title: Evidence for a subventricular zone neural stem cell phagocytic activity stimulated by the vitamin K-dependent factor protein S.
abstract: Neural stem cells, whose major reservoir in the adult mammalian brain is the subventricular zone (SVZ), ensure neuropoiesis, a process during which many generated cells die. Removal of dead cells and debris by phagocytes is necessary for tissue homeostasis. Using confocal and electron microscopy, we demonstrate that cultured SVZ cells phagocytose both 1 and 2 µm latex beads and apoptotic cell-derived fragments. We determine by flow cytometry that phagocytic cells represent more than 10% of SVZ cultured cells. Phenotyping of SVZ cells using nestin, GFAP, Sox2, or LeX/SSEA and quantification of aldehyde dehydrogenase (ALDH) activity, reveals that cells with neural stem-cell features phagocytose and represent more than 30% of SVZ phagocytic cells. In vivo, nestin-, Sox2-, and ALDH-expressing neural stem-like cells engulfed latex beads or apoptotic cell-derived fragments that were injected into mice lateral brain ventricles. We show also that SVZ cell phagocytic activity is an active process, which depends both on cytoskeleton dynamic and on recognition of phosphatidylserine eat-me signal, and is stimulated by the vitamin K-dependent factor protein S (ProS). ProS neutralizing antibodies inhibit SVZ cell phagocytic activity and exposure of SVZ cells to apoptotic cell-derived fragments induces a transient Mer tyrosine kinase receptor (MerTK) phosphorylation. Conversely, MerTK blocking antibodies impair both basal and ProS-stimulated SVZ cell phagocytic activity. By revealing that neural stem-like cells act within the SVZ neurogenic niche as phagocytes and that the ProS/MerTK path represents an endogenous regulatory mechanism for SVZ cell phagocytic activity, the present report opens-up new perspectives for both stem cell biology and brain physiopathology.
authors.affiliation: CNRS ERL 7368, Signalisation et Transports Ioniques Membranaires, University of Poitiers, Poitiers cedex 09, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Ginisty
authors.forename: Aurore
authors.initials: A
authors.lastname: Gély-Pernot
authors.forename: Loubna
authors.initials: L
authors.lastname: Abaamrane
authors.forename: Franck
authors.initials: F
authors.lastname: Morel
authors.forename: Patricia
authors.initials: P
authors.lastname: Arnault
authors.forename: Valérie
authors.initials: V
authors.lastname: Coronas
authors.forename: Omar
authors.initials: O
authors.lastname: Benzakour
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D002478:Cells, Cultured; D020547:Lateral Ventricles / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism*; D010587:Phagocytosis / Q000187:drug effects / Q000502:physiology*; D017293:Protein S / Q000378:metabolism* / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D000076202:c-Mer Tyrosine Kinase
chemical_list: D000943:Antigens, Differentiation; D017293:Protein S; D011518:Proto-Oncogene Proteins; C490767:Mertk protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D000076202:c-Mer Tyrosine Kinase
keywords: Brain; Efferocytosis; Mer tyrosine kinase receptor; Microenvironment; Mouse; Neural stem cell; Phagocytosis; Protein S; Rat; Rodent; Subventricular zone; Vitamin K