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Ramified microglial cells promote astrogliogenesis and maintenance of neural stem cells through activation of Stat3 function

Pengxiang Zhu^*, Ryuji Hata^*,1, Fang Cao^*, Feng Gu^*, Yasushi Hanakawa, Koji Hashimoto and Masahiro Sakanaka^*

^* Department of Functional Histology and

Department of Dermatology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, Japan

¹ Correspondence: Department of Functional Histology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime 791-0295, Japan. E-mail: hata{at}m.ehime-u.ac.jp

The differentiation and proliferation of neural stem cells (NSCs) are regulated by a combination of their intrinsic properties (e.g., transcription factors, epigenetic factors, and microRNA regulation) and cell-extrinsic properties from the microenvironment around NSC (e.g., cytokines, growth factors, and cell-cell contact). Recently, there has been a great interest in clarifying the mechanism of the influence of the microenvironment on NSCs, especially cell-cell contact between NSCs and other types of cells nearby. In this study, we investigated whether microglial (Mi) cells influence the fate of NSCs. Coculture study showed that ramified Mi cells promoted astrogliogenesis and maintenance of NSCs through their paracrine effects. This microglia-induced astrogliogenesis was inhibited by AG490 and by overexpression of the dominant-negative form of Stat3 and SOCS3. Promoter assay revealed transactivation of Stat3 function in NSCs by Mi cells. Gene expression study revealed that mRNA of Notch family members (notch1–3) and sox9 in NSCs was significantly upregulated by Mi cells, and this up-regulation was inhibited by AG490. These results demonstrated that ramified Mi cells promoted astrogliogenesis and maintenance of NSCs by activating Stat3 function and via notch and sox9 signaling pathways.—Zhu, P., Hata, R., Cao, F., Gu, F., Hanakawa, Y., Hashimoto, K., Sakanaka, M. Ramified microglial cells promote astrogliogenesis and maintenance of neural stem cells through activation of Stat3 function.

Key Words: neurogenesis • NSC • SOCS3 • AG490 • notch