Real-time gigahertz free-space quantum key distribution within an emulated satellite overpass.

Satellite quantum key distribution (SatQKD) intermediated by a trusted satellite in a low-Earth orbit to ground stations along the satellite's path allows remote users to connect securely. To establish a secure connection, a SatQKD session must be conducted to each user over a dynamically changing free-space link, all within just a few hundred seconds. Because of the short time and large losses under which the QKD protocol will be implemented, it has not yet been possible to form a complete key by transmitting all the relevant information required within a single overpass of the satellite. Here, we demonstrate a real-time QKD system that is capable of forming a 4.58-megabit secure key between two nodes within an emulated satellite overpass. We anticipate that our system will set the stage for practical implementations of intercontinental quantum secure communications that can operate over large networks of nodes and enable the secure transmission of data globally.

Exosomal non-coding RNAs in glioma progression: insights into tumor microenvironment dynamics and therapeutic implications.

Gliomas are the most common and deadly types of brain tumors, known for their extensive genetic and epigenetic variability, which poses considerable challenges for pharmacological treatment. Glioma heterogeneity is also related to their intricate and dynamic tumor microenvironment (TME), which comprises a diverse array of cell types, including immune cells, vascular cells, glial cells, and neural precursors, collectively influencing tumor behavior and progression. A pivotal aspect of this intercellular communication relies on the exchange of extracellular vesicles (EVs), which contain and transfer complex molecular cargoes typical of their cells of origin, such as proteins, lipids, carbohydrates, metabolites, and non-coding RNAs (ncRNAs), that encompass microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs). Glioma cells actively release EVs loaded with specific ncRNAs that can target genes and other ncRNAs in recipient cells residing within the TME. Among these recipient cells, prominent players include tumor-associated macrophages and microglia (TAMs), non-neoplastic astrocytes and endothelial cells. The intricate interplay between EVs derived from glioma cells and these recipient cells significantly contributes to the establishment of a tumor-permissive microenvironment, promoting tumor cell proliferation, migration, angiogenesis, and invasion, by targeting various downstream pathways. This review critically examines the current understanding of the intricate interplay between glioma, exosomal ncRNAs, and various components of the glioma TME. By shedding light on the roles of ncRNAs in mediating intercellular communication, this review underscores their significance in orchestrating TME transformation and highlights their potential as novel therapeutic targets for effectively tackling glioma progression.

G protein-coupled receptor 17 is regulated by WNT pathway during oligodendrocyte precursor cell differentiation.

G protein-coupled receptor 17 (GPR17) and the WNT pathway are critical players of oligodendrocyte (OL) differentiation acting as essential timers in developing brain to achieve fully-myelinating cells. However, whether and how these two systems are related to each other is still unknown. Of interest, both factors are dysregulated in developing and adult brain diseases, including white matter injury and cancer, making the understanding of their reciprocal interactions of potential importance for identifying new targets and strategies for myelin repair. Here, by a combined pharmacological and biotechnological approach, we examined regulatory mechanisms linking WNT signaling to GPR17 expression in OLs. We first analyzed the relative expression of mRNAs encoding for GPR17 and the T cell factor/Lymphoid enhancer-binding factor-1 (TCF/LEF) transcription factors of the canonical WNT/ß-CATENIN pathway, in PDGFRα+ and O4+ OLs during mouse post-natal development. In O4+ cells, Gpr17 mRNA level peaked at post-natal day 14 and then decreased concomitantly to the physiological uprise of WNT tone, as shown by increased Lef1 mRNA level. The link between WNT signaling and GPR17 expression was further reinforced in vitro in primary PDGFRα+ cells and in Oli-neu cells. High WNT tone impaired OL differentiation and drastically reduced GPR17 mRNA and protein levels. In Oli-neu cells, WNT/ß-CATENIN activation repressed Gpr17 promoter activity through both putative WNT response elements (WRE) and upregulation of the inhibitor of DNA-binding protein 2 (Id2). We conclude that the WNT pathway influences OL maturation by repressing GPR17, which could have implications in pathologies characterized by dysregulations of the OL lineage including multiple sclerosis and oligodendroglioma.

Rewiring of Glucose and Lipid Metabolism Induced by G Protein-Coupled Receptor 17 Silencing Enables the Transition of Oligodendrocyte Progenitors to Myelinating Cells.

