PI3K/AKT/mTOR Signaling Mediates Valproic Acid-Induced Neuronal Differentiation of Neural Stem Cells through Epigenetic Modifications

Zhang, Xi; He, Xiaosong; Li, Qingqing; Kong, Xuejian; Ou, Zhanhui; Zhang, Le; Gong, Zhuo; Long, Dahong; Li, Jianhua; Zhang, Meng; Ji, Weidong; Zhang, Wenjuan; Xu, Liping; Xuan, Aiguo

doi:10.1016/j.stemcr.2017.04.006

Cited by 63 publications

(45 citation statements)

References 48 publications

(54 reference statements)

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“…mTor is also needed for the of dendritic arbors development and stabilization in the newly born olfactory bulb neurons (55). The mTor signaling pathway was reported to mediate valproic acid-induced neural differentiation of nScs (56). inhibition of the mTor signaling pathway by rapamycin was observed to suppress neural differentiation in the present study.…”

Section: Discussionsupporting

confidence: 65%

Ketamine promotes the neural differentiation of mouse embryonic stem cells by activating mTOR

Zhou

Zhang

et al. 2020

Mol Med Report

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Ketamine is a widely used general anesthetic and has been reported to demonstrate neurotoxicity and neuroprotection. investigation into the regulatory mechanism of ketamine on influencing neural development is of importance for a better and safer way of relieving pain. reverse transcription-quantitative polymerase chain reaction and western blotting were used to detect the critical neural associated gene expression, and flow cytometry to detect the neural differentiation effect. Hence, in the present study the underlying mechanism of ketamine (50 nM) on neural differentiation of the mouse embryonic stem cell (meSc) line 46c was investigated. The results demonstrated that a low dose of ketamine (50 nM) promoted the differentiation of meScs to neural stem cells (nScs) and activated mammalian target of rapamycin (mTor) by upregulating the expression levels of phosphorylated (p)-mTor. Furthermore, inhibition of the mTor signaling pathway by rapamycin or knockdown of mTor suppressed neural differentiation. a rescue experiment further confirmed that downregulation of mTOR inhibited the promotion of neural differentiation induced by ketamine. Taken together, the present study indicated that a low level of ketamine upregulated p-mTor expression levels, promoting neural differentiation.

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Section: Discussionsupporting

confidence: 65%

Ketamine promotes the neural differentiation of mouse embryonic stem cells by activating mTOR

Zhou

Zhang

et al. 2020

Mol Med Report

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“…The selection of the three agents applied to skin explants, valproic acid, resveratrol, and ascorbic acid, was based on previously established data supporting their capacity to stimulate stem cells with potential impact on hair growth. Specifically, valproic acid has been shown to induce differentiation of stem cells through epigenetic modifications and promote HF growth in human patients . In 2013, Jo et al used valproic acid to induce anagen in HFs of 7‐week‐old female C57BL/6 mice .…”

Section: Discussionmentioning

confidence: 99%

Differential distribution of the epigenetic marker 5‐hydroxymethylcytosine occurs in hair follicle stem cells during bulge activation

et al. 2019

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Background Hair follicle (HF) cycling is dependent upon activation and differentiation of an epithelial subpopulation of cells with stem‐like characteristics. These cells express cytokeratin 15 (CK15) and are sequestered within a specialized niche termed the follicular bulge. The pathways that mediate bulge activation are poorly understood, although growing evidence suggests a role for epigenetic events. Methods Here we investigated murine and human HFs to determine whether a recently described epigenetic hydroxymethylation marker, 5‐hmC, known to mediate cell growth and differentiation, may play a role in bulge activation. Results We found the bulge region of murine HFs to show variable 5‐hmC distribution within the nuclei of CK15‐positive stem cells during early anagen, a pattern that was not associated with resting stem cells of telogen follicles, which did not express 5‐hmC. Moreover, during phases of early anagen that were induced in an organ culture model, spatial alterations in bulge stem cell 5‐hmC reactivity, as assessed by dual labeling, were noted. Conclusions These preliminary findings suggest that 5‐hmC may play a dynamic role in bulge activation during anagen growth, and provide a foundation for further experimental inquiry into epigenomic regulation of HF stem cells.

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“…Since VPA induces changes in the expression of many genes as an epigenetic drug ( 40 ), we initially assumed that the altered expression of numerous genes in NS/PCs induced by prenatal VPA exposure would be sustained until adulthood. However, that was not the case: Only one DEG at the embryonic stage (E15) persisted until the adult stage, even though there existed hundreds of DEGs in NS/PCs between control and VPA mice at each developmental stage (E15, P5, and 12w).…”

Section: Discussionmentioning

confidence: 99%

Ectopic neurogenesis induced by prenatal antiepileptic drug exposure augments seizure susceptibility in adult mice

Sakai

Matsuda

Doi

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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SignificanceRecent clinical studies suggest that environmental insults, such as valproic acid (VPA) exposure, in utero can have adverse effects on brain function of the offspring in later life, although the underlying mechanisms of these impairments remain poorly understood. By focusing on the property of neural stem/progenitor cells (NS/PCs) residing in the adult hippocampus, we identified the mechanism of increased seizure sensitivity in prenatally VPA-exposed adult mice. Furthermore, we found that voluntary exercise can overcome the adverse effects through normalizing VPA-induced transcriptome alterations in NS/PCs. We believe that our study provides insights for further understanding and developing treatment strategies for neurological disorders induced by prenatal environmental insults.

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PI3K/AKT/mTOR Signaling Mediates Valproic Acid-Induced Neuronal Differentiation of Neural Stem Cells through Epigenetic Modifications

Cited by 63 publications

References 48 publications

Ketamine promotes the neural differentiation of mouse embryonic stem cells by activating mTOR

Ketamine promotes the neural differentiation of mouse embryonic stem cells by activating mTOR

Differential distribution of the epigenetic marker 5‐hydroxymethylcytosine occurs in hair follicle stem cells during bulge activation

Ectopic neurogenesis induced by prenatal antiepileptic drug exposure augments seizure susceptibility in adult mice

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