Delarasse Cécile, Gonnord Pauline, Galante Micaela, Auger Rodolphe, Daniel Hervé, Motta Iris, Kanellopoulos Jean M
Institut de Biochimie et Biophysique Moléculaire et Cellulaire, Univ Paris-Sud, CNRS, UMR 8619, Orsay Cedex, France.
J Neurochem. 2009 May;109(3):846-57. doi: 10.1111/j.1471-4159.2009.06008.x. Epub 2009 Feb 24.
Neural progenitor cells (NPCs) are capable of self-renewal and differentiation into neurons, astrocytes and oligodendrocytes, and have been used to treat several animal models of CNS disorders. In the present study, we show that the P2X7 purinergic receptor (P2X7R) is present on NPCs. In NPCs, P2X7R activation by the agonists extracellular ATP or benzoyl ATP triggers opening of a non-selective cationic channel. Prolonged activation of P2X7R with these nucleotides leads to caspase independent death of NPCs. P2X7R ligation induces NPC lysis/necrosis demonstrated by cell membrane disruption accompanied with loss of mitochondrial membrane potential. In most cells that express P2X7R, sustained stimulation with ATP leads to the formation of a non-selective pore allowing the entry of solutes up to 900 Da, which are reportedly involved in P2X7R-mediated cell lysis. Surprisingly, activation of P2X7R in NPCs causes cell death in the absence of pore formation. Our data support the notion that high levels of extracellular ATP in inflammatory CNS lesions may delay the successful graft of NPCs used to replace cells and repair CNS damage.
神经祖细胞（NPCs）能够自我更新并分化为神经元、星形胶质细胞和少突胶质细胞，已被用于治疗多种中枢神经系统疾病的动物模型。在本研究中，我们发现NPCs上存在P2X7嘌呤能受体（P2X7R）。在NPCs中，激动剂细胞外ATP或苯甲酰ATP激活P2X7R会触发非选择性阳离子通道的开放。用这些核苷酸长时间激活P2X7R会导致NPCs发生不依赖半胱天冬酶的死亡。P2X7R连接诱导NPCs裂解/坏死，表现为细胞膜破坏并伴有线粒体膜电位丧失。在大多数表达P2X7R的细胞中，ATP持续刺激会导致形成一个允许分子量高达900 Da的溶质进入的非选择性孔道，据报道这与P2X7R介导的细胞裂解有关。令人惊讶的是，NPCs中P2X7R的激活在没有孔道形成的情况下也会导致细胞死亡。我们的数据支持这样一种观点，即炎症性中枢神经系统病变中高水平的细胞外ATP可能会延迟用于替代细胞和修复中枢神经系统损伤的NPCs的成功移植。
