title: A new role for the P2Y-like GPR17 receptor in the modulation of multipotency of oligodendrocyte precursor cells in vitro.
abstract: Oligodendrocyte precursor cells (OPCs, also called NG2 cells) are scattered throughout brain parenchyma, where they function as a reservoir to replace lost or damaged oligodendrocytes, the myelin-forming cells. The hypothesis that, under some circumstances, OPCs can actually behave as multipotent cells, thus generating astrocytes and neurons as well, has arisen from some in vitro and in vivo evidence, but the molecular pathways controlling this alternative fate of OPCs are not fully understood. Their identification would open new opportunities for neuronal replace strategies, by fostering the intrinsic ability of the brain to regenerate. Here, we show that the anti-epileptic epigenetic modulator valproic acid (VPA) can promote the generation of new neurons from NG2+OPCs under neurogenic protocols in vitro, through their initial de-differentiation to a stem cell-like phenotype that then evolves to "hybrid" cell population, showing OPC morphology but expressing the neuronal marker βIII-tubulin and the GPR17 receptor, a key determinant in driving OPC transition towards myelinating oligodendrocytes. Under these conditions, the pharmacological blockade of the P2Y-like receptor GPR17 by cangrelor, a drug recently approved for human use, partially mimics the effects mediated by VPA thus accelerating cells' neurogenic conversion. These data show a co-localization between neuronal markers and GPR17 in vitro, and suggest that, besides its involvement in oligodendrogenesis, GPR17 can drive the fate of neural precursor cells by instructing precursors towards the neuronal lineage. Being a membrane receptor, GPR17 represents an ideal "druggable" target to be exploited for innovative regenerative approaches to acute and chronic brain diseases.
authors.affiliation: Laboratory of Molecular and Cellular Pharmacology of Purinergic Transmission-Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, via Balzaretti, 9, 20133, Milan, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Boccazzi
authors.affiliation: Laboratory of Molecular and Cellular Pharmacology of Purinergic Transmission-Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, via Balzaretti, 9, 20133, Milan, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Lecca
authors.affiliation: Laboratory of Molecular and Cellular Pharmacology of Purinergic Transmission-Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, via Balzaretti, 9, 20133, Milan, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Marangon
authors.affiliation: Sanofi Midy Research Center-Exploratory Unit Sanofi R&D, via G. Sbodio, 2, 20100, Milan, Italy.|Present Address: Allergy Therapeutics, via IV Novembre 76-20019 Settimo Milanese, Milan, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Guagnini
authors.affiliation: Laboratory of Molecular and Cellular Pharmacology of Purinergic Transmission-Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, via Balzaretti, 9, 20133, Milan, Italy.
authors.forename: Maria P
authors.initials: MP
authors.lastname: Abbracchio
authors.affiliation: Laboratory of Molecular and Cellular Pharmacology of Purinergic Transmission-Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, via Balzaretti, 9, 20133, Milan, Italy. stefania.ceruti@unimi.it.
authors.forename: Stefania
authors.identifier: 0000-0003-1663-4211
authors.initials: S
authors.lastname: Ceruti
mesh_terms: D000818:Animals; D019070:Cell Lineage / Q000502:physiology; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism; D039902:Multipotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism*; D055495:Neurogenesis / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D009836:Oligodendroglia / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*
chemical_list: C514731:GPR17 protein, rat; D043562:Receptors, G-Protein-Coupled
keywords: GPR17; NG2 cells; Neurogenesis; Oligodendrocyte precursor cells; Valproic acid