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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    • "This signaling has been suggested to operate through covalent modifications in the target proteins or through specific sensors able to detect and directly respond to intracellular changes through redoxbased mechanisms (D'Autré aux and Toledano, 2007; Nathan, 2003). The physiological ROS signals, not associated with oxidative damage, are especially important for stem cell functions, promoting progenitor cell proliferation (Le Belle et al., 2011; Suda et al., 2011). mtDNA mutator mice manifest a severe early onset SSC dysfunction, explaining the progeroid phenotype of these mice (Ahlqvist et al., 2012; Chen et al., 2009; Norddahl et al., 2011). "
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    ABSTRACT: mtDNA mutagenesis in somatic stem cells leads to their dysfunction and to progeria in mouse. The mechanism was proposed to involve modification of reactive oxygen species (ROS)/redox signaling. We studied the effect of mtDNA mutagenesis on reprogramming and stemness of pluripotent stem cells (PSCs) and show that PSCs select against specific mtDNA mutations, mimicking germline and promoting mtDNA integrity despite their glycolytic metabolism. Furthermore, mtDNA mutagenesis is associated with an increase in mitochondrial H2O2, reduced PSC reprogramming efficiency, and self-renewal. Mitochondria-targeted ubiquinone, MitoQ, and N-acetyl-L-cysteine efficiently rescued these defects, indicating that both reprogramming efficiency and stemness are modified by mitochondrial ROS. The redox sensitivity, however, rendered PSCs and especially neural stem cells sensitive to MitoQ toxicity. Our results imply that stem cell compartment warrants special attention when the safety of new antioxidants is assessed and point to an essential role for mitochondrial redox signaling in maintaining normal stem cell function. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 05/2015; 11(10). DOI:10.1016/j.celrep.2015.05.009 · 8.36 Impact Factor
    • "In addition, sulfhydryl oxidases generate disulfide bonds with the reduction of oxygen to H 2 O 2 in the mitochondrial IMS [7]. H 2 O 2 , at intracellular concentrations less than 1 μM, is involved in regulatory processes [52] [90]. Intracellular H 2 O 2 at concentrations above 1 μM is toxic to cells [52] [91]. "
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    • "If mild brain undergrowth also affects early vocalization behavior, this could explain why we failed to see rescue of abnormal behavior until older ages, at which time brain size was normalized in treated offspring. This highlights the difficulty of developing effective therapeutic interventions that aim to restore a normal redox balance in the developing brain, since both too much and too little cellular ROS can have deleterious effects (Le Belle et al., 2011). "
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    ABSTRACT: A period of mild brain overgrowth with an unknown etiology has been identified as one of the most common phenotypes in autism. Here, we test the hypothesis that maternal inflammation during critical periods of embryonic development can cause brain overgrowth and autism-associated behaviors as a result of altered neural stem cell function. Pregnant mice treated with low-dose lipopolysaccharide at embryonic day 9 had offspring with brain overgrowth, with a more pronounced effect in PTEN heterozygotes. Exposure to maternal inflammation also enhanced NADPH oxidase (NOX)-PI3K pathway signaling, stimulated the hyperproliferation of neural stem and progenitor cells, increased forebrain microglia, and produced abnormal autism-associated behaviors in affected pups. Our evidence supports the idea that a prenatal neuroinflammatory dysregulation in neural stem cell redox signaling can act in concert with underlying genetic susceptibilities to affect cellular responses to environmentally altered cellular levels of reactive oxygen species.
    Stem Cell Reports 10/2014; ePub before print publication (Nov)(5). DOI:10.1016/j.stemcr.2014.09.004 · 5.37 Impact Factor
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