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Astrocytes are abundant glial cells in the central nervous system (CNS) that perform diverse functions in health and disease. Astrocyte dysfunction is found in numerous diseases, including multiple sclerosis, Alzheimer disease, Parkinson disease, Huntington disease and neuropsychiatric disorders. Astrocytes regulate glutamate and ion homeostasis, cholesterol and sphingolipid metabolism and respond to environmental factors, all of which have been implicated in neurological diseases. Astrocytes also exhibit significant heterogeneity, driven by developmental programmes and stimulus-specific cellular responses controlled by CNS location, cell–cell interactions and other mechanisms. In this Review, we highlight general mechanisms of astrocyte regulation and their potential as therapeutic targets, including drugs that alter astrocyte metabolism, and therapies that target transporters and receptors on astrocytes. Emerging ideas, such as engineered probiotics and glia-to-neuron conversion therapies, are also discussed. We further propose a concise nomenclature for astrocyte subsets that we use to highlight the roles of astrocytes and specific subsets in neurological diseases.In this Review, Quintana and colleagues discuss astrocytes, a type of glial cell that could be manipulated to treat neurological conditions. Potential astrocyte targets, and the progess made towards developing astrocyte-directed therapies, are highlighted, along with their potential pitfalls. They also propose a novel nomenclature for astrocyte subsets.

إنه مدير لإحدى شركات الاستثمار الخاصة، اشترى جاي شيلدون شركة تليفزيونية صغيرة من ذوات الاشتراك السلكي في الغرب الأوسط منذ سنوات مضت، وكان لا يعرف كثيرا عن هذه الصناعة، ولكن بدا سعرها ٨ ملايين دولار مغريا، وأن هذه الصفقة يمكن أن تسمح له باختبار الأمر، وسرعان ما فهم جاي وشركاؤه الأمر وجعلوه تجارتهم الرائجة. فبعد عام واحد، أرادوا التوسع من خلال الحصول على الأنظمة المجاورة. وبعد تمحيص الأرقام، حسبوا أنهم يستطيعون دفع ١١مليون دولار وربما ١٢مليون دولار على أقصى تقدير ليقوموا بشراء شركة تليفزيونية أخرى في مدينة مجاورة، وبدأ جاي سلسلة ممتدة من المحادثات مع صاحبها، ولكن بعد شهرين من الشد والجذب، بدا واضحا أن كلا الطرفين بينهما تباعد كبير في السعر، قال صاحبها : اسمع، إنني لم أقم بوضع لافتة تعلن عن رغبتي في البيع ؛ فأنت الذي أتيت، وعليك أن تضع على مكتبي ١٥مليون دولار نقدا حتى تقنعني بالبيع، وربما ندمت بعد ذلك على هذا الرقم، فهم شيلدون أن هذه لم تكن خدعة، ولكنه استشعر أن المطلوب شيء غير واقعي، فبالمنطق المعروف، فإن طرفي الصفقة قد ورطا نفسيهما، فإذا كان آخر سعر طلبه البائع أعلى بثلاثة ملايين من أعلى سعر عرضه المشتري، فلن تكون هناك صفقة، أم أن هذا في إمكانك ؟ قال شيلدون قبل أن ينهض ليغادر المكان : اسمح لي بسؤال أخير : إذا كنت تعتقد أن نظامك يستحق خمسة عشر مليون دولار، فماذا عما لدينا من أنظمة ؟، كانت الإجابة : أوه، إن أنظمتكم تقل عن هذا بقليل. أفترض أنها تستحق أربعة عشر مليونا أو نحو ذلك، لقد قلب شيلدون الصفقة رأسا على عقب، فأصبح ببراعة بائعا بدلا من أن يكون مشتريا، ففي أقل مما يزيد على سنة، حرك نظامه ليكسب تقريبا ضعفي ما دفعته شركته أولا وكان معظم هذا عن طريق الاستدانة، وكان لا يزال متفائلا بالقنوات ذات الاشتراك، ولكن عندما واجه هذا المالك الخاص الذي كان سريعا حيال هذه الصناعة كانت لدى شيلدون المهارة لتحويل طريق مسدود إلى صفقة رابحة، فكان الحل الذي قدمه حلا بارعا، ومع هذا، فكان أهم ما في الأمر هو سرعة بديهته، ففي الشيء الذي عاق أمله في الحصول على الشركة، وضع شيلدون بذرة صفقة أخرى ستخدمه بشكل أفضل، فعندما صرف نظره عن الخطة الأولى، أتت إليه الفكرة كأنها وميض.

Direct interactions between cells in tissue are incompletely understood because the advanced technologies required to examine them are still in their infancy. A new method can decipher cell–cell interactions on a large scale. Tagging method offers versatile way to track interactions between cells.

