Open AccessNitric Oxide Stimulates the Proliferation of Neural Stem Cells Bypassing the Epidermal Growth Factor Receptor
Author(s) -
Carreira Bruno Pereira,
Morte Maria Inês,
Inácio Ângela,
Costa Gabriel,
RosmaninhoSalgado Joana,
Agasse Fabienne,
Carmo Anália,
Couceiro Patrícia,
Brundin Patrik,
Ambrósio António Francisco,
Carvalho Caetana Monteiro,
Araújo Inês Maria
Publication year - 2010
Publication title -
stem cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.159
H-Index - 229
eISSN - 1549-4918
pISSN - 1066-5099
DOI - 10.1002/stem.444
Subject(s) - biology , neural stem cell , cell growth , microbiology and biotechnology , stem cell , mapk/erk pathway , epidermal growth factor , neurogenesis , subventricular zone , cell cycle , neurosphere , cellular differentiation , signal transduction , receptor , cell , adult stem cell , biochemistry , gene
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, p27 KIP1 , 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. S TEM C ELLS 2010;28:1219–1230