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Ischemic stroke is a leading cause of disability worldwide. While much of post-stroke recovery is focused on physical rehabilitation, post-stroke dementia (PSD) is also a significant contributor to poor functional outcomes. Predictive tools to identify stroke survivors at risk for the development of PSD are limited to brief screening cognitive tests. Emerging biochemical, genetic, and neuroimaging biomarkers are being investigated in an effort to unveil better indicators of PSD. Additionally, acetylcholinesterase inhibitors, NMDA receptor antagonists, dopamine receptor agonists, antidepressants, and cognitive rehabilitation are current therapeutic options for PSD. Focusing on the chronic sequelae of stroke that impair neuroplasticity highlights the need for continued investigative trials to better assess functional outcomes in treatments targeted for PSD.
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Biomarcadores , Demencia , Accidente Cerebrovascular Isquémico , Humanos , Accidente Cerebrovascular Isquémico/metabolismo , Accidente Cerebrovascular Isquémico/terapia , Demencia/etiología , Demencia/metabolismoRESUMEN
Zinc tungstate is a semiconductor known for its favorable photocatalytic, photoluminescence, and scintillation properties, coupled with its relatively low cost, reduced toxicity, and high stability in biological and catalytic environments. In particular, zinc tungstate evinces scintillation properties, namely the ability to emit visible light upon absorption of energetic radiation such as x rays, which has led to applications not only as radiation detectors but also for biomedical applications involving the delivery of optical light to deep tissue, such as photodynamic therapy and optogenetics. Here, we report on the synthesis of zinc tungstate nanorods generated via an optimized but facile method, which allows for synthetic control over the aspect ratio of the as-synthesized anisotropic motifs via rational variation of the solution pH. We investigate the effect of aspect ratio on their resulting photoluminescent and radioluminescent properties. We further demonstrate the potential of these zinc tungstate nanorods for biomedical applications, such as photodynamic therapy for cancer treatment, by analyzing their toxicological profile within cell lines and neurons.
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Nanotubos , Compuestos de Tungsteno , Compuestos de Tungsteno/química , Compuestos de Tungsteno/toxicidad , Nanotubos/química , Humanos , Animales , Fotoquimioterapia , Supervivencia Celular/efectos de los fármacos , Compuestos de Zinc/química , Ratones , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Zinc/químicaRESUMEN
Glioblastoma (GBM) is the most frequently diagnosed primary central nervous system tumor in adults. Despite the standard of care therapy, which includes surgical resection, temozolomide chemotherapy, radiation and the newly added tumor-treating fields, median survival remains only â¼20 months. Unfortunately, GBM has a â¼100% recurrence rate, but after recurrence there are no Food and Drug Administration-approved therapies to limit tumor growth and enhance patient survival, as these tumors are resistant to temozolomide (TMZ). Recently, our laboratory reported that lucanthone slows GBM by inhibiting autophagic flux through lysosome targeting and decreases the number of Olig2+ glioma stem-like cells (GSC) in vitro and in vivo. We now additionally report that lucanthone efficiently abates stemness in patient-derived GSC and reduces tumor microtube formation in GSC, an emerging hallmark of treatment resistance in GBM. In glioma tumors derived from cells with acquired resistance to TMZ, lucanthone retains the ability to perturb tumor growth, inhibits autophagy by targeting lysosomes, and reduces Olig2 positivity. We also find that lucanthone may act as an inhibitor of palmitoyl protein thioesterase 1. Our results suggest that lucanthone may function as a potential treatment option for GBM tumors that are not amenable to TMZ treatment. SIGNIFICANCE STATEMENT: We report that the antischistosome agent lucanthone impedes tumor growth in a preclinical model of temozolomide-resistant glioblastoma and reduces the numbers of stem-like glioma cells. In addition, it acts as an autophagy inhibitor, and its mechanism of action may be via inhibition of palmitoyl protein thioesterase 1. As there are no defined therapies approved for recurrent, TMZ-resistant tumor, lucanthone could emerge as a treatment for glioblastoma tumors that may not be amenable to TMZ both in the newly diagnosed and recurrent settings.
