Stroke is the leading cause of mortality globally,ultimately leading to severe,lifelong neurological impairments.Patients often suffer from a secondary cascade of damage,including neuroinflammation,cytotoxicity,oxidat...Stroke is the leading cause of mortality globally,ultimately leading to severe,lifelong neurological impairments.Patients often suffer from a secondary cascade of damage,including neuroinflammation,cytotoxicity,oxidative stress,and mitochondrial dysfunction.Regrettably,there is a paucity of clinically available therapeutics to address these issues.Emerging evidence underscores the pivotal roles of astrocytes,the most abundant glial cells in the brain,throughout the various stages of ischemic stroke.In this comprehensive review,we initially provide an overview of the fundamental physiological functions of astrocytes in the brain,emphasizing their critical role in modulating neuronal homeostasis,synaptic activity,and blood-brain barrier integrity.We then delve into the growing body of evidence that highlights the functional diversity and heterogeneity of astrocytes in the context of ischemic stroke.Their well-established contributions to energy provision,metabolic regulation,and neurotransmitter homeostasis,as well as their emerging roles in mitochondrial recovery,neuroinflammation regulation,and oxidative stress modulation following ischemic injury,are discussed in detail.We also explore the cellular and molecular mechanisms underpinning these functions,with particular emphasis on recently identified targets within astrocytes that offer promising prospects for therapeutic intervention.In the final section of this review,we offer a detailed overview of the current therapeutic strategies targeting astrocytes in the treatment of ischemic stroke.These astrocyte-targeting strategies are categorized into traditional small-molecule drugs,microRNAs(miRNAs),stem cell-based therapies,cellular reprogramming,hydrogels,and extracellular vesicles.By summarizing the current understanding of astrocyte functions and therapeutic targeting approaches,we aim to highlight the critical roles of astrocytes during and after stroke,particularly in the pathophysiological development in ischemic stroke.We also emphasize promising avenues for novel,astrocyte-targeted therapeutics that could become clinically available options,ultimately improving outcomes for patients with stroke.展开更多
Lactate serves as a key energy metabolite in the central nervous system,facilitating essential brain functions,including energy supply,signaling,and epigenetic modulation.Moreover,it links epigenetic modifications wit...Lactate serves as a key energy metabolite in the central nervous system,facilitating essential brain functions,including energy supply,signaling,and epigenetic modulation.Moreover,it links epigenetic modifications with metabolic reprogramming.Nonetheless,the specific mechanisms and roles of this connection in astrocytes remain unclear.Therefore,this review aims to explore the role and specific mechanisms of lactate in the metabolic reprogramming of astrocytes in the central nervous system.The close relationship between epigenetic modifications and metabolic reprogramming was discussed.Therapeutic strategies for targeting metabolic reprogramming in astrocytes in the central nervous system were also outlined to guide future research in central nervous system diseases.In the nervous system,lactate plays an essential role.However,its mechanism of action as a bridge between metabolic reprogramming and epigenetic modifications in the nervous system requires future investigation.The involvement of lactate in epigenetic modifications is currently a hot research topic,especially in lactylation modification,a key determinant in this process.Lactate also indirectly regulates various epigenetic modifications,such as N6-methyladenosine,acetylation,ubiquitination,and phosphorylation modifications,which are closely linked to several neurological disorders.In addition,exploring the clinical applications and potential therapeutic strategies of lactic acid provides new insights for future neurological disease treatments.展开更多