In the mature central nervous system (CNS), oligodendrocytes (OLs) provide support and insulation to axons thanks to the production of a myelin sheath. During their maturation to myelinating cells, OLs require energy and building blocks for lipids, which implies a great investment of energy fuels and molecular sources of carbon. The oligodendroglial G protein-coupled receptor 17 (GPR17) has emerged as a key player in OL maturation; it reaches maximal expression in pre-OLs, but then it has to be internalized to allow terminal maturation. In this study, we aim at elucidating the role of physiological GPR17 downregulation in OL metabolism by applying transcriptomics, metabolomics and lipidomics on differentiating OLs. After GPR17 silencing, we found a significant increase in mature OL markers and alteration of several genes involved in glucose metabolism and lipid biosynthesis. We also observed an increased release of lactate, which is partially responsible for the maturation boost induced by GPR17 downregulation. Concomitantly, GPR17 depletion also changed the kinetics of specific myelin lipid classes. Globally, this study unveils a functional link between GPR17 expression, lactate release and myelin composition, and suggests that innovative interventions targeting GPR17 may help to foster endogenous myelination in demyelinating diseases.

Neuronal and Glial Communication via Non-Coding RNAs: Messages in Extracellular Vesicles.

Extracellular vesicles (EVs) have been increasingly recognized as essential players in cell communication in many organs and systems, including the central nervous system (CNS). A proper interaction between neural cells is fundamental in the regulation of neurophysiological processes and its alteration could induce several pathological phenomena, such as neurodegeneration, neuroinflammation, and demyelination. EVs contain and transfer complex molecular cargoes typical of their cells of origin, such as proteins, lipids, carbohydrates, and metabolites to recipient cells. EVs are also enriched in non-coding RNAs (e.g., microRNAs, lncRNAs, and circRNA), which were formerly considered as cell-intrinsic regulators of CNS functions and pathologies, thus representing a new layer of regulation in the cell-to-cell communication. In this review, we summarize the most recent and advanced studies on the role of EV-derived ncRNAs in the CNS. First, we report the potential of neural stem cell-derived ncRNAs as new therapeutic tools for neurorepair. Then, we discuss the role of neuronal ncRNAs in regulating glia activation, and how alteration in glial ncRNAs influences neuronal survival and synaptic functions. We conclude that EV-derived ncRNAs can act as intercellular signals in the CNS to either propagate neuroinflammatory waves or promote reparative functions.

Prenatal Stress Impairs Spinal Cord Oligodendrocyte Maturation via BDNF Signaling in the Experimental Autoimmune Encephalomyelitis Model of Multiple Sclerosis.

One of the most substantial and established environmental risk factors for neurological and psychiatric disorders is stress exposure, whose detrimental consequences hinge on several variables including time. In this regard the gestational period is known to present an intrinsic vulnerability to environmental insults and thus stressful events during pregnancy can lead to severe consequences on the offspring's brain development with long-term repercussions throughout adulthood. On this basis, we investigated the long-lasting impact of prenatal stress exposure on the susceptibility to the experimental autoimmune encephalomyelitis (EAE), a well-established murine model of multiple sclerosis. Although stress is considered a triggering factor for this chronic, progressive, autoimmune disease, little is known about the underlying mechanisms. To this end, EAE was induced by immunization with MOG35-55/CFA and pertussis toxin administration in adult female C57BL/6 mice born from control or stressed dams exposed to restraint stress during the last days of gestation. Our results demonstrate that gestational stress induces a marked increase in the severity of EAE symptoms in adulthood. Further, we highlight an altered maturation of oligodendrocytes in the spinal cord of prenatally stressed EAE mice, as indicated by the higher levels of GPR17, a marker of immature oligodendrocyte precursor cells. These behavioral and molecular alterations are paralleled by changes in the expression and signaling of the neurotrophin BDNF, an important mediator of neural plasticity that may contribute to stress-induced impaired remyelination. Since several already marketed drugs are able to modulate BDNF levels, these results pave the way to the possibility of repositioning these drugs in multiple sclerosis.

Novel in vitro Experimental Approaches to Study Myelination and Remyelination in the Central Nervous System.

