Skip to main content

Advertisement

SpringerLink
Log in

Specific downregulation of microRNA-186 induces neural stem cell self-renewal by upregulating Bmi-1/FoxG1 expression

  • Research Article
  • Published:
Human Cell Aims and scope Submit manuscript

Abstract

Self-renewal and differentiation in neural stem cells (NSCs) are modulated by microRNAs (miRNAs). However, the recent evidence available is not enough to elucidate the role of miRNA in the self-renewal and differentiation of NSCs from developing brain. In this study, we isolated primary NSCs from the forebrain of fetal rat for in vitro analysis. Downregulation of miRNA-186 in response to a specific miRNA inhibitor resulted in upregulation of Bmi-1 and FoxG1, while maintaining NCS self-renewal. Bmi-1 overexpression restored the maintenance of NSCs in vitro. FoxG1 was found to promote the methylation of Foxo3 promoter and inhibited Foxo3 expression. miR-186 upregulation increased the expression of Foxo3 and inhibited NSC self-renewal in the absence of Foxo3. Therefore, we propose that downregulation of miR-186 maintained NSC self-renewal in the postnatal brain by upregulating the Bmi1/FoxG1 expression via FoxO3 elevation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Data availability

The datasets generated and/or analyzed during the current study are available in the manuscript and supplementary materials.

Abbreviations

NSCs:

Neural stem cells

SVZ:

Subventricular zone

FOXO3:

Forkhead box O3

NC:

Negative control

SGZ:

Subgranular zone

References

  1. Praca C, Rai A, Santos T, Cristovao AC, Pinho SL, Cecchelli R, Dehouck MP, Bernardino L, Ferreira LS. A nanoformulation for the preferential accumulation in adult neurogenic niches. J Control Release. 2018;284:57–72. https://doi.org/10.1016/j.jconrel.2018.06.013.

    Article  CAS  PubMed  Google Scholar 

  2. Bago JR, Sheets KT, Hingtgen SD. Neural stem cell therapy for cancer. Methods. 2016;99:37–43. https://doi.org/10.1016/j.ymeth.2015.08.013.

    Article  CAS  PubMed  Google Scholar 

  3. Vieira MS, Santos AK, Vasconcellos R, Goulart VAM, Parreira RC, Kihara AH, Ulrich H, Resende RR. Neural stem cell differentiation into mature neurons: mechanisms of regulation and biotechnological applications. Biotechnol Adv. 2018;36:1946–70. https://doi.org/10.1016/j.biotechadv.2018.08.002.

    Article  CAS  PubMed  Google Scholar 

  4. Zhou FC, Balaraman Y, Teng M, Liu Y, Singh RP, Nephew KP. Alcohol alters DNA methylation patterns and inhibits neural stem cell differentiation. Alcohol Clin Exp Res. 2011;35:735–46. https://doi.org/10.1111/j.1530-0277.2010.01391.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Zhu K, Su Y, Xu B, Wang Z, Sun H, Wang L, Sun C, He X. MicroRNA-186-5p represses neuroblastoma cell growth via downregulation of Eg5. Am J Transl Res. 2019;11:2245–56.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Silva MM, Rodrigues B, Fernandes J, Santos SD, Carreto L, Santos MAS, Pinheiro P, Carvalho AL. MicroRNA-186-5p controls GluA2 surface expression and synaptic scaling in hippocampal neurons. Proc Natl Acad Sci U S A. 2019;116:5727–36. https://doi.org/10.1073/pnas.1900338116.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Wu DM, Wen X, Wang YJ, Han XR, Wang S, Shen M, Fan SH, Zhuang J, Zhang ZF, Shan Q, Li MQ, Hu B, Sun CH, et al. Effect of microRNA-186 on oxidative stress injury of neuron by targeting interleukin 2 through the janus kinase-signal transducer and activator of transcription pathway in a rat model of Alzheimer’s disease. J Cell Physiol. 2018;233:9488–502. https://doi.org/10.1002/jcp.26843.