Epilepsy is a leading cause of disability and mortality worldwide. However, despite the availability of more than 20 antiseizure medications, more than one-third of patients continue to experience seizures. Given the ...Epilepsy is a leading cause of disability and mortality worldwide. However, despite the availability of more than 20 antiseizure medications, more than one-third of patients continue to experience seizures. Given the urgent need to explore new treatment strategies for epilepsy, recent research has highlighted the potential of targeting gliosis, metabolic disturbances, and neural circuit abnormalities as therapeutic strategies. Astrocytes, the largest group of nonneuronal cells in the central nervous system, play several crucial roles in maintaining ionic and energy metabolic homeostasis in neurons, regulating neurotransmitter levels, and modulating synaptic plasticity. This article briefly reviews the critical role of astrocytes in maintaining balance within the central nervous system. Building on previous research, we discuss how astrocyte dysfunction contributes to the onset and progression of epilepsy through four key aspects: the imbalance between excitatory and inhibitory neuronal signaling, dysregulation of metabolic homeostasis in the neuronal microenvironment, neuroinflammation, and the formation of abnormal neural circuits. We summarize relevant basic research conducted over the past 5 years that has focused on modulating astrocytes as a therapeutic approach for epilepsy. We categorize the therapeutic targets proposed by these studies into four areas: restoration of the excitation–inhibition balance, reestablishment of metabolic homeostasis, modulation of immune and inflammatory responses, and reconstruction of abnormal neural circuits. These targets correspond to the pathophysiological mechanisms by which astrocytes contribute to epilepsy. Additionally, we need to consider the potential challenges and limitations of translating these identified therapeutic targets into clinical treatments. These limitations arise from interspecies differences between humans and animal models, as well as the complex comorbidities associated with epilepsy in humans. We also highlight valuable future research directions worth exploring in the treatment of epilepsy and the regulation of astrocytes, such as gene therapy and imaging strategies. The findings presented in this review may help open new therapeutic avenues for patients with drugresistant epilepsy and for those suffering from other central nervous system disorders associated with astrocytic dysfunction.展开更多
The early developmental period is a critical window during which brain cells mature and contribute to both brain development and later life functions.Gamma-aminobutyric acid(GABA),recognized as a major neurotransmitte...The early developmental period is a critical window during which brain cells mature and contribute to both brain development and later life functions.Gamma-aminobutyric acid(GABA),recognized as a major neurotransmitter,plays a crucial role in coordinating synapse formation,neuronal proliferation,and migration during this time.展开更多
Alzheimer’s disease(AD)is the most common form of dementia characterized pathologically by the deposition of amyloid plaques and hyperphosphorylated tau containing neurofibrillary tangles.The disease presents clinica...Alzheimer’s disease(AD)is the most common form of dementia characterized pathologically by the deposition of amyloid plaques and hyperphosphorylated tau containing neurofibrillary tangles.The disease presents clinically with progressive memory loss and disruption of cognitive function.Currently,there is no cure for AD;recent advances in the therapeutics aimed at clearing the amyloid protein from the brain have led to potential disease stabilization,however,this does not prevent eventual disease progression(Cummings et al.,2024).展开更多
Astrocytes have important neurosupportive functions in the brain that are altered in neurodegenerative diseases by unresolved mechanisms.We showed previously that astrocytes cultured from mice transgenic for human P30...Astrocytes have important neurosupportive functions in the brain that are altered in neurodegenerative diseases by unresolved mechanisms.We showed previously that astrocytes cultured from mice transgenic for human P301S-tau(P301S-mice)recapitulate the deficit in production and secretion of thrombospondin1 found in symptomatic P301S mouse brains,causing both reduced synapse formation and survival of cultured neurons.To further characterize how P301S-derived astrocytes differ from controls,we have compared the astrocyte-conditioned media of cultured astrocytes from postnatal day 7/8 P301S mice(P301S-astrocyte-conditioned media)versus controls(C57-astrocyte-conditioned media)using label-free liquid chromatography-mass spectrometry.We verified that thrombospondin1 secretion was significantly reduced in the P301S-astrocyte-conditioned media versus C57-astrocyte-conditioned media,demonstrating the robustness of the analysis.The most notable distinction was that~57%of the P301S-astrocyte-conditioned media-enriched proteins were cytoplasmic proteins linked to cellular metabolism that are not predicted to be secreted via classical or non-classical secretion pathways,whereas~88%of C57-astrocyte-conditioned media-enriched proteins comprised classically secreted proteins enriched in extracellular matrix components.These differences are associated with the finding that P301S-derived cultured astrocytes were smaller and in vivo appeared less mature in the cortex of P301S mice.The unconventional secretion pathway that P301S-astrocyte-conditioned media display shares similarities with several amyloid-β-exposed astrocyte-conditioned media,indicating that stimuli induced by tau and amyloid-βmay induce a common adverse response pathway.Altogether,members of this adverse pathway may serve as a potential set of biomarkers to aid the clinical diagnosis of Alzheimer’s disease and other tauopathies,while the list of reduced neurosupportive factors could indicate new approaches to enhance neuronal survival by factor supplementation in tauopathies.展开更多