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Neoplasias Encefálicas , Glioblastoma , Glioma , Lucantona , Humanos , Temozolomida/farmacología , Temozolomida/uso terapéutico , Glioblastoma/tratamiento farmacológico , Glioblastoma/metabolismo , Lucantona/farmacología , Lucantona/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/metabolismo , Línea Celular Tumoral , Resistencia a Antineoplásicos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/patología , Glioma/tratamiento farmacológico , Glioma/patología , Ensayos Antitumor por Modelo de Xenoinjerto , Antineoplásicos Alquilantes/farmacología , Antineoplásicos Alquilantes/uso terapéutico , Proteínas de la Membrana , Tioléster HidrolasasRESUMEN
Chronic environmental stress and traumatic social experiences induce maladaptive behavioral changes and is a risk factor for major depressive disorder (MDD) and various anxiety-related psychiatric disorders. Clinical studies and animal models of chronic stress have reported that symptom severity is correlated with innate immune responses and upregulation of neuroinflammatory cytokine signaling in brain areas implicated in mood regulation (mPFC; medial Prefrontal Cortex). Despite increasing evidence implicating impairments of neuroplasticity and synaptic signaling deficits into the pathophysiology of stress-related mental disorders, how microglia may modulate neuronal homeostasis in response to chronic stress has not been defined. Here, using the repeated social defeat stress (RSDS) mouse model we demonstrate that microglial-induced inflammatory responses are regulating neuronal plasticity associated with psychosocial stress. Specifically, we show that chronic stress induces a rapid activation and proliferation of microglia as well as macrophage infiltration in the mPFC, and these processes are spatially related to neuronal activation. Moreover, we report a significant association of microglial inflammatory responses with susceptibility or resilience to chronic stress. In addition, we find that exposure to chronic stress exacerbates phagocytosis of synaptic elements and deficits in neuronal plasticity. Importantly, by utilizing two different CSF1R inhibitors (the brain penetrant PLX5622 and the non-penetrant PLX73086) we highlight a crucial role for microglia (and secondarily macrophages) in catalyzing the pathological manifestations linked to psychosocial stress in the mPFC and the resulting behavioral deficits usually associated with depression.
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Trastorno Depresivo Mayor , Microglía , Ratones , Animales , Humanos , Microglía/patología , Macrófagos , Neuronas , Estrés Psicológico/complicaciones , Estrés Psicológico/patologíaRESUMEN
Ischemic stroke is a highly morbid disease, with over 50% of large vessel stroke (middle cerebral artery or internal carotid artery terminus occlusion) patients suffering disability despite maximal acute reperfusion therapy with thrombolysis and thrombectomy. The discovery of the ischemic penumbra in the 1980s laid the foundation for a salvageable territory in ischemic stroke. Since then, the concept of neuroprotection has been a focus of post-stroke care to (1) minimize the conversion from penumbra to core irreversible infarct, (2) limit secondary damage from ischemia-reperfusion injury, inflammation, and excitotoxicity and (3) to encourage tissue repair. However, despite multiple studies, the preclinical-clinical research enterprise has not yet created an agent that mitigates post-stroke outcomes beyond thrombolysis and mechanical clot retrieval. These translational gaps have not deterred the scientific community as agents are under continuous investigation. The NIH has recently promoted the concept of cerebroprotection to consider the whole brain post-stroke rather than just the neurons. This review will briefly outline the translational science of past, current, and emerging breakthroughs in cerebroprotection and use of these foundational ideas to develop a novel paradigm for optimizing stroke outcomes.
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Major Depressive Disorder (MDD) is a highly prevalent, debilitating disorder. According to the World Health Organization, approximately 5% of adults suffer from depression worldwide and more women than men are affected. Yet, we have a very limited understanding of the pathogenesis of the disease, how sex and genetics influence the pathophenotype of MDD, and how they contribute to the responses to pharmacological treatment. This chapter addresses key theories about the etiology of depression, the variations in epidemiology and presentation, and the treatment options with respect to sex and gender. Additionally, we discuss the emerging wave of treatment modalities, diagnosis, and research focusing on MDD.
