Proliferative Neural Stem Cells Have High Endogenous ROS Levels that Regulate Self-Renewal and Neurogenesis in a PI3K/Akt-Dependant Manner

NPI-Semel Institute for Neuroscience & Human Behavior and Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
Cell stem cell (Impact Factor: 22.27). 01/2011; 8(1):59-71. DOI: 10.1016/j.stem.2010.11.028
Source: PubMed


The majority of research on reactive oxygen species (ROS) has focused on their cellular toxicities. Stem cells generally have been thought to maintain low levels of ROS as a protection against these processes. However, recent studies suggest that ROS can also play roles as second messengers, activating normal cellular processes. Here, we investigated ROS function in primary brain-derived neural progenitors. Somewhat surprisingly, we found that proliferative, self-renewing multipotent neural progenitors with the phenotypic characteristics of neural stem cells (NSC) maintained a high ROS status and were highly responsive to ROS stimulation. ROS-mediated enhancements in self-renewal and neurogenesis were dependent on PI3K/Akt signaling. Pharmacological or genetic manipulations that diminished cellular ROS levels also interfered with normal NSC and/or multipotent progenitor function both in vitro and in vivo. This study has identified a redox-mediated regulatory mechanism of NSC function that may have significant implications for brain injury, disease, and repair.

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Available from: Janel Le Belle, May 13, 2014
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    • "With regard to redox status, enhanced oxidative environments were registered in NSC mitochondria with diminished FAO activity , suggesting that enhanced oxidative microenvironments impair NSC self-renewal in the mouse embryonic neocortex. Although reactive oxygen species are reported to regulate NSC self-renewal in the adult mouse brain (Le Belle et al., 2011), in that case, oxidative stress promoted NSC self-renewal rather than diminishing that capacity; i.e., the conclusion we arrive at here. Perhaps NSC self-renewal is regulated differentially as a function of magnitude of the oxidative stimulus. "
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    • "Indeed, it was shown later that NSCs have relatively high ROS-status and the majority of these ROS is generated endogenously by NADPH oxidase [92]. In addition, NSCs respond to the challenge of ROS by enhanced selfrenewal and neurogenesis by activating the PI3K/Akt signaling pathway [92]. Interestingly, this redox-dependent signaling is true for embryonic stem cells, since the loss of stem cells is associated with the level of ROS [93]. "
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    • "Similar to those findings , we demonstrated that triclosan stimulation in cultured rat NSCs upregulated the phosphorylation of p38 MAPK and JNK proteins, which could have resulted from the increased ROS generation and decreased antioxidant capacity. In the other study with mice, high ROS levels activate the PI3/Akt/mTOR pathway to initiate NADPH oxidase neural stem cell regulation (Le Belle et al., 2011). However, we observed decreased phosphorylation of these signals although we also found increased ROS generation in our experiment. "
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