Inflammasomes,a category of protein complexes,recognize exogenous pathogens and endogenous tissue damage.In response,they induce inflammatory responses and pyroptosis,and are involved in both innate immunity and the r...Inflammasomes,a category of protein complexes,recognize exogenous pathogens and endogenous tissue damage.In response,they induce inflammatory responses and pyroptosis,and are involved in both innate immunity and the regulation of adaptive immunity,with significant effects in disease and health.Neuroinflammation is closely related to neurological disorders.Nervous system homeostasis is primarily regulated by glial cells,with microglia and astrocytes playing a dual role in both neuroprotection and neurotoxicity.Recent studies highlight the importance of microglia and astrocytes within the central nervous system in mediating neuroinflammation associated with neuropsychiatric diseases.In particular,the role of inflammasomes in glial cells and neuroinflammation has garnered growing attention.This review classifies inflammasomes and their activation mechanisms as well as explores their involvement in the activation of microglia and astrocytes in various neurological diseases,aiming to contribute a deeper understanding of the pathogenesis of neurodegenerative disease and brain injury and identification of novel therapeutic targets.展开更多
Neuroinflammation plays an important role in the occurrence and development of neurological diseases.In addition to microglia,the role of astrocytes in neuroinflammation has gradually attracted attention.Photobiomodul...Neuroinflammation plays an important role in the occurrence and development of neurological diseases.In addition to microglia,the role of astrocytes in neuroinflammation has gradually attracted attention.Photobiomodulation(PBM),as a non-invasive treatment,has been shown potential to alleviate inflammation of microglia or astrocytes.In this study,the spatiotemporal regulation and molecular mechanism of PBM on astrocytes were deeply explored by analyzing the effects and genomics at different time points.The results showed that PBM significantly attenuated the upregulation of inflammatory factors and mitochondrial dysfunction in astrocytes under LPS stimulation for 4 h and 24 h.RNA-seq analysis showed that the JAK-STAT pathway played an important role in the early stage of both LPS-induced astrocytic neuroin-flammation and PBM-alleviated astrocytic neuroinflammation.Under PBM treatment,Stat5a translocation to the nucleus and upregulated Socs3 expression were observed in LPS-treated astrocytes,which may inhibit the overactivation of the JAK-STAT inflammatory signaling pathway and thus alleviate astrocyte inflammation.Taken together,this study provides new insight into the molecular mechanism of the potential application of PBM in the treatment of neuroinflammation.展开更多
Cell function has a tight relationship with cell architecture.Distribution of proteins to the correct compartment is one of the functions of the traffic pathway through the Golgi apparatus.The others are to ensure pro...Cell function has a tight relationship with cell architecture.Distribution of proteins to the correct compartment is one of the functions of the traffic pathway through the Golgi apparatus.The others are to ensure proper protein folding,the addition of post-translational modifications,and delive ring to intracellular and extracellular destinations.Astrocytes are fundamental homeostatic cells,controlling multiple aspects of the central nervous system physiology,such as ion balance,nutrients,blood flow,neurotransmitte rs,and responses to insults.Astrocytes are polarized cells,and,such as neurons,extensively use the secretory pathway for secreting factors and exposing functional receptors,channels,and transporte rs on the plasma membrane.In this review,we will underline the importance of studying the Golgi apparatus and the secretory pathway in astrocytes,based on the possible tight connection between the Golgi apparatus and astrocytes'homeostatic function.Given the topic of this review,we will provide examples mostly about the Golgi apparatus structure,function,localization,and its involvement in astrocytes'homeostatic response,with an insight into congenital glycosylation disorders,as an example of a potential future field in the study of astrocyte homeostatic failu re and Golgi apparatus alteration.展开更多
