Original Article

Cell Research (2008) 18:686–694. doi: 10.1038/cr.2008.48; published online 8 April 2008

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

  1. 1Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea;
  2. 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;
  3. 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

Received 11 July 2007; Revised 12 September 2007; Accepted 10 December 2007.

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Abstract

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-3beta (GSK3beta) 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 GSK3beta 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.

Keywords:

neural stem cells, nitric oxide, GSK3beta, Niemann-Pick type C1 disease, caspase-3

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