4-Cholesten-3-one promotes differentiation of neural stem cells into dopaminergic neurons through TET1 and FoxA2.

Sen Ye, Jun Zhong, Jiapei Huang, SaiXia Zhang, Hui Li, DongFeng Chen, CaiXia Li

Neuroscience letters 2020 Sep 14

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In this paper, we report the results of treating cells with an effective small molecule, (+)4-cholesten-3-one (PubChem CID: 91477), which can promote neural stem cell(NSC) differentiation into dopaminergic neurons. This study used rat neural stem cells stimulated with two different concentrations (7.8 μM and 78 μM) of (+)4-cholesten-3-one. Cell phenotypic analysis showed that (+)4-cholesten-3-one induced NSC differentiation into dopaminergic neurons, and the level of tyrosine hydroxylase(TH), which is specific for dopaminergic cells, was significantly increased compared with that of the drug-free control group. Furthermore, in this study, we found that this effect may be related to the transcription factor fork-head box a2 (FoxA2) and ten-eleven translocation 1 (TET1). The expression of TET1 and FoxA2 was upregulated after treatment with (+)4-cholesten-3-one. To verify the relationship between (+)4-cholesten-3-one and these genes, we found that the binding rate of TET1 and FoxA2 increased after the application of (+)4-cholesten-3-one, as confirmed by a coimmunoprecipitation (Co-IP) assay. With a small interfering RNA (siRNA) experiment, we found that only when Tet1 and Foxa2 were not silenced was the mRNA level of Th increased after (+)4-cholesten-3-one treatment. Taken together, these data show that (+)4-cholesten-3-one can promote the differentiation of NSCs into dopaminergic neurons by upregulating the expression of TET1 and FoxA2 and by increasing their binding. Thus, (+)4-cholesten-3-one may help address the application of neural stem cell replacement therapy in neurodegenerative diseases. Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.

Citation

Sen Ye, Jun Zhong, Jiapei Huang, SaiXia Zhang, Hui Li, DongFeng Chen, CaiXia Li. 4-Cholesten-3-one promotes differentiation of neural stem cells into dopaminergic neurons through TET1 and FoxA2. Neuroscience letters. 2020 Sep 14;735:135239