Ischemic stroke,a frequently occurring form of stroke,is caused by obstruction of cerebral blood flow,which leads to ischemia,hypoxia,and necrosis of local brain tissue.After ischemic stroke,both astrocytes and the bl...Ischemic stroke,a frequently occurring form of stroke,is caused by obstruction of cerebral blood flow,which leads to ischemia,hypoxia,and necrosis of local brain tissue.After ischemic stroke,both astrocytes and the blood–brain barrier undergo morphological and functional transformations.However,the interplay between astrocytes and the blood–brain barrier has received less attention.This comprehensive review explores the physiological and pathological morphological and functional changes in astrocytes and the blood–brain barrier in ischemic stroke.Post-stroke,the structure of endothelial cells and peripheral cells undergoes alterations,causing disruption of the blood–brain barrier.This disruption allows various pro-inflammatory factors and chemokines to cross the blood–brain barrier.Simultaneously,astrocytes swell and primarily adopt two phenotypic states:A1 and A2,which exhibit different roles at different stages of ischemic stroke.During the acute phase,A1 reactive astrocytes secrete vascular endothelial growth factor,matrix metalloproteinases,lipid carrier protein-2,and other cytokines,exacerbating damage to endothelial cells and tight junctions.Conversely,A2 reactive astrocytes produce pentraxin 3,Sonic hedgehog,angiopoietin-1,and other protective factors for endothelial cells.Furthermore,astrocytes indirectly influence blood–brain barrier permeability through ferroptosis and exosomes.In the middle and late(recovery)stages of ischemic stroke,A1 and A2 astrocytes show different effects on glial scar formation.A1 astrocytes promote glial scar formation and inhibit axon growth via glial fibrillary acidic protein,chondroitin sulfate proteoglycans,and transforming growth factor-β.In contrast,A2 astrocytes facilitate axon growth through platelet-derived growth factor,playing a crucial role in vascular remodeling.Therefore,enhancing our understanding of the pathological changes and interactions between astrocytes and the blood–brain barrier is a vital therapeutic target for preventing further brain damage in acute stroke.These insights may pave the way for innovative therapeutic strategies for ischemic stroke.展开更多
The concept of the brain cognitive reserve is derived from the well-acknowledged notion that the degree of brain damage does not always match the severity of clinical symptoms and neurological/cognitive outcomes.It ha...The concept of the brain cognitive reserve is derived from the well-acknowledged notion that the degree of brain damage does not always match the severity of clinical symptoms and neurological/cognitive outcomes.It has been suggested that the size of the brain(brain reserve) and the extent of neural connections acquired through life(neural reserve) set a threshold beyond which noticeable impairments occur.In contrast,cognitive reserve refers to the brain's ability to adapt and reo rganize stru cturally and functionally to resist damage and maintain function,including neural reserve and brain maintenance,resilience,and compensation(Verkhratsky and Zorec,2024).展开更多
Cell function has a tight relationship with cell architecture.Distribution of proteins to the correct compartment is one of the functions of the traffic pathway through the Golgi apparatus.The others are to ensure pro...Cell function has a tight relationship with cell architecture.Distribution of proteins to the correct compartment is one of the functions of the traffic pathway through the Golgi apparatus.The others are to ensure proper protein folding,the addition of post-translational modifications,and delivering to intracellular and extracellular destinations.Astrocytes are fundamental homeostatic cells,controlling multiple aspects of the central nervous system physiology,such as ion balance,nutrients,blood flow,neurotransmitters,and responses to insults.Astrocytes are polarized cells,and,such as neurons,extensively use the secretory pathway for secreting factors and exposing functional receptors,channels,and transporters on the plasma membrane.In this review,we will underline the importance of studying the Golgi apparatus and the secretory pathway in astrocytes,based on the possible tight connection between the Golgi apparatus and astrocytes’homeostatic function.Given the topic of this review,we will provide examples mostly about the Golgi apparatus structure,function,localization,and its involvement in astrocytes’homeostatic response,with an insight into congenital glycosylation disorders,as an example of a potential future field in the study of astrocyte homeostatic failure and Golgi apparatus alteration.展开更多