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We have synthesized several morphologies and crystal structures of MgWO4 using a one-pot hydrothermal method, producing not only monoclinic stars and large nanoparticles but also triclinic wool balls and sub-10 nm nanoparticles. Herein we describe the importance of reaction parameters in demonstrating morphology control of as-prepared MgWO4. Moreover, we correlate structure and composition with the resulting photoluminescence and radioluminescence properties. Specifically, triclinic-phase samples yielded a photoluminescence emission of 421 nm, whereas monoclinic-phase materials gave rise to an emission maximum of 515 nm. The corresponding radioluminescence data were characterized by a broad emission peak, located at 500 nm for all samples. Annealing the wool balls and sub-10 nm particles to transform the crystal structure from a triclinic to a monoclinic phase yielded a radioluminescence (RL) emission signal that was two orders of magnitude greater than that of their unannealed counterparts. Finally, to confirm the practical utility of these materials for biomedical applications, a series of sub-10 nm particles, including as-prepared and annealed samples, were functionalized with biocompatible PEG molecules, and subsequently were found to be readily taken up by various cell lines as well as primary cultured hippocampal neurons with low levels of toxicity, thereby highlighting for the first time the potential of this particular class of metal oxides as viable and readily generated platforms for a range of biomedical applications.
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In the past several years there has been a marked increase in our understanding of the pathophysiological hallmarks of glioblastoma development and progression, with specific respect to the contribution of the glioma tumor microenvironment to the rapid progression and treatment resistance of high-grade gliomas. Despite these strides, standard of care therapy still only targets rapidly dividing tumor cells in the glioma, and does little to curb the pro-tumorigenic functions of non-cancerous cells entrenched in the glioma microenvironment. This tumor promoting environment as well as the heterogeneity of high-grade gliomas contribute to the poor prognosis of this malignancy. The interaction of non-malignant cells in the microenvironment with the tumor cells accentuate phenotypes such as rapid proliferation or immunosuppression, so therapeutically modulating one target expressed on one cell type may be insufficient to restrain these rapidly developing neoplasias. With this in mind, identifying a target expressed on multiple cell types and understanding how it governs tumor-promoting functions in each cell type may have great utility in better managing this disease. Herein, we review the physiology and pathological effects of Neuropilin-1, a transmembrane co-receptor which mediates signal transduction pathways when associated with multiple other receptors. We discuss its effects on the properties of endothelial cells and on immune cell types within gliomas including glioma-associated macrophages, microglia, cytotoxic T cells and T regulatory cells. We also consider its effects when elaborated on the surface of tumor cells with respect to proliferation, stemness and treatment resistance, and review attempts to target Neuroplin-1 in the clinical setting.
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Glioma , Neuropilina-1 , Células Endoteliales/metabolismo , Glioma/genética , Humanos , Microglía , Neuropilina-1/metabolismo , Microambiente TumoralRESUMEN
BACKGROUND: Early invasion of the central nervous system (CNS) by human immunodeficiency virus (HIV) (Gray et al. in Brain Pathol 6:1-15, 1996; An et al. in Ann Neurol 40:611-6172, 1996), results in neuroinflammation, potentially through extracellular vesicles (EVs) and their micro RNAs (miRNA) cargoes (Sharma et al. in FASEB J 32:5174-5185, 2018; Hu et al. in Cell Death Dis 3:e381, 2012). Although the basal ganglia (BG) is a major target and reservoir of HIV in the CNS (Chaganti et al. in Aids 33:1843-1852, 2019; Mintzopoulos et al. in Magn Reson Med 81:2896-2904, 2019), whether BG produces EVs and the effect of HIV and/or the phytocannabinoid-delta-9-tetrahydrocannabinol (THC) on BG-EVs and HIV neuropathogenesis remain unknown. METHODS: We used the simian immunodeficiency virus (SIV) model of HIV and THC treatment in rhesus macaques (Molina et al. in AIDS Res Hum Retroviruses 27:585-592, 2011) to demonstrate for the first time that BG contains EVs (BG-EVs), and that BG-EVs cargo and function are modulated by SIV and THC. We also used primary astrocytes from the brains of wild type (WT) and CX3CR1+/GFP mice to investigate the significance of BG-EVs in CNS cells. RESULTS: Significant changes in BG-EV-associated miRNA specific to SIV infection and THC treatment were observed. BG-EVs from SIV-infected rhesus macaques (SIV EVs) contained 11 significantly downregulated miRNAs. Remarkably, intervention with THC led to significant upregulation of 37 miRNAs in BG-EVs (SIV-THC EVs). Most of these miRNAs are predicted to regulate pathways related to inflammation/immune regulation, TLR signaling, Neurotrophin TRK receptor signaling, and cell death/response. BG-EVs activated WT and CX3CR1+/GFP astrocytes and altered the expression of CD40, TNFα, MMP-2, and MMP-2 gene products in primary mouse astrocytes in an EV and CX3CR1 dependent manners. CONCLUSIONS: Our findings reveal a role for BG-EVs as a vehicle with potential to disseminate HIV- and THC-induced changes within the CNS.
