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Possible Involvement of PI3-K/Akt-Dependent GSK-3β Signaling in Proliferation of Neural Progenitor Cells After Hypoxic Exposure

  • Keishi Kisoh
  • Hideki Hayashi
  • Miho Arai
  • Maiko Orita
  • Bo Yuan
  • Norio Takagi
Article
  • 104 Downloads

Abstract

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.

Keywords

Cerebral ischemia Neural progenitor cell Neurogenesis GSK-3β PI3-K/Akt Hypoxia 

Abbreviations

GSK

Glycogen synthase kinase

PI3-K

Phosphatidylinositol 3-kinase

SGZ

Sub-granular zone

Notes

Funding Information

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.

References

  1. 1.
    Mochizuki N, Takagi N, Onozato C, Moriyama Y, Takeo S, Tanonaka K (2008) Delayed injection of neural progenitor cells improved spatial learning dysfunction after cerebral ischemia. Biochem Biophys Res Commun 368(1):151–156CrossRefPubMedGoogle Scholar
  2. 2.
    Kawai T, Takagi N, Miyake-Takagi K, Okuyama N, Mochizuki N, Takeo S (2004) Characterization of BrdU-positive neurons induced by transient global ischemia in adult hippocampus. J Cereb Blood Flow Metab 24(5):548–555.  https://doi.org/10.1097/00004647-200405000-00009 CrossRefPubMedGoogle Scholar
  3. 3.
    Arvidsson A, Collin T, Kirik D, Kokaia Z, Lindvall O (2002) Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat Med 8(9):963–970CrossRefPubMedGoogle Scholar
  4. 4.
    Parent JM, Vexler ZS, Gong C, Derugin N, Ferriero DM (2002) Rat forebrain neurogenesis and striatal neuron replacement after focal stroke. Ann Neurol 52(6):802–813CrossRefPubMedGoogle Scholar
  5. 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. 6.
    Chae JH, Stein GH, Lee JE (2004) NeuroD: the predicted and the surprising. Mol Cells 18(3):271–288PubMedGoogle Scholar
  7. 7.
    Miyata T, Maeda T, Lee JE (1999) NeuroD is required for differentiation of the granule cells in the cerebellum and hippocampus. Genes Dev 13(13):1647–1652CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Moriyama Y, Takagi N, Tanonaka K (2011) Intravenous injection of neural progenitor cells improved depression-like behavior after cerebral ischemia. Transl Psychiatry 1:e29.  https://doi.org/10.1038/tp.2011.32 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Mochizuki N, Takagi N, Kurokawa K, Kawai T, Besshoh S, Tanonaka K, Takeo S (2007) Effect of NMDA receptor antagonist on proliferation of neurospheres from embryonic brain. Neurosci Lett 417(2):143–148CrossRefPubMedGoogle Scholar
  10. 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 CrossRefPubMedGoogle Scholar
  11. 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
  12. 12.
    Goncalves JT, Schafer ST, Gage FH (2016) Adult neurogenesis in the hippocampus: from stem cells to behavior. Cell 167(4):897–914.  https://doi.org/10.1016/j.cell.2016.10.021 CrossRefPubMedGoogle Scholar
  13. 13.
    Gao Z, Ure K, Ables JL, Lagace DC, Nave KA, Goebbels S, Eisch AJ, Hsieh J (2009) Neurod1 is essential for the survival and maturation of adult-born neurons. Nat Neurosci 12(9):1090–1092.  https://doi.org/10.1038/nn.2385 CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Mochizuki N, Takagi N, Kurokawa K, Onozato C, Moriyama Y, Tanonaka K, Takeo S (2008) Injection of neural progenitor cells improved learning and memory dysfunction after cerebral ischemia. Exp Neurol 211(1):194–202CrossRefPubMedGoogle Scholar
  15. 15.
    Cameron HA, Hazel TG, McKay RD (1998) Regulation of neurogenesis by growth factors and neurotransmitters. J Neurobiol 36(2):287–306CrossRefPubMedGoogle Scholar
  16. 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
  17. 17.
    O’Kusky JR, Ye P, D’Ercole AJ (2000) Insulin-like growth factor-I promotes neurogenesis and synaptogenesis in the hippocampal dentate gyrus during postnatal development. J Neurosci 20(22):8435–8442CrossRefPubMedGoogle Scholar
  18. 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. 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 CrossRefPubMedGoogle Scholar
  20. 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
  21. 21.
    Giese AK, Frahm J, Hubner R, Luo J, Wree A, Frech MJ, Rolfs A, Ortinau S (2010) Erythropoietin and the effect of oxygen during proliferation and differentiation of human neural progenitor cells. BMC Cell Biol 11:94.  https://doi.org/10.1186/1471-2121-11-94 CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Kuwabara T, Hsieh J, Muotri A, Yeo G, Warashina M, Lie DC, Moore L, Nakashima K et al (2009) Wnt-mediated activation of NeuroD1 and retro-elements during adult neurogenesis. Nat Neurosci 12(9):1097–1105.  https://doi.org/10.1038/nn.2360 CrossRefPubMedPubMedCentralGoogle Scholar
  23. 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
  24. 24.
    Kim SE, Lee WJ, Choi KY (2007) The PI3 kinase-Akt pathway mediates Wnt3a-induced proliferation. Cell Signal 19(3):511–518.  https://doi.org/10.1016/j.cellsig.2006.08.008 CrossRefPubMedGoogle Scholar
  25. 25.
    Ashton RS, Conway A, Pangarkar C, Bergen J, Lim KI, Shah P, Bissell M, Schaffer DV (2012) Astrocytes regulate adult hippocampal neurogenesis through ephrin-B signaling. Nat Neurosci 15(10):1399–1406.  https://doi.org/10.1038/nn.3212 CrossRefPubMedPubMedCentralGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Applied BiochemistryTokyo University of Pharmacy and Life SciencesTokyoJapan

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