Spared regions of the damaged central nervous system undergo dynamic remodelling and exhibit a remarkable potential for therapeutic exploitation1.Lesion-remote astrocytes(LRAs),which interact with viable neurons and g...Spared regions of the damaged central nervous system undergo dynamic remodelling and exhibit a remarkable potential for therapeutic exploitation1.Lesion-remote astrocytes(LRAs),which interact with viable neurons and glia,undergo reactive transformations whose molecular and functional properties are poorly understood2.Here,using multiple transcriptional profiling methods,we investigated LRAs from spared regions of mouse spinal cord following traumatic spinal cord injury.展开更多
Astrocytes are the most abundant glial cells in the central nervous system.They perform a diverse array of functions,with a critical role in structural integrity,synapse formation,and neurotransmission.These cells exh...Astrocytes are the most abundant glial cells in the central nervous system.They perform a diverse array of functions,with a critical role in structural integrity,synapse formation,and neurotransmission.These cells exhibit substantial regional heterogeneity and display variable responses to different neurological diseases.Such diversity in astrocyte morphology and function is essential for understanding both normal brain function and the underlying mechanisms of neurological disorders.To investigate this heterogeneity,we developed a novel method for the selective and sparse labeling of astrocytes in various brain regions.This technique utilizes a dual adeno-associated virus system that allows for the expression of Cre recombinase and enhanced green fluorescent protein under the control of the glial fibrillary acidic protein(GfaABC1D)promoter.The system was tested in C57BL/6J mice and successfully labeled astrocytes across multiple brain regions.The method enabled the detailed visualization of individual astrocytes-including their intricate peripheral processes-through three-dimensional reconstructions from confocal microscopy images.Furthermore,the labeling efficiency of this dual adeno-associated virus technology was validated by examining astrocyte function in a spared nerve injury model and through chemogenetic modulation.This innovative approach holds great promise for future research because it enables a more comprehensive understanding of astrocyte variation not only in spared nerve injury but also in a broad spectrum of neurological diseases.The ability to selectively label and study astrocytes in different brain regions provides a powerful tool for exploring the complexities of these essential cells and their roles in physiological and pathological conditions.展开更多
In a recent work published in Neuron,Xu et al.identified a novel contribution of G protein-coupled receptor 37-like 1(GPR37L1),which is identified to be expressed by spinal astrocytes,to the regulation of neuropathic ...In a recent work published in Neuron,Xu et al.identified a novel contribution of G protein-coupled receptor 37-like 1(GPR37L1),which is identified to be expressed by spinal astrocytes,to the regulation of neuropathic pain[1].By interacting and enhancing the activity of glutamate transporter-1(GLT-1)in spinal astrocytes,GPR37L1 promotes glutamate uptake by spinal astrocytes and reduces excitatory synaptic transmission in the spinal dorsal horn,all of which contribute to the resolution of chronic neuropathic pain.展开更多
Neurotoxic astrocytes are a promising therapeutic target for the attenuation of cerebral ischemia/reperfusion injury.Low-density lipoprotein receptor,a classic cholesterol regulatory receptor,has been found to inhibit...Neurotoxic astrocytes are a promising therapeutic target for the attenuation of cerebral ischemia/reperfusion injury.Low-density lipoprotein receptor,a classic cholesterol regulatory receptor,has been found to inhibit NLR family pyrin domain containing protein 3(NLRP3)inflammasome activation in neurons following ischemic stroke and to suppress the activation of microglia and astrocytes in individuals with Alzheimer’s disease.However,little is known about the effects of low-density lipoprotein receptor on astrocytic activation in ischemic stroke.To address this issue in the present study,we examined the mechanisms by which low-density lipoprotein receptor regulates astrocytic polarization in ischemic stroke models.First,we examined low-density lipoprotein receptor expression in astrocytes via immunofluorescence staining and western blotting analysis.We observed significant downregulation of low-density lipoprotein receptor following middle