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Vesículas Extracelulares , MicroARNs , Síndrome de Inmunodeficiencia Adquirida del Simio , Virus de la Inmunodeficiencia de los Simios , Animales , Ganglios Basales/metabolismo , Ganglios Basales/patología , Dronabinol/farmacología , Vesículas Extracelulares/metabolismo , Humanos , Macaca mulatta/genética , Macaca mulatta/metabolismo , Metaloproteinasa 2 de la Matriz/metabolismo , Ratones , MicroARNs/metabolismo , Síndrome de Inmunodeficiencia Adquirida del Simio/tratamiento farmacológicoRESUMEN
Microglia, the dynamic innate immune cells of the central nervous system, become activated in epilepsy. The process of microglial activation in epilepsy results in the creation of an inflammatory environment around the site of seizure onset, which contributes to the epileptogenic process and epilepsy progression. Cannabidiol (CBD) has been effective for use as an adjunctive treatment for two severe pediatric seizure disorders. Newly recognized as an Food and Drug Administration (FDA)-approved drug treatment in epilepsy, it has gained in popularity primarily for pain management. Although CBD is readily available in stores and online retailers, its mechanism of action and specifically its effects on microglia and their functions are yet fully understood. In this study, we examine the effects of commercially available CBD on microglia inflammatory activation and neurogenic response, in the presence and absence of seizures. We use systemic administration of kainate to elicit seizures in mice, which are assessed behaviorally. Artisanal CBD is given in different modes of administration and timing to dissect its effect on seizure intensity, microglial activation and aberrant seizure-related neurogenesis. CBD significantly dampens microglial migration and accumulation to the hippocampus. While long term artisanal CBD use does not prevent or lessen seizure severity, CBD is a promising adjunctive partner for its ability to depress epileptogenic processes. These studies indicate that artisanal CBD is beneficial as it both decreases inflammation in the CNS and reduces the number of ectopic neurons deposited in the hippocampal area post seizure.
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Cannabidiol , Epilepsia , Animales , Anticonvulsivantes/farmacología , Anticonvulsivantes/uso terapéutico , Cannabidiol/farmacología , Epilepsia/tratamiento farmacológico , Humanos , Ácido Kaínico/toxicidad , Ratones , Microglía , Neurogénesis/fisiología , Convulsiones/inducido químicamente , Convulsiones/tratamiento farmacológico , Convulsiones/prevención & controlRESUMEN
Oligodendroglia play a critical role in CNS homeostasis by myelinating neuronal axons in their mature stages. Dysfunction in this lineage occurs when early stage OPCs are not able to differentiate to replace dying Mature Myelinating Oligodendrocytes. Many hypotheses exist as to why de- and hypo-myelinating disorders and diseases occur. In this review, we present data to show that oligodendroglia can adopt components of the immune proteasome under inflammatory conditions. The works reviewed further reflect that these immune-component expressing oligodendroglia can in fact function as antigen presenting cells, phagocytosing foreign entities and presenting them via MHC II to activate CD4+ T cells. Additionally, we hypothesize, based on the limited literature, that the adoption of immune components by oligodendroglia may contribute to their stalled differentiation in the context of these disorders and diseases. The present review will underline: (1) Mechanisms of neuroinflammation in diseases associated with Immune Oligodendroglia; (2) the first associations between the immune proteasome and oligodendroglia and the subtle distinctions between these works; (3) the suggested functionality of these cells as it is described by current literature; and (4) the hypothesized consequences on metabolism. In doing so we aim to shed light on this fairly under-explored cell type in hopes that study of their functionality may lead to further mechanistic understanding of hypo- and de-myelinating neuroinflammatory disorders and diseases.
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The mechanisms that regulate neural stem cell (NSC) lineage progression and maintain NSCs within different domains of the adult neural stem cell niche, the subventricular zone are not well defined. Quiescent NSCs are arranged at the apical ventricular wall, while mitotically activated NSCs are found in the basal, vascular region of the subventricular zone. Here, we found that ADAM10 (a disintegrin and metalloproteinase 10) is essential in NSC association with the ventricular wall, and via this adhesion to the apical domain, ADAM10 regulates the switch from quiescent and undifferentiated NSC to an actively proliferative and differentiating cell state. Processing of JAMC (junctional adhesion molecule C) by ADAM10 increases Rap1GAP activity. This molecular machinery promotes NSC transit from the apical to the basal compartment and subsequent lineage progression. Understanding the molecular mechanisms responsible for regulating the proper positioning of NSCs within the subventricular zone niche and lineage progression of NSCs could provide new targets for drug development to enhance the regenerative properties of neural tissue.
