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Nitric oxide stimulates the proliferation of neural stem cells bypassing the epidermal growth factor receptor

Bruno Pereira Carreira1, Maria Inês Morte, Angela Inácio

  • 1Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.

Stem Cells (Dayton, Ohio)
|May 28, 2010
PubMed

Insights

Nitric oxide (NO) can stimulate neural stem cell proliferation by activating the MAPK pathway. This effect is crucial for brain repair after injury, as shown in a mouse model.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Biochemistry

Background:

  • Nitric oxide (NO) has a dual role in neural stem cell (NSC) proliferation, with evidence suggesting both inhibitory and proliferative effects.
  • The precise mechanisms underlying NO's potential to promote NSC proliferation remain largely unelucidated.
  • Understanding NO's role is critical for developing therapeutic strategies targeting neural regeneration.

Purpose of the Study:

  • To investigate and characterize the proliferative effects of NO on neural stem cells.
  • To elucidate the molecular pathways involved in NO-mediated NSC proliferation.
  • To determine the in vivo relevance of NO in NSC proliferation following brain injury.

Main Methods:

  • Primary mouse subventricular zone neural stem cell cultures were treated with varying concentrations of the NO donor NOC-18.
  • The involvement of the mitogen-activated protein kinase (MAPK) pathway and epidermal growth factor (EGF) receptor was assessed.
  • Mice lacking inducible nitric oxide synthase (iNOS(-/-)) were used to study NO's role in vivo following seizure-induced brain injury.

Main Results:

  • Low concentrations (10 microM) of NOC-18 increased NSC proliferation, while higher concentrations (100 microM) inhibited it.
  • NO-induced proliferation was rapid and dependent on the MAPK pathway, independent of the EGF receptor.
  • NO activated p21Ras and the MAPK pathway, leading to decreased nuclear p27(KIP1) and cell cycle progression.
  • In vivo, iNOS(-/-) mice exhibited reduced NSC proliferation after seizures compared to wild-type mice, highlighting NO's role in brain repair.

Conclusions:

  • Nitric oxide can stimulate neural stem cell proliferation through a mechanism involving the MAPK pathway, bypassing the EGF receptor.
  • Endogenous NO, particularly from iNOS, plays a significant role in promoting NSC proliferation in response to brain insults.
  • These findings offer insights into NO-mediated neurogenesis and potential therapeutic targets for neurological disorders.

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