cerebral artery occlusion reperfusion and oxygen-glucose deprivation/reoxygenation.Second,we induced the astrocyte-specific overexpression of low-density lipoprotein receptor using astrocyte-specific adeno-associated virus.Low-density lipoprotein receptor overexpression in astrocytes improved neurological outcomes in middle cerebral artery occlusion mice and reversed neurotoxic astrocytes to create a neuroprotective phenotype.Finally,we found that the overexpression of low-density lipoprotein receptor inhibited NLRP3 inflammasome activation in oxygen-glucose deprivation/reoxygenation injured astrocytes and that the addition of nigericin,an NLRP3 agonist,restored the neurotoxic astrocyte phenotype.These findings suggest that low-density lipoprotein receptor could inhibit the NLRP3-meidiated neurotoxic polarization of astrocytes and that increasing low-density lipoprotein receptor in astrocytes might represent a novel strategy for treating cerebral ischemic stroke.展开更多
In the mammalian central nervous system(CNS),astrocytes are the ubiquitous glial cells that have complex morphological and molecular characteristics.These fascinating cells play essential neurosupportive and homeostat...In the mammalian central nervous system(CNS),astrocytes are the ubiquitous glial cells that have complex morphological and molecular characteristics.These fascinating cells play essential neurosupportive and homeostatic roles in the healthy CNS and undergo morphological,molecular,and functional changes to adopt so-called‘reactive’states in response to CNS injury or disease.In recent years,interest in astrocyte research has increased dramatically and some new biological features and roles of astrocytes in physiological and pathological conditions have been discovered thanks to technological advances.Here,we will review and discuss the wellestablished and emerging astroglial biology and functions,with emphasis on their potential as therapeutic targets for CNS injury,including traumatic and ischemic injury.This review article will highlight the importance of astrocytes in the neuropathological process and repair of CNS injury.展开更多
Astrocytes in the spinal dorsal horn(SDH)exhibit diverse reactive phenotypes under neuropathic conditions,yet the mechanisms driving this diversity and its implications in chronic pain remain unclear.Here,we report th...Astrocytes in the spinal dorsal horn(SDH)exhibit diverse reactive phenotypes under neuropathic conditions,yet the mechanisms driving this diversity and its implications in chronic pain remain unclear.Here,we report that spared nerve injury(SNI)induces marked upregulation of both complement component 3(C3⁺,A1-like)and S100 calcium-binding protein A10(S100A10⁺,A2-like)astrocyte subpopulations in the SDH,with elevated microglial cytokines including interleukin-1α,tumor necrosis factor-α,and complement component 1q.Transcriptomic,immunohistochemical,and Western blot analyses reveal co-activation of multiple reactive astrocyte states over a unidirectional shift toward an A1-like phenotype.Fibroblast growth factor 8(FGF8),a neuroprotective factor via FGFR3,mitigated microglia-induced C3⁺astrocyte reactivity in vitro and suppressed spinal C3 expression and mechanical allodynia following intrathecal administration in SNI mice.These findings reveal a microglia–astrocyte signaling axis that promotes A1 reactivity and position FGF8 as a promising therapeutic candidate for neuropathic pain by modulating astrocyte heterogeneity.展开更多
Traumatic brain injury is a global health crisis,causing significant death and disability worldwide.Neuroinflammation that follows traumatic brain injury has serious consequences for neuronal survival and cognitive im...Traumatic brain injury is a global health crisis,causing significant death and disability worldwide.Neuroinflammation that follows traumatic brain injury has serious consequences for neuronal survival and cognitive impairments,with astrocytes involved in this response.Following traumatic brain injury,astrocytes rapidly become reactive,and astrogliosis propagates from the injury core to distant brain regions.Homeostatic astroglial proteins are downregulated near the traumatic brain injury core,while pro-inflammatory astroglial genes are overexpressed.This altered gene expression is considered a pathological remodeling of astrocytes that produces serious consequences for neuronal survival and cognitive recovery.In addition,glial scar formed by reactive astrocytes is initially necessary to limit immune cell infiltration,but in the long term impedes axonal reconnection and functional recovery.Current therapeutic strategies for traumatic brain injury are focused on preventing acute complications.Statins,cannabinoids,progesterone,beta-blockers,and cerebrolysin demonstrate neuroprotective benefits but most of them have not been studied in the context of astrocytes.In this review,we discuss the cell signaling pathways activated in reactive astrocytes following traumatic brain injury and we discuss some of the potential new strategies aimed to modulate astroglial responses in traumatic brain injury,especially using cell-targeted strategies with miRNAs or lncRNA,viral vectors,and repurposed drugs.展开更多
