IGF-1 Promotes Brn-4 Expression and Neuronal Differentiation of Neural Stem Cells via the PI3K/Akt Pathway

Zhang, Xinhua; Zhang, Lei; Cheng, Xiang; Guo, Yunfei; Sun, Xinwei; Chen, Geng; Li, Haoming; Li, Pengcheng; Lü, Xiaohui; Tian, Mei; Qin, Jianbing; Zhou, Huaiyu; Jin, Guohua

doi:10.1371/journal.pone.0113801

Cited by 47 publications

(37 citation statements)

References 56 publications

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“…NSCs were prepared from the hippocampus of Sprague–Dawley (SD) rats at embryonic days 14 (E14), which were obtained from Laboratory Animal Centre of Cheeloo College of Medicine, Shandong University. The protocol was the same as that described previously (Zhang et al, ). In brief, rats were anesthetized with chloral hydrate (2‐ml/kg body weight), followed by a quick dissection of hippocampus under sterile condition.…”

Section: Methodsmentioning

confidence: 99%

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Retracted: Ganoderic acid A alleviates hypoxia‐induced apoptosis, autophagy, and inflammation in rat neural stem cells through the PI3K/AKT/mTOR pathways

Chang

Kong

2019

Phytotherapy Research

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Effects of ganoderic acid A (GAA), a lanostane triterpene, on hypoxia‐ischemia encephalopathy (HIE) remain unclear. We aimed to figure out the specific role of GAA in hypoxia‐treated neural stem cells (NSCs) as well as the regulatory mechanisms. Primary rat NSCs were incubated under hypoxia to simulate HIE. Viability and apoptosis of hypoxia‐injured NSCs were measured by cell counting kit‐8 and flow cytometry assays, respectively. Proteins related to apoptosis, autophagy, and the PI3K/AKT/mTOR pathways were evaluated by Western blot analysis. LY294002 and rapamycin were added to inhibit the PI3K/AKT pathway and mTOR pathway, respectively. Enzyme‐linked immunosorbent assay was carried out to test the release of proinflammatory cytokines. We found that hypoxia‐induced decrease of cell viability, increases of apoptotic cells and autophagy, and the release of IL‐6, IL‐1β, and TNF‐α were all attenuated by GAA stimulation. Activation of caspases induced by hypoxia was alleviated by GAA. Furthermore, we found that inhibition of the PI3K/AKT pathway eliminated the effects of GAA on apoptosis and proinflammatory cytokines release in hypoxia‐injured NSCs. Meanwhile, inhibition of the mTOR pathway abrogated the effects of GAA on cell autophagy in hypoxia‐injured NSCs. In conclusion, GAA alleviated hypoxia‐induced injury in NSCs might be through activating the PI3K/AKT and mTOR pathways.

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Section: Methodsmentioning

confidence: 99%

“…The protocol was the same as that described previously (Zhang et al, 2014). In brief, rats were anesthetized with chloral hydrate (2ml/kg body weight), followed by a quick dissection of hippocampus under sterile condition.…”

Section: Primary Cell Culturementioning

confidence: 99%

Retracted: Ganoderic acid A alleviates hypoxia‐induced apoptosis, autophagy, and inflammation in rat neural stem cells through the PI3K/AKT/mTOR pathways

Chang

Kong

2019

Phytotherapy Research

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“…However, the outcome of the therapeutic effects of MSCs on neurogenesis and recovery of brain function is not sufficient, and remains to be further improved. Brn-4 is a transcription factor that plays a critical role in neuronal development [18,19,20,21], whereas the effects of Brn-4 overexpression in transplanted MSCs on AD are unknown. Therefore, increasing the levels of Brn-4 in MSCs may be examined to evaluate its effects on the outcome of MSC transplantation.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic Effects of Transplantation of As-MiR-937-Expressing Mesenchymal Stem Cells in Murine Model of Alzheimer's Disease

