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

ABSTRACT 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
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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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    • "The significant reduction in the size of endothelial spheroids by NAC treatment alone when compared to control showed that endogenous levels of ROS contributed to sphere formation and cell survival. This importance of endogenous ROS levels was not surprising because clonal stem cell sphere formation and self-renewal have been reported to depend on high endogenous ROS levels [32]. Based on our data, the individual contributions of ROS from cellular metabolism or PCB exposure to spheroid formation cannot be distinguished. "
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    ABSTRACT: Microvascular lesions resulting from endothelial cell dysfunction are produced in the brain, lung, kidney, and retina of patients of complex chronic diseases. The environmental and molecular risk factors which may contribute in the development of microvascular damage are unclear. The mechanism(s) responsible for initiating microvascular damage remain poorly defined, although several inciting factors have been proposed, including environmental toxicants-induced oxidative stress. Enhanced neovascularization has been implicated in either the development or progression of proliferative vascular lesions. Here, we present evidence for how PCB-induced ROS may contribute to the development of a neovascular phenotype with the aim of elucidating the role of environmental toxicants in endothelial dysfunction with a specific focus on the inhibitor of differentiation protein ID3. We used a combination of phenotype and immunohistochemical analysis followed by validating with protein expression and post-translational modifications with Western Blot and MALDI-TOF/TOF analysis. We also looked for a correlation between ID3 expression in vascular tissue. Our results showed that PCB-induced ROS mediated a highly tube branched neovascular phenotype that also depended on ID3 and Pyk2; and PCB153 treatment increased the size of endothelial spheroids under conditions typically used for clonal selection of stem cell spheroids. High ID3 protein expression correlated with a greater degree of malignancy and oxidative DNA damage marker 8-OHdG in blood vessels from human subjects. PCB153 treatment increased both serine and tyrosine phosphorylation of endothelial ID3. Stable ID3 overexpression increased cell survival of human microvascular endothelial cell line hCMEC/D3. In summary, our data provide evidence that ID3 may play a critical role in regulating vascular endothelial cell survival and development of microvascular lesions induced by persistent environmental pollutants such as PCB153. Findings of this study are important because they provide a new paradigm by which PCBs may contribute to the growth of microvascular lesions.
    PLoS ONE 08/2014; 9(8):e104159-. DOI:10.1371/journal.pone.0104159 · 3.23 Impact Factor
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