P-hydroxy benzaldehyde facilitates reprogramming of reactive astrocytes into neurons via endogenous transcriptional regulation

Abstract

Background

Cerebral ischemia leads to linguistic and motor dysfunction, as the death of neurons in ischemic core is permanent and non-renewable. An innovative avenue is to induce and/or facilitate reprogramming of adjacent astrocytes into neurons to replace the lost neurons and re-establish brain homeostasis.

Purpose

This study aimed to investigate whether the p-hydroxy benzaldehyde (p-HBA), a phenolic compound isolated from Gastrodia elata Blume, could facilitate the reprogramming of oxygen-glucose deprivation/reperfusion (OGD/R)-damaged astrocytes into neurons.

Study Design/Methods

The primary parenchymal astrocytes of rat were exposure to OGD and reperfusion with define culture medium. Cells were then incubated with different concentration of p-HBA (1, 10, 100, 400 μM) and collected at desired time point for reprogramming process analysis.

Results

OGD/R could elicit endogenous neurogenic program in primary parenchymal astrocytes of rat under define culture condition, and these so-called reactive astrocytes could be reprogrammed into neurons. However, the neonatal neurons produced by this endogenous procedure could not develop into mature neurons, and the conversion rate was only 1.9%. Treatment of these reactive astrocytes with p-HBA could successfully promote the conversion rate to 6.1%, and the neonatal neurons could develop into mature neurons within 14 days. Further analysis showed that p-HBA down-regulated the Notch signal component genes Dll1, Hes1 and SOX2, while the transcription factor NeuroD1 was up-regulated.

Conclusion

The results of this study demonstrated that p-HBA facilitated the astrocyte-to-neuron conversion. This chemical reprogramming was mediated by inhibition of Notch1 signaling pathway and transcriptional activation of NeuroD1.

Keywords:

• Primary parenchymal astrocytes
• oxygen-glucose deprivation/reperfusion
• reprogramming
• p-hydroxy benzaldehyde

Acknowledgements

We are thankful for all the individuals who participated in the original studies. The content is solely the responsibility of the authors.

Availability of data and materials

All data generated or analysed during this study are included in this published article.

Ethics approval and consent to participate

The experiments were approved by the Animal Experiment Ethics Committee of Yunnan University of Chinese Medicine and were also conducted according to the National Institutes of Health Guide for the Care and Use of Laboratory Animals.

Consent for publication

Not applicable.

Declaration of interest statement

The authors declare that they have no conflict of interest.

Author contributions

All authors took part in the study and take responsibility for the data analysis. Research idea and design: NZ. Experimental performance: XL, YY, XM, interpretation of data: JX. Writing and revising of the manuscript: RF, JX, NZ. Statistical analysis: RF, JX. Study supervision: NZ. All authors reviewed and approved the manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by National Natural Science Foundation of China 81860714; The University Scientific and Technological Innovation Team of Prevention and Treatment of Metabolic Diseases by Chinese Medicine of Yunnan; Kunming Key Laboratory for Metabolic Diseases Prevention and Treatment by Chinese Medicine; Yang Guoyuan Expert Workstation in Kunming, Yunnan.