Myelin is the lipidic insulating structure enwrapping axons and allowing fast saltatory nerve conduction. In the central nervous system, myelin sheath is the result of the complex packaging of multilamellar extensions of oligodendrocyte (OL) membranes. Before reaching myelinating capabilities, OLs undergo a very precise program of differentiation and maturation that starts from OL precursor cells (OPCs). In the last 20 years, the biology of OPCs and their behavior under pathological conditions have been studied through several experimental models. When co-cultured with neurons, OPCs undergo terminal maturation and produce myelin tracts around axons, allowing to investigate myelination in response to exogenous stimuli in a very simple in vitro system. On the other hand, in vivo models more closely reproducing some of the features of human pathophysiology enabled to assess the consequences of demyelination and the molecular mechanisms of remyelination, and they are often used to validate the effect of pharmacological agents. However, they are very complex, and not suitable for large scale drug discovery screening. Recent advances in cell reprogramming, biophysics and bioengineering have allowed impressive improvements in the methodological approaches to study brain physiology and myelination. Rat and mouse OPCs can be replaced by human OPCs obtained by induced pluripotent stem cells (iPSCs) derived from healthy or diseased individuals, thus offering unprecedented possibilities for personalized disease modeling and treatment. OPCs and neural cells can be also artificially assembled, using 3D-printed culture chambers and biomaterial scaffolds, which allow modeling cell-to-cell interactions in a highly controlled manner. Interestingly, scaffold stiffness can be adopted to reproduce the mechanosensory properties assumed by tissues in physiological or pathological conditions. Moreover, the recent development of iPSC-derived 3D brain cultures, called organoids, has made it possible to study key aspects of embryonic brain development, such as neuronal differentiation, maturation and network formation in temporal dynamics that are inaccessible to traditional in vitro cultures. Despite the huge potential of organoids, their application to myelination studies is still in its infancy. In this review, we shall summarize the novel most relevant experimental approaches and their implications for the identification of remyelinating agents for human diseases such as multiple sclerosis.

The Distribution of GPR17-Expressing Cells Correlates with White Matter Inflammation Status in Brain Tissues of Multiple Sclerosis Patients.

In multiple sclerosis (MS), oligodendrocyte precursor cells (OPCs) are recruited to the site of injury to remyelinate damaged axons; however, in patients this process is often ineffective due to defects in OPC maturation. The membrane receptor GPR17 timely regulates the early stages of OPC differentiation; however, after reaching its highest levels in immature oligodendrocytes, it has to be downregulated to allow terminal maturation. Since, in several animal models of disease GPR17 is upregulated, the aim of this work was to characterize GPR17 alterations in MS patients. We developed immunohistochemistry and immunofluorescence procedures for the detection of GPR17 in human tissues and stained post-mortem MS brain lesions from patients with secondary progressive MS and control subjects. The inflammatory activity in each lesion was evaluated by immunohistochemistry for the myelin protein MOG and the HLA antigen to classify them as active, chronic inactive or chronic active. Hence, we assessed the distribution of GPR17-positive cells in these lesions compared to normal appearing white matter (NAWM) and white matter (WM) of control subjects. Our data have shown a marked increase of GPR17-expressing oligodendroglial cells accumulating at NAWM, in which moderate inflammation was also found. Furthermore, we identified two distinct subpopulations of GPR17-expressing oligodendroglial cells, characterized by either ramified or rounded morphology, that differently populate the WM of healthy controls and MS patients. We concluded that the coordinated presence of GPR17 in OPCs at the lesion sites and inflamed NAWM areas suggests that GPR17 could be exploited to support endogenous remyelination through advanced pharmacological approaches.

Pathway-Focused Profiling of Oligodendrocytes Over-Expressing miR-125a-3p Reveals Alteration of Wnt and Cell-to-Cell Signaling.

