Neural progenitor cell death is induced by extracellular ATP via ligation of P2X7 receptor.
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.
Delarasse
Cécile
C
Institut de Biochimie et Biophysique Moléculaire et Cellulaire, Univ Paris-Sud, CNRS, UMR 8619, Orsay Cedex, France.
Gonnord
Pauline
P
Galante
Micaela
M
Auger
Rodolphe
R
Daniel
Hervé
H
Motta
Iris
I
Kanellopoulos
Jean M
JM
D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D003342:Corpus Striatum / Q000166:cytology; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004622:Embryo, Mammalian; D053595:Embryonic Stem Cells / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D045604:Extracellular Fluid / Q000187:drug effects; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009336:Necrosis / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects*; D018048:Receptors, Purinergic P2 / Q000172:deficiency / Q000378:metabolism*; D058486:Receptors, Purinergic P2X7; D019311:Staurosporine / Q000494:pharmacology; D013778:Tetrazolium Salts; D013844:Thiazoles; D013997:Time Factors
D002614:Chelating Agents; D004791:Enzyme Inhibitors; C546469:P2rx7 protein, mouse; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; D013778:Tetrazolium Salts; D013844:Thiazoles; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; C033901:3'-O-(4-benzoyl)benzoyladenosine 5'-triphosphate; D004533:Egtazic Acid; D000255:Adenosine Triphosphate; D007770:L-Lactate Dehydrogenase; D020169:Caspases; C022616:thiazolyl blue; D019311:Staurosporine; D002118:Calcium