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20(S)-protopanaxadiol promotes the migration, proliferation, and differentiation of neural stem cells by targeting GSK-3β in the Wnt/GSK-3β/β-catenin pathway

Journal of Ginseng Research 2020년 44권 3호 p.475 ~ 482
 ( Lin Kaili ) - Hong Kong Baptist University Faculty of Science Department of Biology

 ( Liu Bin ) - Guangzhou Medical University Second Affiliated Hospital Guangzhou Institute of Cardiovascular Disease
 ( Lim Sze-Lam ) - Hong Kong Baptist University Faculty of Science Department of Biology
 ( Fu Xiuqiong ) - HKBU School of Chinese Medicine Center for Cancer and Inflammation Research
 ( Sze Stephen C. W. ) - Hong Kong Baptist University Faculty of Science Department of Biology
 ( Yung Ken K. L. ) - Hong Kong Baptist University Faculty of Science Department of Biology
 ( Zhang Shiqing ) - Hong Kong Baptist University Faculty of Science Department of Biology

Abstract


Background: Active natural ingredients, especially small molecules, have recently received wide attention as modifiers used to treat neurodegenerative disease by promoting neurogenic regeneration of neural stem cell (NSC) in situ. 20(S)-protopanaxadiol (PPD), one of the bioactive ingredients in ginseng, possesses neuroprotective properties. However, the effect of PPD on NSC proliferation and differentiation and its mechanism of action are incompletely understood.

Methods: In this study, we investigated the impact of PPD on NSC proliferation and neuronal lineage differentiation through activation of the Wnt/glycogen synthase kinase (GSK)-3β/β-catenin pathway. NSC migration and proliferation were investigated by neurosphere assay, Cell Counting Kit-8 assay, and EdU assay. NSC differentiation was analyzed by Western blot and immunofluorescence staining. Involvement of the Wnt/GSK3β/β-catenin pathway was examined by molecular simulation and Western blot and verified using gene transfection.

Results: PPD significantly promoted neural migration and induced a significant increase in NSC proliferation in a time- and dose-dependent manner. Furthermore, a remarkable increase in antimicrotubule-associated protein 2 expression and decrease in nestin protein expression were induced by PPD. During the differentiation process, PPD targeted and stimulated the phosphorylation of GSK-3β at Ser9 and the active forms of β-catenin, resulting in activation of the Wnt/GSK-3β/β-catenin pathway. Transfection of NSCs with a constitutively active GSK-3β mutant at S9A significantly hampered the proliferation and neural differentiation mediated by PPD.

Conclusion: PPD promotes NSC proliferation and neural differentiation in vitro via activation of the Wnt/GSK-3β/β-catenin pathway by targeting GSK-3β, potentially having great significance for the treatment of neurodegenerative diseases.

키워드

20(S)-protopanaxadiol; Neural differentiation; Neural stem cell; Proliferation; Wnt/GSK-3β/β-catenin pathway
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