Cerebral edema caused by blood-brain barrier injury after intracerebral hemorrhage is an important factor leading to poor prognosis.Human-induced pluripotent stem cell-derived neural stem cell exosomes(hiPSC-NSC-Exos)...Cerebral edema caused by blood-brain barrier injury after intracerebral hemorrhage is an important factor leading to poor prognosis.Human-induced pluripotent stem cell-derived neural stem cell exosomes(hiPSC-NSC-Exos)have shown potential for brain injury repair in central nervous system diseases.In this study,we explored the impact of hiPSC-NSC-Exos on blood-brain barrier preservation and the underlying mechanism.Our results indicated that intranasal delivery of hiPSC-NSC-Exos mitigated neurological deficits,enhanced blood-brain barrier integrity,and reduced leukocyte infiltration in a mouse model of intracerebral hemorrhage.Additionally,hiPSC-NSC-Exos decreased immune cell infiltration,activated astrocytes,and decreased the secretion of inflammatory cytokines like monocyte chemoattractant protein-1,macrophage inflammatory protein-1α,and tumor necrosis factor-αpost-intracerebral hemorrhage,thereby improving the inflammatory microenvironment.RNA sequencing indicated that hiPSC-NSC-Exo activated the PI3K/AKT signaling pathway in astrocytes and decreased monocyte chemoattractant protein-1 secretion,thereby improving blood-brain barrier integrity.Treatment with the PI3K/AKT inhibitor LY294002 or the monocyte chemoattractant protein-1 neutralizing agent C1142 abolished these effects.In summary,our findings suggest that hiPSC-NSC-Exos maintains blood-brain barrier integrity,in part by downregulating monocyte chemoattractant protein-1 secretion through activation of the PI3K/AKT signaling pathway in astrocytes.展开更多
基金supported by the National Natural Science Foundation of China,No.82001325Visiting Scholar Foundation of Shandong Province,No.20236-01(both to CS).
文摘Stroke is the leading cause of mortality globally,ultimately leading to severe,lifelong neurological impairments.Patients often suffer from a secondary cascade of damage,including neuroinflammation,cytotoxicity,oxidative stress,and mitochondrial dysfunction.Regrettably,there is a paucity of clinically available therapeutics to address these issues.Emerging evidence underscores the pivotal roles of astrocytes,the most abundant glial cells in the brain,throughout the various stages of ischemic stroke.In this comprehensive review,we initially provide an overview of the fundamental physiological functions of astrocytes in the brain,emphasizing their critical role in modulating neuronal homeostasis,synaptic activity,and blood-brain barrier integrity.We then delve into the growing body of evidence that highlights the functional diversity and heterogeneity of astrocytes in the context of ischemic stroke.Their well-established contributions to energy provision,metabolic regulation,and neurotransmitter homeostasis,as well as their emerging roles in mitochondrial recovery,neuroinflammation regulation,and oxidative stress modulation following ischemic injury,are discussed in detail.We also explore the cellular and molecular mechanisms underpinning these functions,with particular emphasis on recently identified targets within astrocytes that offer promising prospects for therapeutic intervention.In the final section of this review,we offer a detailed overview of the current therapeutic strategies targeting astrocytes in the treatment of ischemic stroke.These astrocyte-targeting strategies are categorized into traditional small-molecule drugs,microRNAs(miRNAs),stem cell-based therapies,cellular reprogramming,hydrogels,and extracellular vesicles.By summarizing the current understanding of astrocyte functions and therapeutic targeting approaches,we aim to highlight the critical roles of astrocytes during and after stroke,particularly in the pathophysiological development in ischemic stroke.We also emphasize promising avenues for novel,astrocyte-targeted therapeutics that could become clinically available options,ultimately improving outcomes for patients with stroke.
基金supported by the National Natural Science Foundation of China,Nos.82071383,82371392(to BN)the Natural Science Foundation of Shandong Province of China(Key Project),No.ZR2020KH007(to BN)+1 种基金“Taishan Scholar Distinguished Expert Program”of Shandong Province,No.tstp20231257(to BN)Health Commission Science and Technology Plan Project of Jinan,No.2023-1-8(to YZ).