MicroRNAs are small post-transcriptional regulators that modulate gene expression by directly interacting with their target transcripts. Since the interaction between miRNAs and target mRNAs does not require a perfect match, one single miRNA can influence the expression of several genes and lead to a very broad array of functional consequences. Recently, we identified miR-125a-3p as a new regulator of oligodendrocyte development, showing that its over-expression is associated to impaired oligodendrocyte maturation. However, whether and how miR-125a-3p over-expression is causally related to oligodendrocyte maturation is still obscure, as well as the pathways responsible for this effect. To shed light on this issue and to identify the underlying molecular mechanisms, we determined the transcriptomic profile of miR-125a-3p over-expressing oligodendrocytes and, by means of two complementary bioinformatic approaches, we have identified pathways and biological processes consistently modulated by miR-125a-3p alteration. This analysis showed that miR-125a-3p is involved in the regulation of cell-cell interactions and Wnt signaling. By means of pathway-focused PCR arrays, we confirmed that miR-125a-3p induces changes in the expression of several genes encoding for adhesion molecules and gap junctions, which play key roles in oligodendrocytes after exposure to pathological demyelinating stimuli. Moreover, the expression changes of different Wnt targets suggest an over-activation of this pathway. Globally, our studies show that miR-125a-3p over-expression can alter signaling pathways and biological processes essential for myelin formation in oligodendrocytes, suggesting that alteration of miR-125a-3p levels may contribute to impairing oligodendrocyte maturation in demyelinating diseases.

Development of the first in vivo GPR17 ligand through an iterative drug discovery pipeline: A novel disease-modifying strategy for multiple sclerosis.

The GPR17 receptor, expressed on oligodendroglial precursors (OPCs, the myelin producing cells), has emerged as an attractive target for a pro-myelinating strategy in multiple sclerosis (MS). However, the proof-of-concept that selective GPR17 ligands actually exert protective activity in vivo is still missing. Here, we exploited an iterative drug discovery pipeline to prioritize novel and selective GPR17 pro-myelinating agents out of more than 1,000,000 compounds. We first performed an in silico high-throughput screening on GPR17 structural model to identify three chemically-diverse ligand families that were then combinatorially exploded and refined. Top-scoring compounds were sequentially tested on reference pharmacological in vitro assays with increasing complexity, ending with myelinating OPC-neuron co-cultures. Successful ligands were filtered through in silico simulations of metabolism and pharmacokinetics, to select the most promising hits, whose dose and ability to target the central nervous system were then determined in vivo. Finally, we show that, when administered according to a preventive protocol, one of them (named by us as galinex) is able to significantly delay the onset of experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. This outcome validates the predictivity of our pipeline to identify novel MS-modifying agents.

In vivo silencing of miR-125a-3p promotes myelin repair in models of white matter demyelination.

In the last decade, microRNAs have been increasingly recognized as key modulators of glial development. Recently, we identified miR-125a-3p as a new player in oligodendrocyte physiology, regulating in vitro differentiation of oligodendrocyte precursor cells (OPCs). Here, we show that miR-125a-3p is upregulated in active lesions of multiple sclerosis (MS) patients and in OPCs isolated from the spinal cord of chronic experimental autoimmune encephalomyelitis (EAE) mice, but not in those isolated from the spontaneously remyelinating corpus callosum of lysolecithin-treated mice. To test whether a sustained expression of miR-125a-3p in OPCs contribute to defective remyelination, we modulated miR-125a-3p expression in vivo and ex vivo after lysolecithin-induced demyelination. We found that lentiviral over-expression of miR-125a-3p impaired OPC maturation, whereas its downregulation accelerated remyelination. Transcriptome analysis and luciferase reporter assay revealed that these effects are partly mediated by the direct interaction of miR-125a-3p with Slc8a3, a sodium-calcium membrane transporter, and identified novel candidate targets, such as Gas7, that we demonstrated necessary to correctly address oligodendrocytes to terminal maturation. These findings show that miR-125a-3p upregulation negatively affects OPC maturation in vivo, suggest its role in the pathogenesis of demyelinating diseases and unveil new targets for future promyelinating protective interventions.

Regulation of Oligodendrocyte Functions: Targeting Lipid Metabolism and Extracellular Matrix for Myelin Repair.

