Tissue-Specific Stem Cells

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Nitric Oxide Stimulates the Proliferation of Neural Stem Cells Bypassing the Epidermal Growth Factor Receptor†‡§

  1. Bruno Pereira Carreira1,
  2. Maria Inês Morte1,
  3. Ângela Inácio1,
  4. Gabriel Costa1,
  5. Joana Rosmaninho-Salgado1,
  6. Fabienne Agasse1,
  7. Anália Carmo1,
  8. Patrícia Couceiro2,
  9. Patrik Brundin3,
  10. António Francisco Ambrósio1,4,
  11. Caetana Monteiro Carvalho1,
  12. Inês Maria Araújo1,¶,*

Article first published online: 18 MAY 2010

DOI: 10.1002/stem.444

Issue

STEM CELLS

STEM CELLS

Volume 28, Issue 7, pages 1219–1230, July 2010

Additional Information

How to Cite

Carreira, B. P., Morte, M. I., Inácio, Â., Costa, G., Rosmaninho-Salgado, J., Agasse, F., Carmo, A., Couceiro, P., Brundin, P., Ambrósio, A. F., Carvalho, C. M. and Araújo, I. M. (2010), Nitric Oxide Stimulates the Proliferation of Neural Stem Cells Bypassing the Epidermal Growth Factor Receptor. STEM CELLS, 28: 1219–1230. doi: 10.1002/stem.444

Author Information

  1. 1

    Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal

  2. 2

    Institute of Pathological Anatomy, Faculty of Medicine, University of Coimbra, Coimbra, Portugal

  3. 3

    Wallenberg Neuroscience Center, Neuronal Survival Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden

  4. 4

    Center of Ophthalmology and Vision Sciences, IBILI, Faculty of Medicine, University of Coimbra, Coimbra, Portugal

  1. Telephone: +351239822752; Fax: +351239822776

*Center for Neuroscience and Cell Biology, University of Coimbra, Largo Marquês de Pombal, 3004-517 Coimbra, Portugal

  1. †

    Author contributions: B.P.C.: conception and design, collection and/or assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript; M.I.M.: collection and/or assembly of data, final approval of manuscript; Â.I.: collection and/or assembly of data, final approval of manuscript; G.C.: collection and/or assembly of data, final approval of manuscript; J.R.-S.: collection and/or assembly of data, data analysis and interpretation, final approval of manuscript; F.A.: collection and/or assembly of data, final approval of manuscript; A.C.: collection and/or assembly of data, data analysis and interpretation, final approval of manuscript; P.C.: collection and/or assembly of data, Final approval of manuscript; P.B.: data analysis and interpretation, manuscript writing, final approval of manuscript; A.F.A.: data analysis and interpretation, manuscript writing, final approval of manuscript; C.M.C.: conception and design, data analysis and interpretation, manuscript writing, final approval of manuscript; I.M.A.: conception and design, financial support, data analysis and interpretation, manuscript writing, final approval of manuscript.

  2. ‡

    First published online in STEM CELLSEXPRESS May 18, 2010.

  3. §

    Disclosure of potential conflicts of interest is found at the end of this article.

Publication History

  1. Issue published online: 20 JUL 2010
  2. Article first published online: 18 MAY 2010
  3. Manuscript Accepted: 5 MAY 2010
  4. Manuscript Received: 27 MAY 2009

Funded by

  • Calouste Gulbenkian Foundation
  • L'Oreal, UNESCO
  • European Neuroscience Institutes Network (ENI-NET)
  • Foundation for Science and Technology (FCT), Portugal. Grant Numbers: SFRH/BPD/17196/2004, SFRH/BPD/31547/2006, SFRH/BD/23754/2005, SAU-NEU/102612/2008

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Keywords:

  • Nitric oxide;
  • Neural stem cells;
  • Cell proliferation;
  • Epidermal growth factor receptor

Abstract

Nitric oxide (NO) was described to inhibit the proliferation of neural stem cells. Some evidence suggests that NO, under certain conditions, can also promote cell proliferation, although the mechanisms responsible for a potential proliferative effect of NO in neural stem cells have remained unaddressed. In this work, we investigated and characterized the proliferative effect of NO in cell cultures obtained from the mouse subventricular zone. We found that the NO donor NOC-18 (10 μM) increased cell proliferation, whereas higher concentrations (100 μM) inhibited cell proliferation. Increased cell proliferation was detected rapidly following exposure to NO and was prevented by blocking the mitogen-activated kinase (MAPK) pathway, independently of the epidermal growth factor (EGF) receptor. Downstream of the EGF receptor, NO activated p21Ras and the MAPK pathway, resulting in a decrease in the nuclear presence of the cyclin-dependent kinase inhibitor 1, p27KIP1, allowing for cell cycle progression. Furthermore, in a mouse model that shows increased proliferation of neural stem cells in the hippocampus following seizure injury, we observed that the absence of inducible nitric oxide synthase (iNOS−/− mice) prevented the increase in cell proliferation observed following seizures in wild-type mice, showing that NO from iNOS origin is important for increased cell proliferation following a brain insult. Overall, we show that NO is able to stimulate the proliferation of neural stem cells bypassing the EGF receptor and promoting cell division. Moreover, under pathophysiological conditions in vivo, NO from iNOS origin also promotes proliferation in the hippocampus. STEM CELLS 2010;28:1219–1230

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