Possible Involvement of PI3-K/Akt-Dependent GSK-3β Signaling in Proliferation of Neural Progenitor Cells After Hypoxic Exposure
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We previously demonstrated that proliferation of endogenous neural progenitor cells is enhanced by cerebral ischemia and that phosphatidylinositol 3-kinase (PI3-K)/Akt-dependent glycogen synthase kinase (GSK)-3β signaling is involved in ischemia-induced neurogenesis. It is important to learn more about the regulation of proliferation and differentiation of neural progenitor cells under ischemic conditions, as such knowledge that may serve as the basis for the development of new therapeutic approaches for stroke. However, it remains to be addressed whether a change in that signaling pathway is induced in neural progenitor cells. We prepared neural progenitor cells by using the neurosphere method and conducted experiments to determine the relative contributions of the PI3-K/Akt-dependent GSK-3β signaling pathway to the proliferation and differentiation of neural progenitor cells under the hypoxic condition in vitro. We showed that hypoxic exposure induced the proliferation of neural progenitor cells. This proliferation was accompanied by phosphorylation of Akt and GSK-3β at its Ser9. Furthermore, treatment with a PI3-K inhibitor decreased the hypoxia-induced phosphorylation of GSK-3β and proliferation of neural progenitor cells. Furthermore, hypoxic exposure enhanced the differentiation of neural progenitor cells, and this increased differentiation was not affected by treatment with the PI3-K inhibitor. Although the expression of NeuroD1 mRNA during cell differentiation was also enhanced by hypoxic exposure, this increased expression was not affected by treatment with the PI3-K inhibitor. Our findings suggest that the PI3K/Akt-dependent GSK-3β signaling pathway was involved in the proliferation of neural progenitor cells under a pathologic condition, such as hypoxia and/or cerebral ischemia in vivo.
KeywordsCerebral ischemia Neural progenitor cell Neurogenesis GSK-3β PI3-K/Akt Hypoxia
Glycogen synthase kinase
This research was supported in part by the Takeda Science Foundation.
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no competing interests.
- 5.Kisoh K, Hayashi H, Itoh T, Asada M, Arai M, Yuan B, Tanonaka K, Takagi N (2016) Involvement of GSK-3beta phosphorylation through PI3-K/Akt in cerebral ischemia-induced neurogenesis in rats. Mol Neurobiol 54:7917–7927. https://doi.org/10.1007/s12035-016-0290-8 CrossRefPubMedPubMedCentralGoogle Scholar
- 6.Chae JH, Stein GH, Lee JE (2004) NeuroD: the predicted and the surprising. Mol Cells 18(3):271–288Google Scholar
- 10.Yuan B, He J, Kisoh K, Hayashi H, Tanaka S, Si N, Zhao HY, Hirano T et al (2016) Effects of active bufadienolide compounds on human cancer cells and CD4+CD25+Foxp3+ regulatory T cells in mitogen-activated human peripheral blood mononuclear cells. Oncol Rep 36(3):1377–1384. https://doi.org/10.3892/or.2016.4946 CrossRefGoogle Scholar
- 11.Zhang J, Kang N, Yu X, Ma Y, Pang X (2017) Radial extracorporeal shock wave therapy enhances the proliferation and differentiation of neural stem cells by notch, PI3K/AKT, and Wnt/beta-catenin signaling. Sci Rep 7(1):15321. https://doi.org/10.1038/s41598-017-15662-5 CrossRefPubMedPubMedCentralGoogle Scholar
- 16.Chao J, Yang L, Yao H, Buch S (2014) Platelet-derived growth factor-BB restores HIV Tat-mediated impairment of neurogenesis: role of GSK-3beta/beta-catenin. Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology 9(2):259–268. https://doi.org/10.1007/s11481-013-9509-x CrossRefGoogle Scholar
- 18.Geranmayeh MH, Baghbanzadeh A, Barin A, Salar-Amoli J, Dehghan MM, Rahbarghazi R, Azari H (2015) Paracrine neuroprotective effects of neural stem cells on glutamate-induced cortical neuronal cell excitotoxicity. Adv Pharm Bull 5(4):515–521. https://doi.org/10.15171/apb.2015.070 CrossRefPubMedPubMedCentralGoogle Scholar
- 19.Kim JS, Chang MY, Yu IT, Kim JH, Lee SH, Lee YS, Son H (2004) Lithium selectively increases neuronal differentiation of hippocampal neural progenitor cells both in vitro and in vivo. J Neurochem 89(2):324–336. https://doi.org/10.1046/j.1471-4159.2004.02329.x CrossRefPubMedPubMedCentralGoogle Scholar
- 20.Tiwari SK, Seth B, Agarwal S, Yadav A, Karmakar M, Gupta SK, Choubey V, Sharma A et al (2015) Ethosuximide induces hippocampal neurogenesis and reverses cognitive deficits in an amyloid-beta toxin-induced Alzheimer rat model via the phosphatidylinositol 3-kinase (PI3K)/Akt/Wnt/beta-catenin pathway. J Biol Chem 290(47):28540–28558. https://doi.org/10.1074/jbc.M115.652586 CrossRefPubMedPubMedCentralGoogle Scholar
- 23.Bernis ME, Oksdath M, Dupraz S, Nieto Guil A, Fernandez MM, Malchiodi EL, Rosso SB, Quiroga S (2013) Wingless-type family member 3A triggers neuronal polarization via cross-activation of the insulin-like growth factor-1 receptor pathway. Front Cell Neurosci 7:194. https://doi.org/10.3389/fncel.2013.00194 CrossRefPubMedPubMedCentralGoogle Scholar