: Myelin is an essential structure that protects axons, provides metabolic support to neurons and allows fast nerve transmission. Several neurological diseases, such as multiple sclerosis, are characterized by myelin damage, which is responsible of severe functional impairment. Myelin repair requires the timely recruitment of adult oligodendrocyte precursor cells (OPCs) at the lesion sites, their differentiation and maturation into myelinating oligodendrocytes. As a consequence, OPCs undergo profound changes in their morphology, functions, and interactions with other cells and extracellular environment, thus requiring the reorganization of both their lipid metabolism and their membrane composition, which is substantially different compared to other plasma membranes. Despite the growing knowledge in oligodendroglia biology and in the mechanisms involved in OPC-mediated regeneration, the identification of strategies to promote remyelination still remains a challenge. Here, we describe how altered lipid metabolism in oligodendrocytes influences the pathogenesis of demyelination, and we show that several FDA-approved drugs with a previously unknown remyelination potential do act on cholesterol and lipid biosynthetic pathways. Since the interplay between myelin lipids and axons is strictly coordinated by the extracellular matrix (ECM), we also discuss the role of different ECM components, and report the last findings on new ECM-modifiers able to foster endogenous remyelination.

MicroRNAs change the games in central nervous system pharmacology.

MicroRNAs (miRNAs) represent a class of important post-transcriptional regulators of gene expression, enabling cells to follow their intrinsic developmental program. By directly binding to their targets, miRNAs can both promote transcriptional patterns in crucial steps of cell growth, and act as powerful buffering system that titrate protein content in case of aberrant gene expression. The literature of the last decade showed that the presence of tissue-enriched miRNAs in body fluids could be reminiscent of disease state. This is particularly relevant in neurodegenerative disorders, in which peripheral biomarkers could be helpful means to detect disease onset. However, dysregulation of miRNAs is not merely a consequence of disease, but directly contributes to pathological outcomes. On this basis, increasing interest is growing in the development of pharmacological agents targeting specific miRNAs. Actually, this apparently futuristic approach is already part of the current therapies. In fact, several drugs approved for CNS disorders, such as L-Dopa or valproic acid, were also demonstrated to restore some miRNAs. Moreover, ongoing clinical trials demonstrated that miRNA-based drugs are effective against tumors, suggesting that miRNAs also represent a promising class of therapeutic molecules. However, several issues still need to be addressed, particularly in case of CNS diseases, in which stability and delivery are crucial aspects of the therapy. In this commentary, we highlighted potential advantages and limitations of miRNAs as next generation targets in CNS pharmacology, focusing on multiple sclerosis, a chronic demyelinating disease lacking specific therapeutic targets and bona-fide biomarkers.

Source-device-independent heterodyne-based quantum random number generator at 17 Gbps.

Random numbers are commonly used in many different fields, ranging from simulations in fundamental science to security applications. In some critical cases, as Bell's tests and cryptography, the random numbers are required to be both private and to be provided at an ultra-fast rate. However, practical generators are usually considered trusted, but their security can be compromised in case of imperfections or malicious external actions. In this work we introduce an efficient protocol which guarantees security and speed in the generation. We propose a source-device-independent protocol based on generic Positive Operator Valued Measurements and then we specialize the result to heterodyne measurements. Furthermore, we experimentally implemented the protocol, reaching a secure generation rate of 17.42 Gbit/s, without the need of an initial source of randomness. The security of the protocol has been proven for general attacks in the finite key scenario.

Exploring the boundaries of quantum mechanics: advances in satellite quantum communications.

Recent interest in quantum communications has stimulated great technological progress in satellite quantum technologies. These advances have rendered the aforesaid technologies mature enough to support the realization of experiments that test the foundations of quantum theory at unprecedented scales and in the unexplored space environment. Such experiments, in fact, could explore the boundaries of quantum theory and may provide new insights to investigate phenomena where gravity affects quantum objects. Here, we review recent results in satellite quantum communications and discuss possible phenomena that could be observable with current technologies. Furthermore, stressing the fact that space represents an incredible resource to realize new experiments aimed at highlighting some physical effects, we challenge the community to propose new experiments that unveil the interplay between quantum mechanics and gravity that could be realizable in the near future.This article is part of a discussion meeting issue 'Foundations of quantum mechanics and their impact on contemporary society'.

Differential local tissue permissiveness influences the final fate of GPR17-expressing oligodendrocyte precursors in two distinct models of demyelination.