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Glioblastoma is the most common and aggressive primary brain tumor in adults. Median survival time remains at 16-20 months despite multimodal treatment with surgical resection, radiation, temozolomide and tumor-treating fields therapy. After genotoxic stress glioma cells initiate cytoprotective autophagy, which contributes to treatment resistance, limiting the efficacy of these therapies and providing an avenue for glioma recurrence. Antagonism of autophagy steps has recently gained attention as it may enhance the efficacy of classical chemotherapies and newer immune-stimulating therapies. The modulation of autophagy in the clinic is limited by the low potency of common autophagy inhibitors and the inability of newer ones to cross the blood-brain barrier. Herein, we leverage lucanthone, an anti-schistosomal agent which crosses the blood-brain barrier and was recently reported to act as an autophagy inhibitor in breast cancer cells. Our studies show that lucanthone was toxic to glioma cells by inhibiting autophagy. It enhanced anti-glioma temozolomide (TMZ) efficacy at sub-cytotoxic concentrations, and suppressed the growth of stem-like glioma cells and temozolomide-resistant glioma stem cells. In vivo lucanthone slowed tumor growth: reduced numbers of Olig2+ glioma cells, normalized tumor vasculature, and reduced tumor hypoxia. We propose that lucanthone may serve to perturb a mechanism of temozolomide resistance and allow for successful treatment of TMZ-resistant glioblastoma.
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Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS) that is characterized by progressive demyelination and neurodegeneration. It is considered an autoimmune disorder as autologous myelin-reactive T cells infiltrate the CNS, activate peripheral and resident innate immune cells, and promote local inflammation. MS in humans is characterized by a wide variety of clinical disease courses, which has made this disease complex to model in an experimental system. Experimental autoimmune encephalomyelitis (EAE) is currently the most common animal model for MS. Animals who undergo EAE recapitulate many of the hallmarks of MS in humans, such as motor deficits and CNS demyelination. Most importantly, all models of EAE utilize myelin-reactive T cells to target the myelin sheath, which allows for the effective investigation and testing of immunomodulatory therapies for MS. Here, we describe several methods by which EAE can be induced, observed, scored, and quantified experimentally.
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Encefalomielitis Autoinmune Experimental , Esclerosis Múltiple , Animales , Modelos Animales de Enfermedad , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Esclerosis Múltiple/tratamiento farmacológico , Vaina de Mielina , Linfocitos TRESUMEN
Multiple Sclerosis (MS) is characterized by the presence of demyelinating lesions in the Central Nervous System (CNS). The demyelination is accompanied by axonal degeneration and the activation of cells of the innate and adaptive immune systems that accumulate around the demyelinated plaques. Oligodendrocyte cell dysfunction and death are also evident. In the relapsing-remitting form of MS, this dysfunction is followed by periods of recovery, and newly mature oligodendrocytes have the ability to remyelinate the pathological axons. To specifically study the localized demyelination/remyelination processes, animal models involving specific demyelinating toxins or viruses have been generated. Through these models the pathological effects on oligodendrocytes can be analyzed, and pharmacological treatments that can restore oligodendrocyte myelination capabilities can be assessed. Here we describe the most commonly used models of toxic or viral demyelination, and provide protocols to induce and analyze them.
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Esclerosis Múltiple , Animales , Axones , Sistema Nervioso Central/patología , Modelos Animales de Enfermedad , Esclerosis Múltiple/patología , OligodendroglíaRESUMEN
Major depressive disorder (MDD) is a chronic debilitating illness affecting yearly 300 million people worldwide. Oligodendrocyte-lineage cells have emerged as important neuromodulators in synaptic plasticity and crucial components of MDD pathophysiology. Using the repeated social defeat (RSDS) mouse model, we demonstrate that chronic psychosocial stress induces long-lasting losses and transient proliferation of oligodendrocyte-precursor cells (OPCs), aberrant differentiation into oligodendrocytes, and severe hypomyelination in the prefrontal cortex. Exposure to chronic stress results in OPC morphological impairments, excessive oxidative stress, and oligodendroglial apoptosis, implicating integrative-stress responses in depression. Analysis of single-nucleus transcriptomic data from MDD patients revealed oligodendroglial-lineage dysregulation and the presence of immune-oligodendrocytes (Im-OL), a novel population of cells with immune properties and myelination deficits. Im-OL were also identified in mice after RSDS, where oligodendrocyte-lineage cells expressed immune-related markers. Our findings demonstrate cellular and molecular changes in the oligodendroglial lineage in response to chronic stress and associate hypomyelination with Im-OL emergence during depression.
