TY - JOUR
T1 - Nitric oxide stimulates the proliferation of neural stem cells bypassing the epidermal growth factor receptor
AU - Carreira, Bruno Pereira
AU - Morte, Maria Inês
AU - Inácio, Ângela
AU - Costa, Gabriel
AU - Rosmaninho-Salgado, Joana
AU - Agasse, Fabienne
AU - Carmo, Anália
AU - Couceiro, Patrícia
AU - Brundin, Patrik
AU - Ambrósio, António Francisco
AU - Carvalho, Caetana Monteiro
AU - Araújo, Inês Maria
N1 - Copyright:
Copyright 2010 Elsevier B.V., All rights reserved.
PY - 2010/7
Y1 - 2010/7
N2 - 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.
AB - 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.
KW - Cell proliferation
KW - Epidermal growth factor receptor
KW - Neural stem cells
KW - Nitric oxide
UR - http://www.scopus.com/inward/record.url?scp=77954821915&partnerID=8YFLogxK
U2 - 10.1002/stem.444
DO - 10.1002/stem.444
M3 - Article
C2 - 20506358
AN - SCOPUS:77954821915
SN - 1066-5099
VL - 28
SP - 1219
EP - 1230
JO - Stem Cells
JF - Stem Cells
IS - 7
ER -