Promoting remyelination is recognized as a novel strategy to foster repair in neurodegenerative demyelinating diseases, such as multiple sclerosis. In this respect, the receptor GPR17, recently emerged as a new target for remyelination, is expressed by early oligodendrocyte precursors (OPCs) and after a certain differentiation stage it has to be downregulated to allow progression to mature myelinating oligodendrocytes. Here, we took advantage of the first inducible GPR17 reporter mouse line (GPR17-iCreERT2 xCAG-eGFP mice) allowing to follow the final fate of GPR17+ cells by tamoxifen-induced GFP-labeling to unveil the destiny of these cells in two demyelination models: experimental autoimmune encephalomyelitis (EAE), characterized by marked immune cell activation and inflammation, and cuprizone induced demyelination, where myelin dysfunction is achieved by a toxic insult. In both models, demyelination induced a strong increase of fluorescent GFP+ cells at damaged areas. However, only in the cuprizone model reacting GFP+ cells terminally differentiated to mature oligodendrocytes, thus contributing to remyelination. In EAE, GFP+ cells were blocked at immature stages and never became myelinating oligodendrocytes. We suggest these strikingly distinct fates be due to different permissiveness of the local CNS environment. Based on previously reported GPR17 activation by emergency signals (e.g., Stromal Derived Factor-1), we propose that a marked inflammatory milieu, such as that reproduced in EAE, induces GPR17 overactivation resulting in impaired downregulation, untimely and prolonged permanence in OPCs, leading, in turn, to differentiation blockade. Combined treatments with remyelinating agents and anti-inflammatory drugs may represent new potential adequate strategies to halt neurodegeneration and foster recovery.

Extending Wheeler's delayed-choice experiment to space.

Gedankenexperiments have consistently played a major role in the development of quantum theory. A paradigmatic example is Wheeler's delayed-choice experiment, a wave-particle duality test that cannot be fully understood using only classical concepts. We implement Wheeler's idea along a satellite-ground interferometer that extends for thousands of kilometers in space. We exploit temporal and polarization degrees of freedom of photons reflected by a fast-moving satellite equipped with retroreflecting mirrors. We observe the complementary wave- or particle-like behaviors at the ground station by choosing the measurement apparatus while the photons are propagating from the satellite to the ground. Our results confirm quantum mechanical predictions, demonstrating the need of the dual wave-particle interpretation at this unprecedented scale. Our work paves the way for novel applications of quantum mechanics in space links involving multiple photon degrees of freedom.

Source-Device-Independent Ultrafast Quantum Random Number Generation.

Secure random numbers are a fundamental element of many applications in science, statistics, cryptography and more in general in security protocols. We present a method that enables the generation of high-speed unpredictable random numbers from the quadratures of an electromagnetic field without any assumption on the input state. The method allows us to eliminate the numbers that can be predicted due to the presence of classical and quantum side information. In particular, we introduce a procedure to estimate a bound on the conditional min-entropy based on the entropic uncertainty principle for position and momentum observables of infinite dimensional quantum systems. By the above method, we experimentally demonstrated the generation of secure true random bits at a rate greater than 1.7 Gbit/s.

MiR-125a-3p timely inhibits oligodendroglial maturation and is pathologically up-regulated in human multiple sclerosis.

In the mature central nervous system (CNS), oligodendrocytes provide support and insulation to axons thanks to the production of a myelin sheath. During their maturation to myelinating cells, oligodendroglial precursors (OPCs) follow a very precise differentiation program, which is finely orchestrated by transcription factors, epigenetic factors and microRNAs (miRNAs), a class of small non-coding RNAs involved in post-transcriptional regulation. Any alterations in this program can potentially contribute to dysregulated myelination, impaired remyelination and neurodegenerative conditions, as it happens in multiple sclerosis (MS). Here, we identify miR-125a-3p, a developmentally regulated miRNA, as a new actor of oligodendroglial maturation, that, in the mammalian CNS regulates the expression of myelin genes by simultaneously acting on several of its already validated targets. In cultured OPCs, over-expression of miR-125a-3p by mimic treatment impairs while its inhibition with an antago-miR stimulates oligodendroglial maturation. Moreover, we show that miR-125a-3p levels are abnormally high in the cerebrospinal fluid of MS patients bearing active demyelinating lesions, suggesting that its pathological upregulation may contribute to MS development, at least in part by blockade of OPC differentiation leading to impaired repair of demyelinated lesions.

A new role for the P2Y-like GPR17 receptor in the modulation of multipotency of oligodendrocyte precursor cells in vitro.

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 ßIII-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.