Women with a history of gestational diabetes mellitus (GDM) have a 7-fold higher risk of developing type 2 diabetes (T2D) during midlife and an elevated risk of developing hypertension and cardiovascular disease. Glucose tolerance reclassification after delivery is recommended, but fewer than 40% of women with GDM are tested. Thus, improved risk stratification methods are needed, as is a deeper understanding of the pathology underlying the transition from GDM to T2D. We hypothesize that metabolites during the early postpartum period accurately distinguish risk of progression from GDM to T2D and that metabolite changes signify underlying pathophysiology for future disease development. The study utilized fasting plasma samples collected from a well-characterized prospective research study of 1,035 women diagnosed with GDM. The cohort included racially/ethnically diverse pregnant women (aged 20-45 years-33% primiparous, 37% biparous, 30% multiparous) who delivered at Kaiser Permanente Northern California hospitals from 2008 to 2011. Participants attended in-person research visits including 2-hour 75-g oral glucose tolerance tests (OGTTs) at study baseline (6-9 weeks postpartum) and annually thereafter for 2 years, and we retrieved diabetes diagnoses from electronic medical records for 8 years. In a nested case-control study design, we collected fasting plasma samples among women without diabetes at baseline (n = 1,010) to measure metabolites among those who later progressed to incident T2D or did not develop T2D (non-T2D). We studied 173 incident T2D cases and 485 controls (pair-matched on BMI, age, and race/ethnicity) to discover metabolites associated with new onset of T2D. Up to 2 years post-baseline, we analyzed samples from 98 T2D cases with 239 controls to reveal T2D-associated metabolic changes. The longitudinal analysis tracked metabolic changes within individuals from baseline to 2 years of follow-up as the trajectory of T2D progression. By building prediction models, we discovered a distinct metabolic signature in the early postpartum period that predicted future T2D with a median discriminating power area under the receiver operating characteristic curve of 0.883 (95% CI 0.820-0.945, p < 0.001). At baseline, the most striking finding was an overall increase in amino acids (AAs) as well as diacyl-glycerophospholipids and a decrease in sphingolipids and acyl-alkyl-glycerophospholipids among women with incident T2D. Pathway analysis revealed up-regulated AA metabolism, arginine/proline metabolism, and branched-chain AA (BCAA) metabolism at baseline. At follow-up after the onset of T2D, up-regulation of AAs and down-regulation of sphingolipids and acyl-alkyl-glycerophospholipids were sustained or strengthened. Notably, longitudinal analyses revealed only 10 metabolites associated with progression to T2D, implicating AA and phospholipid metabolism. A study limitation is that all of the analyses were performed with the same cohort. It would be ideal to validate our findings in an independent longitudinal cohort of women with GDM who had glucose tolerance tested during the early postpartum period. In this study, we discovered a metabolic signature predicting the transition from GDM to T2D in the early postpartum period that was superior to clinical parameters (fasting plasma glucose, 2-hour plasma glucose). The findings suggest that metabolic dysregulation, particularly AA dysmetabolism, is present years prior to diabetes onset, and is revealed during the early postpartum period, preceding progression to T2D, among women with GDM. ClinicalTrials.gov Identifier: NCT01967030.

Microglia, the brain’s resident macrophages, help to regulate brain function by removing dying neurons, pruning non-functional synapses, and producing ligands that support neuronal survival 1 . Here we show that microglia are also critical modulators of neuronal activity and associated behavioural responses in mice. Microglia respond to neuronal activation by suppressing neuronal activity, and ablation of microglia amplifies and synchronizes the activity of neurons, leading to seizures. Suppression of neuronal activation by microglia occurs in a highly region-specific fashion and depends on the ability of microglia to sense and catabolize extracellular ATP, which is released upon neuronal activation by neurons and astrocytes. ATP triggers the recruitment of microglial protrusions and is converted by the microglial ATP/ADP hydrolysing ectoenzyme CD39 into AMP; AMP is then converted into adenosine by CD73, which is expressed on microglia as well as other brain cells. Microglial sensing of ATP, the ensuing microglia-dependent production of adenosine, and the adenosine-mediated suppression of neuronal responses via the adenosine receptor A 1 R are essential for the regulation of neuronal activity and animal behaviour. Our findings suggest that this microglia-driven negative feedback mechanism operates similarly to inhibitory neurons and is essential for protecting the brain from excessive activation in health and disease. Microglia, the brain’s immune cells, suppress neuronal activity in response to synaptic ATP release and alter behavioural responses in mice.

Astrocytes are glial cells that are abundant in the central nervous system (CNS) and that have important homeostatic and disease-promoting functions1. However, little is known about the homeostatic anti-inflammatory activities of astrocytes and their regulation. Here, using high-throughput flow cytometry screening, single-cell RNA sequencing and CRISPR-Cas9-based cell-specific in vivo genetic perturbations in mice, we identify a subset of astrocytes that expresses the lysosomal protein LAMP12 and the death receptor ligand TRAIL3. LAMP1+TRAIL+ astrocytes limit inflammation in the CNS by inducing T cell apoptosis through TRAIL-DR5 signalling. In homeostatic conditions, the expression of TRAIL in astrocytes is driven by interferon-γ (IFNγ) produced by meningeal natural killer (NK) cells, in which IFNγ expression is modulated by the gut microbiome. TRAIL expression in astrocytes is repressed by molecules produced by T cells and microglia in the context of inflammation. Altogether, we show that LAMP1+TRAIL+ astrocytes limit CNS inflammation by inducing T cell apoptosis, and that this astrocyte subset is maintained by meningeal IFNγ+ NK cells that are licensed by the microbiome.

Brain cancers carry bleak prognoses, with therapeutic advances helping only a minority of patients over the past decade. The brain tumour microenvironment (TME) is highly immunosuppressive and differs from that of other malignancies as a result of the glial, neural and immune cell populations that constitute it. Until recently, the study of the brain TME was limited by the lack of methods to de-convolute this complex system at the single-cell level. However, novel technical approaches have begun to reveal the immunosuppressive and tumour-promoting properties of distinct glial and myeloid cell populations in the TME, identifying new therapeutic opportunities. Here, we discuss the immune modulatory functions of microglia, monocyte-derived macrophages and astrocytes in brain metastases and glioma, highlighting their disease-associated heterogeneity and drawing from the insights gained by studying these malignancies and other neurological disorders. Lastly, we consider potential approaches for the therapeutic modulation of the brain TME.This review discusses the immunosuppressive and tumour-promoting properties of microglia, monocyte-derived macrophage and astrocyte subsets in the brain tumour microenvironment, identifying new therapeutic opportunities for primary brain tumours and brain metastases.