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      Antioxidant Role for Lipid Droplets in a Stem Cell Niche of Drosophila

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          Summary

          Stem cells reside in specialized microenvironments known as niches. During Drosophila development, glial cells provide a niche that sustains the proliferation of neural stem cells (neuroblasts) during starvation. We now find that the glial cell niche also preserves neuroblast proliferation under conditions of hypoxia and oxidative stress. Lipid droplets that form in niche glia during oxidative stress limit the levels of reactive oxygen species (ROS) and inhibit the oxidation of polyunsaturated fatty acids (PUFAs). These droplets protect glia and also neuroblasts from peroxidation chain reactions that can damage many types of macromolecules. The underlying antioxidant mechanism involves diverting PUFAs, including diet-derived linoleic acid, away from membranes to the core of lipid droplets, where they are less vulnerable to peroxidation. This study reveals an antioxidant role for lipid droplets that could be relevant in many different biological contexts.

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          Highlights

          • Oxidative stress stimulates lipid droplet biosynthesis in a neural stem cell niche

          • Lipid droplets protect niche and neural stem cells from damaging PUFA peroxidation

          • PUFAs are less vulnerable to peroxidation in lipid droplets than in cell membranes

          Abstract

          Lipid droplets can act as antioxidant organelles that protect Drosophila neural stem cells from hypoxia-triggered ROS. They sequester polyunsaturated fatty acids away from plasma membranes, thereby shielding these lipids from harmful peroxidation that would otherwise compromise proliferation.

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          Most cited references42

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          The stem-cell niche as an entity of action.

          Stem-cell populations are established in 'niches'--specific anatomic locations that regulate how they participate in tissue generation, maintenance and repair. The niche saves stem cells from depletion, while protecting the host from over-exuberant stem-cell proliferation. It constitutes a basic unit of tissue physiology, integrating signals that mediate the balanced response of stem cells to the needs of organisms. Yet the niche may also induce pathologies by imposing aberrant function on stem cells or other targets. The interplay between stem cells and their niche creates the dynamic system necessary for sustaining tissues, and for the ultimate design of stem-cell therapeutics.
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            The cell biology of neurogenesis: toward an understanding of the development and evolution of the neocortex.

            Neural stem and progenitor cells have a central role in the development and evolution of the mammalian neocortex. In this review, we first provide a set of criteria to classify the various types of cortical stem and progenitor cells. We then discuss the issue of cell polarity, as well as specific subcellular features of these cells that are relevant for their modes of division and daughter cell fate. In addition, cortical stem and progenitor cell behavior is placed into a tissue context, with consideration of extracellular signals and cell-cell interactions. Finally, the differences across species regarding cortical stem and progenitor cells are dissected to gain insight into key developmental and evolutionary mechanisms underlying neocortex expansion.
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              Fatty acid uptake and lipid storage induced by HIF-1α contribute to cell growth and survival after hypoxia-reoxygenation.

              An in vivo model of antiangiogenic therapy allowed us to identify genes upregulated by bevacizumab treatment, including Fatty Acid Binding Protein 3 (FABP3) and FABP7, both of which are involved in fatty acid uptake. In vitro, both were induced by hypoxia in a hypoxia-inducible factor-1α (HIF-1α)-dependent manner. There was a significant lipid droplet (LD) accumulation in hypoxia that was time and O2 concentration dependent. Knockdown of endogenous expression of FABP3, FABP7, or Adipophilin (an essential LD structural component) significantly impaired LD formation under hypoxia. We showed that LD accumulation is due to FABP3/7-dependent fatty acid uptake while de novo fatty acid synthesis is repressed in hypoxia. We also showed that ATP production occurs via β-oxidation or glycogen degradation in a cell-type-dependent manner in hypoxia-reoxygenation. Finally, inhibition of lipid storage reduced protection against reactive oxygen species toxicity, decreased the survival of cells subjected to hypoxia-reoxygenation in vitro, and strongly impaired tumorigenesis in vivo.
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                Author and article information

                Contributors
                Journal
                Cell
                Cell
                Cell
                Cell Press
                0092-8674
                1097-4172
                08 October 2015
                08 October 2015
                : 163
                : 2
                : 340-353
                Affiliations
                [1 ]The Francis Crick Institute, Mill Hill Laboratory, The Ridgeway, Mill Hill, London NW7 1AA, UK
                [2 ]Academic Unit of Clinical & Experimental Sciences, Faculty of Medicine, Sir Henry Wellcome Laboratories, Southampton General Hospital, Southampton SO16 6YD, UK
                [3 ]National Resource for Imaging Mass Spectroscopy, Harvard Medical School and Brigham and Women’s Hospital, Cambridge, MA 02139, USA
                Author notes
                []Corresponding author alex.gould@ 123456crick.ac.uk
                Article
                S0092-8674(15)01181-2
                10.1016/j.cell.2015.09.020
                4601084
                26451484
                3f3f0be0-665f-4b48-b19f-8e25e4d27f93
                © 2015 The Authors

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                : 18 December 2014
                : 15 June 2015
                : 12 August 2015
                Categories
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                Cell biology
                Cell biology

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