title: Generation of reactive astrocytes from NG2 cells is regulated by sonic hedgehog.
abstract: NG2 cells, a fourth glial cell type in the adult mammalian central nervous system, produce oligodendrocytes in the healthy nervous tissue, and display wide differentiation potential under pathological conditions, where they could give rise to reactive astrocytes. The factors that control the differentiation of NG2 cells after focal cerebral ischemia (FCI) are largely unknown. Here, we used transgenic Cspg4-cre/Esr1/ROSA26Sortm14(CAG-tdTomato) mice, in which tamoxifen administration triggers the expression of red fluorescent protein (tomato) specifically in NG2 cells and cells derived therefrom. Differentiation potential (in vitro and in vivo) of tomato-positive NG2 cells from control or postischemic brains was determined using the immunohistochemistry, single cell RT-qPCR and patch-clamp method. The ischemic injury was induced by middle cerebral artery occlusion, a model of FCI. Using genetic fate-mapping method, we identified sonic hedgehog (Shh) as an important factor that influences differentiation of NG2 cells into astrocytes in vitro. We also manipulated Shh signaling in the adult mouse brain after FCI. Shh signaling activation significantly increased the number of astrocytes derived from NG2 cells in the glial scar around the ischemic lesion, while Shh signaling inhibition caused the opposite effect. Since Shh signaling modifications did not change the proliferation rate of NG2 cells, we can conclude that Shh has a direct influence on the differentiation of NG2 cells and therefore, on the formation and composition of a glial scar, which consequently affects the degree of the brain damage. GLIA 2016;64:1518-1531.
authors.affiliation: Department of Cellular Neurophysiology, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, 142 20, Czech Republic.
authors.forename: Pavel
authors.initials: P
authors.lastname: Honsa
authors.affiliation: Department of Cellular Neurophysiology, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, 142 20, Czech Republic.
authors.forename: Martin
authors.initials: M
authors.lastname: Valny
authors.affiliation: Department of Cellular Neurophysiology, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, 142 20, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Kriska
authors.affiliation: Department of Cellular Neurophysiology, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, 142 20, Czech Republic.
authors.forename: Hana
authors.initials: H
authors.lastname: Matuskova
authors.affiliation: Department of Cellular Neurophysiology, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, 142 20, Czech Republic.
authors.forename: Lenka
authors.initials: L
authors.lastname: Harantova
authors.affiliation: Department of Cellular Neurophysiology, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, 142 20, Czech Republic.
authors.forename: Denisa
authors.initials: D
authors.lastname: Kirdajova
authors.affiliation: Laboratory of Gene Expression, Institute of Biotechnology, Academy of Sciences of the Czech Republic, Prague, 142 20, Czech Republic.
authors.forename: Lukas
authors.initials: L
authors.lastname: Valihrach
authors.affiliation: Laboratory of Gene Expression, Institute of Biotechnology, Academy of Sciences of the Czech Republic, Prague, 142 20, Czech Republic.
authors.forename: Peter
authors.initials: P
authors.lastname: Androvic
authors.affiliation: Laboratory of Gene Expression, Institute of Biotechnology, Academy of Sciences of the Czech Republic, Prague, 142 20, Czech Republic.
authors.forename: Mikael
authors.initials: M
authors.lastname: Kubista
authors.affiliation: Department of Cellular Neurophysiology, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, 142 20, Czech Republic.
authors.forename: Miroslava
authors.initials: M
authors.lastname: Anderova
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D001921:Brain / Q000166:cytology*; D001930:Brain Injuries / Q000473:pathology; D002545:Brain Ischemia / Q000473:pathology; D002452:Cell Count; D002454:Cell Differentiation / Q000502:physiology*; D053823:Hedgehog Proteins / Q000378:metabolism; D051379:Mice; D009457:Neuroglia / Q000378:metabolism*; D009836:Oligodendroglia / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D053823:Hedgehog Proteins; C465570:Shh protein, mouse
keywords: NG2 cells; astrocytes; glial scar; ischemia; sonic hedgehog