and variability of microglial activation phenotypes. In this study, we systematically explored the activation phenotypes of IFN-γ- or IL-4-induced microglia at different time after stimulation, and investigated the effects of the secretome of different phenotype of microglia on the process of proliferation, differentiation and survival of NSPCs. Moreover, the possible molecular pathways of secretory influence on NSPCS were further explored using western blotting. The result showed that IFN-γ and IL-4 differently regulate microglial phenotypes, IL-4 induced a M2-like phenotype, while IFN-γ induced a M1-like phenotype. These phenotypes of microglia can only be maintained for 24 h after removal of IFN-γ or IL-4 intervention. The secretome from IFN-γ- or IL-4-induced microglia also had opposite effects on NSPCs proliferation, differentiation and survival. The secretome from the IL-4-treated microglia promoted NSPCs proliferation, survival and differentiation into neurons and oligodendrocytes, while factors secreted by the INF-γ-treated microglia stimulated the NSPCs differentiation into astrocyte, inhibited the neurogenesis and oligodendrogliogenesis, and induced NSPCs apoptosis. Furthermore, the PI3K-Akt pathway mediates the effects of the secretome from IFN-γ- or IL-4-induced microglia on NSPC proliferation, differentiation, and survival. In conclusion, our results suggested that the secretome of microglia induced by IL-4 of IFN-γ differently regulate proliferation, differentiation and survival of adult neural stem/progenitor cell by targeting the PI3K-Akt pathway. These findings will help further study the biological mechanism of microglia regulating neurogenesis, and provide a therapeutic strategy for neurological diseases by regulating microglial phenotypes to affect neurogenesis.
据报道，小胶质细胞能够通过调节微环境来调控成年神经干细胞/祖细胞（NSPCs）的增殖、分化和存活，这导致成年神经发生产生不同的结果。然而，由于小胶质细胞激活表型的复杂性和变异性，小胶质细胞激活对NSPCs是有益还是有害仍存在争议。在本研究中，我们系统地探索了IFN-γ或IL-4诱导的小胶质细胞在刺激后不同时间的激活表型，并研究了不同表型小胶质细胞的分泌产物对NSPCs增殖、分化和存活过程的影响。此外，使用蛋白质印迹法进一步探索了分泌产物对NSPCs产生影响的可能分子途径。结果表明，IFN-γ和IL-4对小胶质细胞表型的调节方式不同，IL-4诱导出M2样表型，而IFN-γ诱导出M1样表型。去除IFN-γ或IL-4干预后，这些小胶质细胞表型仅能维持24小时。IFN-γ或IL-4诱导的小胶质细胞的分泌产物对NSPCs的增殖、分化和存活也有相反的影响。IL-4处理的小胶质细胞的分泌产物促进NSPCs的增殖、存活并分化为神经元和少突胶质细胞，而IFN-γ处理的小胶质细胞分泌的因子则刺激NSPCs分化为星形胶质细胞，抑制神经发生和少突胶质细胞生成，并诱导NSPCs凋亡。此外，PI3K-Akt信号通路介导了IFN-γ或IL-4诱导的小胶质细胞的分泌产物对NSPC增殖、分化和存活的影响。总之，我们的结果表明，IL-4或IFN-γ诱导的小胶质细胞的分泌产物通过靶向PI3K-Akt信号通路，对成年神经干细胞/祖细胞的增殖、分化和存活进行不同的调节。这些发现将有助于进一步研究小胶质细胞调节神经发生的生物学机制，并通过调节小胶质细胞表型来影响神经发生，为神经系统疾病提供治疗策略。