    Article  CAS  PubMed  Google Scholar 

  8. Fasano CA, Phoenix TN, Kokovay E, Lowry N, Elkabetz Y, Dimos JT, Lemischka IR, Studer L, Temple S. Bmi-1 cooperates with Foxg1 to maintain neural stem cell self-renewal in the forebrain. Genes Dev. 2009;23:561–74. https://doi.org/10.1101/gad.1743709.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Manoranjan B, Wang X, Hallett RM, Venugopal C, Mack SC, McFarlane N, Nolte SM, Scheinemann K, Gunnarsson T, Hassell JA, Taylor MD, Lee C, Triscott J, et al. FoxG1 interacts with Bmi1 to regulate self-renewal and tumorigenicity of medulloblastoma stem cells. Stem Cells. 2013;31:1266–77. https://doi.org/10.1002/stem.1401.

    Article  CAS  PubMed  Google Scholar 

  10. Renault VM, Rafalski VA, Morgan AA, Salih DA, Brett JO, Webb AE, Villeda SA, Thekkat PU, Guillerey C, Denko NC, Palmer TD, Butte AJ, Brunet A. FoxO3 regulates neural stem cell homeostasis. Cell Stem Cell. 2009;5:527–39. https://doi.org/10.1016/j.stem.2009.09.014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Bulstrode H, Johnstone E, Marques-Torrejon MA, Ferguson KM, Bressan RB, Blin C, Grant V, Gogolok S, Gangoso E, Gagrica S, Ender C, Fotaki V, Sproul D, et al. Elevated FOXG1 and SOX2 in glioblastoma enforces neural stem cell identity through transcriptional control of cell cycle and epigenetic regulators. Genes Dev. 2017;31:757–73. https://doi.org/10.1101/gad.293027.116.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Zheng J, Li XD, Wang P, Liu XB, Xue YX, Hu Y, Li Z, Li ZQ, Wang ZH, Liu YH. CRNDE affects the malignant biological characteristics of human glioma stem cells by negatively regulating miR-186. Oncotarget. 2015;6:25339–55. https://doi.org/10.18632/oncotarget.4509.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Hakes AE, Brand AH. Neural stem cell dynamics: the development of brain tumours. Curr Opin Cell Biol. 2019;60:131–8. https://doi.org/10.1016/j.ceb.2019.06.001.

    Article  CAS  PubMed  Google Scholar 

  14. Chen D, Hu S, Wu Z, Liu J, Li S. The role of MiR-132 in regulating neural stem cell proliferation, differentiation and neuronal maturation. Cell Physiol Biochem. 2018;47:2319–30. https://doi.org/10.1159/000491543.

    Article  CAS  PubMed  Google Scholar 

  15. Murai K, Sun G, Ye P, Tian E, Yang S, Cui Q, Sun G, Trinh D, Sun O, Hong T, Wen Z, Kalkum M, Riggs AD, et al. The TLX-miR-219 cascade regulates neural stem cell proliferation in neurodevelopment and schizophrenia iPSC model. Nat Commun. 2016;7:10965. https://doi.org/10.1038/ncomms10965.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Fawal MA, Jungas T, Kischel A, Audouard C, Iacovoni JS, Davy A. Cross talk between one-carbon metabolism, Eph signaling, and histone methylation promotes neural stem cell differentiation. Cell Rep. 2018;23:2864–73. https://doi.org/10.1016/j.celrep.2018.05.005.

    Article  CAS  PubMed  Google Scholar 

  17. Wang Y, Xu Z, Jiang J, Xu C, Kang J, Xiao L, Wu M, Xiong J, Guo X, Liu H. Endogenous miRNA sponge lincRNA-RoR regulates Oct4, Nanog, and Sox2 in human embryonic stem cell self-renewal. Dev Cell. 2013;25:69–80. https://doi.org/10.1016/j.devcel.2013.03.002.

    Article  CAS  PubMed  Google Scholar 

  18. Kim DK, Seo EJ, Choi EJ, Lee SI, Kwon YW, Jang IH, Kim SC, Kim KH, Suh DS, Seong-Jang K, Lee SC, Kim JH. Crucial role of HMGA1 in the self-renewal and drug resistance of ovarian cancer stem cells. Exp Mol Med. 2016;48:e255. https://doi.org/10.1038/emm.2016.73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Kim J, Yoon H, Chung DE, Brown JL, Belmonte KC, Kim J. miR-186 is decreased in aged brain and suppresses BACE1 expression. J Neurochem. 2016;137:436–45. https://doi.org/10.1111/jnc.13507.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Chen BZ, Yu SL, Singh S, Kao LP, Tsai ZY, Yang PC, Chen BH, Shoei-Lung LS. Identification of microRNAs expressed highly in pancreatic islet-like cell clusters differentiated from human embryonic stem cells. Cell Biol Int. 2011;35:29–37. https://doi.org/10.1042/CBI20090081.

