ORIGINAL ARTICLE

Cell Research (2008): 686-694
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Impaired functions of neural stem cells by abnormal nitric oxide-mediated signaling in an in vitro model of Niemann-Pick type C disease

Sun-Jung Kim1,2, Myung-Sin Lim1,2, Soo-Kyung Kang3, Yong-Soon Lee1,2 and Kyung-Sun Kang1,2

1Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea;
2Laboratory of Stem Cell and Tumor Biology, Department of Veterinary Public Health, College of Veterinary Medicine and BK21 Program for Veterinary Science, Seoul National University, Seoul, Republic of Korea;
3Department of Physiology, College of Medicine, Pusan National University, Busan, Republic of Korea

Correspondence: Kyung-Sun Kang
Tel: +82-2-880-1246; Fax: +82-2-876-7610
E-mail: kangpub@snu.ac.kr

Nitric oxide (NO) has been implicated in the promotion of neurodegeneration. However, little is known about the relationship between NO and the self-renewal or differentiation capacity of neural stem cells (NSCs) in neurodegenerative disease. In this study, we investigated the effect of NO on self-renewal of NSCs in an animal model for Niemann-Pick type C (NPC) disease. We found that NO production was significantly increased in NSCs from NPC1-deficient mice (NPC1-/-), which showed reduced NSC self-renewal. The number of nestin-positive cells and the size of neurospheres were both significantly decreased. The expression of NO synthase (NOS) was increased in neurospheres derived from the brain of NPC1-/- mice in comparison to wild-type neurospheres. NO-mediated activation of glycogen synthase kinase-3β (GSK3β) and caspase-3 was also observed in NSCs from NPC1-/- mice. The self-renewal ability of NSCs from NPC1-/- mice was restored by an NOS inhibitor, L-NAME, which resulted in the inhibition of GSK3β and caspase-3. In addition, the differentiation ability of NSCs was partially restored and the number of Fluoro-Jade C-positive degenerating neurons was reduced. These data suggest that overproduction of NO in NPC disease impaired the self-renewal of NSCs. Control of NO production may be key for the treatment of NPC disease.

Cell Research (2008) 18:686-694. doi: 10.1038/cr.2008.48; published online 08 April 2008

Keywords: neural stem cells, nitric oxide, GSK3β, Niemann-Pick type C1 disease, caspase-3

 

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