P2X7 Receptors Regulate Phagocytosis and Proliferation in Adult Hippocampal and SVZ Neural Progenitor Cells: Implications for Inflammation in Neurogenesis

被引:34
|
作者
Leeson, Hannah C. [1 ]
Kasherman, Maria A. [1 ]
Chan-Ling, Tailoi [2 ,3 ]
Lovelace, Michael D. [2 ,4 ,5 ]
Brownlie, Jeremy C. [6 ]
Toppinen, Kelly M. [1 ]
Gu, Ben J. [7 ]
Weible, Michael W., II [1 ,3 ,6 ]
机构
[1] Griffith Univ, Griffith Inst Drug Discovery, Brisbane, Qld, Australia
[2] Univ Sydney, Sch Med Sci, Fac Med & Hlth, Discipline Anat & Histol, Sydney, NSW, Australia
[3] Univ Sydney, Bosch Inst, Sydney, NSW, Australia
[4] St Vincents Ctr Appl Med Res, Peter Duncan Neurosci Res Unit, Applied Neurosci Program, Sydney, NSW, Australia
[5] Univ New South Wales Med, UNSW, St Vincents Clin Sch, Sydney, NSW, Australia
[6] Griffith Univ, Sch Environm & Sci, Brisbane, Qld, Australia
[7] Univ Melbourne, Florey Inst Neurosci & Mental Hlth, Melbourne, Vic 3010, Australia
基金
澳大利亚研究理事会; 澳大利亚国家健康与医学研究理事会; 英国医学研究理事会;
关键词
P2X7; Adult neurogenesis; Adult neural stem cells; Hippocampus; ATP; Neuro-inflammation; EXTRACELLULAR ATP; INNATE PHAGOCYTOSIS; P2X(7) RECEPTOR; NERVOUS-SYSTEM; DENTATE GYRUS; SPINAL-CORD; STEM-CELLS; PHYSIOLOGY; INHIBITION; EXPRESSION;
D O I
10.1002/stem.2894
中图分类号
Q813 [细胞工程];
学科分类号
摘要
Identifying the signaling mechanisms that regulate adult neurogenesis is essential to understanding how the brain may respond to neuro-inflammatory events. P2X7 receptors can regulate pro-inflammatory responses, and in addition to their role as cation channels they can trigger cell death and mediate phagocytosis. How P2X7 receptors may regulate adult neurogenesis is currently unclear. Here, neural progenitor cells (NPCs) derived from adult murine hippocampal subgranular (SGZ) and cerebral subventricular (SVZ) zones were utilized to characterize the roles of P2X7 in adult neurogenesis, and assess the effects of high extracellular ATP, characteristic of inflammation, on NPCs. Immunocytochemistry found NPCs in vivo and in vitro expressed P2X7, and the activity of P2X7 in culture was demonstrated using calcium influx and pore formation assays. Live cell and confocal microscopy, in conjunction with flow cytometry, revealed P2X7(+) NPCs were able to phagocytose fluorescent beads, and this was inhibited by ATP, indicative of P2X7 involvement. Furthermore, P2X7 receptors were activated with ATP or BzATP, and 5-ethynyl-2 '-deoxyuridine (EdU) used to observe a dose-dependent decrease in NPC proliferation. A role for P2X7 in decreased NPC proliferation was confirmed using chemical inhibition and NPCs from P2X7(-/-) mice. Together, these data present three distinct roles for P2X7 during adult neurogenesis, depending on extracellular ATP concentrations: (a) P2X7 receptors can form transmembrane pores leading to cell death, (b) P2X7 receptors can regulate rates of proliferation, likely via calcium signaling, and (c) P2X7 can function as scavenger receptors in the absence of ATP, allowing NPCs to phagocytose apoptotic NPCs during neurogenesis. Stem Cells 2018;36:1764-1777
引用
收藏
页码:1764 / 1777
页数:14
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