    Article  CAS  PubMed  Google Scholar 

  21. Godlewski J, Nowicki MO, Bronisz A, Williams S, Otsuki A, Nuovo G, Raychaudhury A, Newton HB, Chiocca EA, Lawler S. Targeting of the Bmi-1 oncogene/stem cell renewal factor by microRNA-128 inhibits glioma proliferation and self-renewal. Cancer Res. 2008;68:9125–30. https://doi.org/10.1158/0008-5472.CAN-08-2629.

    Article  CAS  PubMed  Google Scholar 

  22. Ganapathi M, Boles NC, Charniga C, Lotz S, Campbell M, Temple S, Morse RH. Effect of Bmi1 over-expression on gene expression in adult and embryonic murine neural stem cells. Sci Rep. 2018;8:7464. https://doi.org/10.1038/s41598-018-25921-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Vezzali R, Weise SC, Hellbach N, Machado V, Heidrich S, Vogel T. The FOXG1/FOXO/SMAD network balances proliferation and differentiation of cortical progenitors and activates Kcnh3 expression in mature neurons. Oncotarget. 2016;7:37436–55. https://doi.org/10.18632/oncotarget.9545.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Gopinath SD, Webb AE, Brunet A, Rando TA. FOXO3 promotes quiescence in adult muscle stem cells during the process of self-renewal. Stem Cell Reports. 2014;2:414–26. https://doi.org/10.1016/j.stemcr.2014.02.002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Ning Y, Luo C, Ren K, Quan M, Cao J. FOXO3a-mediated suppression of the self-renewal capacity of sphere-forming cells derived from the ovarian cancer SKOV3 cell line by 7-difluoromethoxyl-5,4’-di-n-octyl genistein. Mol Med Rep. 2014;9:1982–8. https://doi.org/10.3892/mmr.2014.2012.

    Article  CAS  PubMed  Google Scholar 

  26. Wu X, Zhao X, Miao X. MicroRNA-374b promotes the proliferation and differentiation of neural stem cells through targeting Hes1. Biochem Biophys Res Commun. 2018;503:593–9. https://doi.org/10.1016/j.bbrc.2018.06.044.

    Article  CAS  PubMed  Google Scholar 

  27. Herman JG, Graff JR, Myohanen S, Nelkin BD, Baylin SB. Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci U S A. 1996;93:9821–6. https://doi.org/10.1073/pnas.93.18.9821.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Guo T, Wang W, Zhang H, Liu Y, Chen P, Ma K, Zhou C. ISL1 promotes pancreatic islet cell proliferation. PLoS ONE. 2011;6:e22387. https://doi.org/10.1371/journal.pone.0022387.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors would like to give our sincere appreciation to the reviewers for their helpful comments on this article.

Funding

This work was supported by Basic Research Funding for Higher Education Institutions in Heilongjiang Province (2022-KYYWF-0786).

Author information

Authors and Affiliations

  1. Department of Neurology, The Third Affiliated Hospital of Qiqihar Medical University, 27 Taishun Street, Tiefeng District, Qiqihar City, 161000, Heilongjiang Province, China

    Tuantuan Chen, Jing Liu, Yang Liu, Yang Chen & Xue Wang

Authors
  1. Tuantuan Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jing Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yang Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yang Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xue Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conception and design: TC, JL, and YL. Administrative support: TC and JL. Provision of study materials or patients: TC, JL, YL, YC, and XW. Collection and assembly of data: YL, YC, and XW. Data analysis and interpretation: TC and JL. Manuscript writing: all authors. Final approval of manuscript: all authors.

Corresponding author

Correspondence to Tuantuan Chen.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

The experimental animals were euthanized in the present study, and all operations were carried out with the approval of the Animal Care and Use Committee of the Third Affiliated Hospital of Qiqihar Medical University (AECC-2022-003).

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 15 KB)

Supplementary file2 (DOCX 96 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, T., Liu, J., Liu, Y. et al. Specific downregulation of microRNA-186 induces neural stem cell self-renewal by upregulating Bmi-1/FoxG1 expression. Human Cell 36, 2016–2026 (2023). https://doi.org/10.1007/s13577-023-00981-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13577-023-00981-9

Keywords

Search

Navigation