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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

Abstract

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.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. All data generated or analyzed during this study are included in this published article and its supplementary information files.

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Acknowledgements

We acknowledge Professor Tao Zhou at the Resource Center of the Chinese Academy of Traditional Chinese Medicine and Zili You at University of Electronic Science and Technology of China for giving us guidance on the experiment and writing.

Funding

This work was supported by the National Natural Science Foundation of China (81960811, 82060726), the PhD Start-up Fund of the Guizhou University of Traditional Chinese Medicine ([2019]31), Guizhou Science and Technology Plan Project ([2019]5611), the Department of Science and Technology of Guizhou High-level Innovative Talents ([2018]5638-2), and the Department of Science and Technology of Guizhou basic research ([2019]1026).

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Contributions

JX, and ZJ designed the conceptual idea for this study and wrote the manuscript. YS, LQ and ZJ performed the experiments. ZJ analyzed these data. All the authors participated in the discussion and approved the manuscript as submitted.

Corresponding author

Correspondence to Jinqiang Zhang.

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Author declares that there is no conflict of interest in this research.

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The animal study was reviewed and approved by the Institutional Animal Care and Use Committee, University of Electronic Science and Technology of China.

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Jiang, X., Yi, S., Liu, Q. et al. 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. Cytotechnology 74, 407–420 (2022). https://doi.org/10.1007/s10616-022-00534-2

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  • DOI: https://doi.org/10.1007/s10616-022-00534-2

Keywords

  • Microglia
  • Interferon-gamma, Interleukin-4, Neural stem/progenitor cell
  • Neurogenesis
  • PI3K/Akt pathway