Liu

Wang

et al. 2015

Cell Physiol Biochem

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Background/Aims: Alzheimer's disease (AD) is one of the most common dementias among aged people, and is clinically characterized by progressive memory loss, behavioral and learning dysfunction and cognitive deficits. So far, this is no cure for AD. A therapeutic effect of transplantation of mesenchymal stem cells (MSCs) into murine model of AD has been reported, but remains to be further improved. Brn-4 is a transcription factor that plays a critical role in neuronal development, whereas the effects of Brn-4 overexpression in transplanted MSCs on AD are unknown. Methods: MSCs were isolated from mouse bone marrow and induced to overexpress antisense of miRNA-937 (as-miR-937) through adeno-associated virus (AAV)-mediated transduction, and purified by flow cytometry based on expression of a GFP co-transgene in the cells. The Brn-4 levels in mouse MSCs were examined in miR-937-modified MSCs by RT-qPCR and by Western blot. These miR-937-modified MSCs were then transplanted into an APP/PS1 transgenic AD model in mice. The effects of saline control, MSCs and asmiR-937 MSCs on AD mice were examined by deposition of amyloid-beta peptide aggregates (Aβ), social recognition test (SR), Plus-Maze Discriminative Avoidance Task (PM-DAT) and the levels of Brain-derived neurotrophic factor (BDNF) in the mouse brain. Results: MSCs expressed high levels of Brn-4 transcripts but low levels of Brn-4 protein. Poor protein vs mRNA levels of Brn-4 in MSCs appeared to result from the presence of high levels of miR-937 in MSCs. miR-937 inhibited translation of Brn-4 mRNA through binding to the 3'-UTR of the Brn-4 mRNA in MSCs. Expression of as-miR-937 significantly increased Brn-4 protein levels in MSCs. Transplantation of as-miR-937-expressing MSCs significantly reduced the deposition of Aβ, increased the levels of BDNF, and significantly improved the appearance in SR and PM-DAT in AD mice. Conclusion: Overexpression of as-miR-937 in MSCs may substantially improve the therapeutic effects of MSCs on AD, possibly through augmenting Brn-4 levels in MSCs.

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“…The extracts of the denervated hippocampus following fimbria fornix transection improved the survival, migration, and neuronal differentiation of NSCs compared with the extracts of normal hippocampus (Zhang et al, ). We also found that IGF‐1 could upregulate Brn4 by activating the PI3K/Akt signaling pathway, which in turn enhances the differentiation of NSCs into neurons (Zhang et al, ). These results suggest that Brn4 plays an important role in the process of NSC differentiation into neurons, and IGF‐1 controls its expression.…”

Section: Introductionmentioning

confidence: 88%

Exploration of the Brn4‐regulated genes enhancing adult hippocampal neurogenesis by RNA sequencing

Guo

Cheng

Zhang

et al. 2017

J of Neuroscience Research

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Adult hippocampal neurogenesis is essential for learning and memory, and its dysfunction is involved in neurodegenerative diseases. However, the molecular mechanisms underlying adult hippocampal neurogenesis are still largely unknown. Our previous studies indicated that the transcription factor Brn4 was upregulated and promoted neuronal differentiation of neural stem cells (NSCs) in the surgically denervated hippocampus in rats. In this study, we use high-throughput RNA sequencing to explore the molecular mechanisms underlying the enhancement of adult hippocampal neurogenesis induced by lentivirus-mediated Brn4 overexpression in vivo. After 10 days of the lentivirus injection, we found that the expression levels of genes related to neuronal development and maturation were significantly increased and the expression levels of genes related to NSC maintenance were significantly decreased, indicating enhanced neurogenesis in the hippocampus after Brn4 overexpression. Through RNA sequencing, we found that 658 genes were differentially expressed in the Brn4-overexpressed hippocampi compared with GFP-overexpressed controls. Many of these differentially expressed genes are involved in NSC division and differentiation. By using quantitative real-time PCR, we validated the expression changes of three genes, including Ctbp2, Notch2, and Gli1, all of which are reported to play key roles in neuronal differentiation of NSCs. Importantly, the expression levels of Ctbp2 and Notch2 were also significantly changed in the hippocampus of Brn4 KO mice, which indicates that the expression levels of Ctbp2 and Notch2 may be directly regulated by Brn4. Our current study provides a solid foundation for further investigation and identifies Ctbp2 and Notch2 as possible downstream targets of Brn4. © 2017 Wiley Periodicals, Inc.

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IGF-1 Promotes Brn-4 Expression and Neuronal Differentiation of Neural Stem Cells via the PI3K/Akt Pathway

Cited by 47 publications

References 56 publications

Retracted: Ganoderic acid A alleviates hypoxia‐induced apoptosis, autophagy, and inflammation in rat neural stem cells through the PI3K/AKT/mTOR pathways

Retracted: Ganoderic acid A alleviates hypoxia‐induced apoptosis, autophagy, and inflammation in rat neural stem cells through the PI3K/AKT/mTOR pathways

Therapeutic Effects of Transplantation of As-MiR-937-Expressing Mesenchymal Stem Cells in Murine Model of Alzheimer's Disease

Exploration of the Brn4‐regulated genes enhancing adult hippocampal neurogenesis by RNA sequencing

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