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Trastorno Depresivo Mayor , Vaina de Mielina , Animales , Diferenciación Celular/fisiología , Homeostasis , Humanos , Ratones , Vaina de Mielina/fisiología , Oligodendroglía , Corteza PrefrontalRESUMEN
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) characterized by peripheral immune cell infiltration into the brain and spinal cord, demyelination, glial cell activation, and neuronal damage. Currently there is no cure for MS, however, available disease-modifying agents minimize inflammation in the CNS by various mechanisms. Approved drugs lessen severity of the disease and delay disease progression, however, they are still suboptimal as patients experience adverse effects and varying efficacies. Additionally, there is only one disease-modifying therapy available for the more debilitating, progressive form of MS. This chapter focuses on the presently-available therapeutics and, importantly, the future directions of MS therapy based on preclinical studies and early clinical trials. Immunosuppression in other neurological disorders including neuromyelitis optica spectrum disorders, myasthenia gravis, and Guillain-Barré syndrome is also discussed.
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Esclerosis Múltiple , Miastenia Gravis , Neuromielitis Óptica , Humanos , Terapia de Inmunosupresión , Esclerosis Múltiple/tratamiento farmacológico , Neuromielitis Óptica/tratamiento farmacológico , Médula EspinalRESUMEN
Microglia are important for brain homeostasis and immunity, but their role in regulating vigilance remains unclear. We employed genetic, physiological, and metabolomic methods to examine microglial involvement in the regulation of wakefulness and sleep. Microglial depletion decreased stable nighttime wakefulness in mice by increasing transitions between wakefulness and non-rapid eye movement (NREM) sleep. Metabolomic analysis revealed that the sleep-wake behavior closely correlated with diurnal variation of the brain ceramide, which disappeared in microglia-depleted mice. Ceramide preferentially influenced microglia in the thalamic reticular nucleus (TRN), and local depletion of TRN microglia produced similar impaired wakefulness. Chemogenetic manipulations of anterior TRN neurons showed that they regulated transitions between wakefulness and NREM sleep. Their firing capacity was suppressed by both microglial depletion and added ceramide. In microglia-depleted mice, activating anterior TRN neurons or inhibiting ceramide production both restored stable wakefulness. These findings demonstrate that microglia can modulate stable wakefulness through anterior TRN neurons via ceramide signaling.
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Potenciales de Acción/fisiología , Neuronas GABAérgicas/fisiología , Microglía/fisiología , Sueño/fisiología , Núcleos Talámicos/fisiología , Vigilia/fisiología , Algoritmos , Animales , Electroencefalografía/métodos , Electromiografía/métodos , Femenino , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Modelos Neurológicos , Núcleos Talámicos/citologíaRESUMEN
The characterization of the tumor microenvironment (TME) in high grade gliomas (HGG) has generated significant interest in an effort to understand how neoplastic lesions in the central nervous system (CNS) are supported and to devise novel therapeutic targets. The TME of the CNS contains unique and specialized cells, including the resident myeloid cells, microglia. Myeloid involvement in HGG, such as glioblastoma, is associated with poor outcomes. Glioma-associated microglia and infiltrating monocytes/macrophages (GAM) accumulate within the neoplastic lesion where they facilitate tumor growth and drive immunosuppression. However, it has been difficult to differentiate whether microglia and macrophages have similar or distinct roles in pathology, and if the spatial organization of these cells informs outcomes. Here, we characterize the tumor-stroma border and identify peritumoral GAM (PGAM) as a unique subpopulation of GAM. Using data mining and analyses of samples derived from both murine and human sources we show that PGAM exhibit a pro-inflammatory and chemotactic phenotype that is associated with peripheral monocyte recruitment, and decreased overall survival. PGAM act as a unique subset of GAM at the tumor-stroma interface. We define a novel gene signature to identify these cells and suggest that PGAM constitute a cellular target of the TME.