title: Purines regulate adult brain subventricular zone cell functions: contribution of reactive astrocytes.
abstract: Brain injuries modulate activation of neural stem cells (NSCs) in the adult brain. In pathological conditions, the concentrations of extracellular nucleotides (eNTs) raise several folds, contribute to reactive gliosis, and possibly directly affect subventricular zone (SVZ) cell functioning. Among eNTs and derived metabolites, the P2Y1 receptor agonist ADP strongly promotes astrogliosis and might also influence SVZ progenitor activity. Here, we tested the ability of the stable P2Y1 agonist adenosine 5'-O-(2-thiodiphosphate) (ADPβS) to control adult NSC functions both in vitro and in vivo, with a focus on the possible effects exerted by reactive astrocytes. In the absence of growth factors, ADPβS promoted proliferation and differentiation of SVZ progenitors. Moreover, ADPβS-activated astrocytes markedly changed the pattern of released cytokines and chemokines, and strongly modulated neurosphere-forming capacity of SVZ progenitors. Notably, a significant enhancement in proliferation was observed when SVZ cells, initially grown in the supernatant of astrocytes exposed to ADPβS, were shifted to normal medium. In vivo, ADPβS administration in the lateral ventricle of adult mice by osmotic minipumps caused diffused reactive astrogliosis, and a strong response of SVZ progenitors. Indeed, proliferation of glial fibrillary acidic protein-positive NSCs increased and led to a significant expansion of SVZ transit-amplifying progenitors and neuroblasts. Lineage tracing experiments performed in the GLAST::CreERT2;Rosa-YFP transgenic mice further demonstrated that ADPβS promoted proliferation of glutamate/aspartate transporter-positive progenitors and sustained their progression toward the generation of rapidly dividing progenitors. Altogether, our results show that the purinergic system crucially affects SVZ progenitor activities both directly and through the involvement of reactive astrocytes.
authors.affiliation: Laboratory of Molecular and Cellular Pharmacology of Purinergic Transmission, Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Boccazzi
authors.forename: Chiara
authors.initials: C
authors.lastname: Rolando
authors.forename: Maria P
authors.initials: MP
authors.lastname: Abbracchio
authors.forename: Annalisa
authors.initials: A
authors.lastname: Buffo
authors.forename: Stefania
authors.initials: S
authors.lastname: Ceruti
mesh_terms: D000244:Adenosine Diphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D053687:Adult Stem Cells / Q000187:drug effects; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects / Q000502:physiology*; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D001921:Brain / Q000033:anatomy & histology*; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D000089622:Doublecortin Domain Proteins; D027341:Excitatory Amino Acid Transporter 1 / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D020547:Lateral Ventricles / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism; D058921:Purinergic P2Y Receptor Antagonists / Q000494:pharmacology; D011687:Purines / Q000378:metabolism*; D013873:Thionucleotides / Q000494:pharmacology
chemical_list: D000244:Adenosine Diphosphate; D051792:Basic Helix-Loop-Helix Proteins; D016207:Cytokines; D000089622:Doublecortin Domain Proteins; D027341:Excitatory Amino Acid Transporter 1; D005904:Glial Fibrillary Acidic Protein; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; D058921:Purinergic P2Y Receptor Antagonists; D011687:Purines; D013873:Thionucleotides; C499317:Ascl1 protein, mouse; C111914:N(6)-methyl-2'-deoxyadenosine 3',5'-diphosphate; C493393:Slc1a3 protein, mouse; C030812:adenosine 5'-O-(2-thiodiphosphate)
keywords: P2Y1 receptor; adult neurogenesis; astrogliosis; neurogenic niche