title: Oxygen regulates proliferation of neural stem cells through Wnt/β-catenin signalling.
abstract: Reduced oxygen levels (1-5% O2, named herein 'physioxia') are beneficial for stem cell cultures leading to enhanced proliferation, better survival and higher differentiation potential, but the underlying molecular mechanisms remain elusive. A potential link between physioxia and the canonical Wnt pathway was found recently, but the differential involvement of this signalling pathway for the various stem cell properties such as proliferation, stem cell maintenance, and differentiation capacity remains enigmatic. We here demonstrate increased Wnt target gene transcription and stabilised active β-catenin upon physioxic cell culture in primary tissue-specific foetal mouse neural stem cells. Knock-out of the main oxygen sensing molecule, hypoxia-inducible factor-1α (Hif-1α), had no impact on Wnt activation assuming that physioxia induces the Wnt pathway independently of Hif-1α. To determine the physiological relevance of physioxia-induced Wnt/β-catenin signalling, we examined proliferation, cell cycle kinetics, survival and stem cell maintenance upon Wnt activation and inhibition. Whereas survival and stem cell maintenance seem to be independent of the Wnt pathway, our studies provide first evidence that Wnt/β-catenin signalling positively stimulates proliferation of physioxic cells by affecting cell cycle regulation. Together, our results provide mechanistic insight into oxygen-mediated regulation of the self-renewal activity of neural stem cells.
authors.affiliation: Division of Neurodegenerative Diseases, Department of Neurology, Technische Universität Dresden, 01307 Dresden, Germany.
authors.forename: Lena
authors.initials: L
authors.lastname: Braunschweig
authors.affiliation: Division of Neurodegenerative Diseases, Department of Neurology, Technische Universität Dresden, 01307 Dresden, Germany; Leibniz Institute for Solid State and Material Research, IFW Dresden, Institute for Integrative Nanosciences, Helmholtzstrasse 20, 01069 Dresden, Germany.
authors.forename: Anne K
authors.initials: AK
authors.lastname: Meyer
authors.affiliation: Division of Neurodegenerative Diseases, Department of Neurology, Technische Universität Dresden, 01307 Dresden, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Wagenführ
authors.affiliation: Division of Neurodegenerative Diseases, Department of Neurology, Technische Universität Dresden, 01307 Dresden, Germany; Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, 01307 Dresden, Germany; German Centre for Neurodegenerative Diseases (DZNE) Dresden, 01307 Dresden, Germany. Electronic address: alexander.storch@neuro.med.tu-dresden.de.
authors.forename: Alexander
authors.initials: A
authors.lastname: Storch
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D049109:Cell Proliferation; D002478:Cells, Cultured; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D058953:Neural Stem Cells / Q000378:metabolism* / Q000502:physiology; D010100:Oxygen / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051153:Wnt Proteins; D051176:beta Catenin; D010100:Oxygen
keywords: Hypoxia; Hypoxia-inducible factor; Neural stem cells; Physioxia; Wnt/β-catenin signalling