文摘Lactate serves as a key energy metabolite in the central nervous system,facilitating essential brain functions,including energy supply,signaling,and epigenetic modulation.Moreover,it links epigenetic modifications with metabolic reprogramming.Nonetheless,the specific mechanisms and roles of this connection in astrocytes remain unclear.Therefore,this review aims to explore the role and specific mechanisms of lactate in the metabolic reprogramming of astrocytes in the central nervous system.The close relationship between epigenetic modifications and metabolic reprogramming was discussed.Therapeutic strategies for targeting metabolic reprogramming in astrocytes in the central nervous system were also outlined to guide future research in central nervous system diseases.In the nervous system,lactate plays an essential role.However,its mechanism of action as a bridge between metabolic reprogramming and epigenetic modifications in the nervous system requires future investigation.The involvement of lactate in epigenetic modifications is currently a hot research topic,especially in lactylation modification,a key determinant in this process.Lactate also indirectly regulates various epigenetic modifications,such as N6-methyladenosine,acetylation,ubiquitination,and phosphorylation modifications,which are closely linked to several neurological disorders.In addition,exploring the clinical applications and potential therapeutic strategies of lactic acid provides new insights for future neurological disease treatments.
基金supported by the National Key Research and Development Program of China,No. 2023YFF0714200 (to CW)the National Natural Science Foundation of China,Nos. 82472038 and 82202224 (both to CW)+3 种基金the Shanghai Rising-Star Program,No. 23QA1407700 (to CW)the Construction Project of Shanghai Key Laboratory of Molecular Imaging,No. 18DZ2260400 (to CW)the National Science Foundation for Distinguished Young Scholars,No. 82025019 (to CL)the Greater Bay Area Institute of Precision Medicine (Guangzhou)(to CW)。
文摘Epilepsy is a leading cause of disability and mortality worldwide. However, despite the availability of more than 20 antiseizure medications, more than one-third of patients continue to experience seizures. Given the urgent need to explore new treatment strategies for epilepsy, recent research has highlighted the potential of targeting gliosis, metabolic disturbances, and neural circuit abnormalities as therapeutic strategies. Astrocytes, the largest group of nonneuronal cells in the central nervous system, play several crucial roles in maintaining ionic and energy metabolic homeostasis in neurons, regulating neurotransmitter levels, and modulating synaptic plasticity. This article briefly reviews the critical role of astrocytes in maintaining balance within the central nervous system. Building on previous research, we discuss how astrocyte dysfunction contributes to the onset and progression of epilepsy through four key aspects: the imbalance between excitatory and inhibitory neuronal signaling, dysregulation of metabolic homeostasis in the neuronal microenvironment, neuroinflammation, and the formation of abnormal neural circuits. We summarize relevant basic research conducted over the past 5 years that has focused on modulating astrocytes as a therapeutic approach for epilepsy. We categorize the therapeutic targets proposed by these studies into four areas: restoration of the excitation–inhibition balance, reestablishment of metabolic homeostasis, modulation of immune and inflammatory responses, and reconstruction of abnormal neural circuits. These targets correspond to the pathophysiological mechanisms by which astrocytes contribute to epilepsy. Additionally, we need to consider the potential challenges and limitations of translating these identified therapeutic targets into clinical treatments. These limitations arise from interspecies differences between humans and animal models, as well as the complex comorbidities associated with epilepsy in humans. We also highlight valuable future research directions worth exploring in the treatment of epilepsy and the regulation of astrocytes, such as gene therapy and imaging strategies. The findings presented in this review may help open new therapeutic avenues for patients with drugresistant epilepsy and for those suffering from other central nervous system disorders associated with astrocytic dysfunction.
基金supported by the Center for Cognition and Sociality,Institute for Basic Science(IBS)(IBS-R001-D2)(to WK).
文摘The early developmental period is a critical window during which brain cells mature and contribute to both brain development and later life functions.Gamma-aminobutyric acid(GABA),recognized as a major neurotransmitter,plays a crucial role in coordinating synapse formation,neuronal proliferation,and migration during this time.
基金funded by Wellcome 4ward North(Ref:216340/Z/19/Z)ARUK Yorkshire Network Centre Small Grant Scheme,ARUK Preparatory Clinical Fellowship scheme(Ref:ARUK-PCRF2016A-1)+3 种基金Academy of Medical Sciences Starter Grants for Clinical Lecturers Scheme(Ref:SGL028\1097),Parkinson’s UK(Ref:F1301)Michael J Fox Foundation(Ref:005021),Australian Research Council(CE200100012)European Union Seventh Framework Programme(Ref:FP7/2007-2013)under grant agreement no.601055the NIHR Sheffield Biomedical Research Centre award(NIHR 203321)(to SMB).
文摘Alzheimer’s disease(AD)is the most common form of dementia characterized pathologically by the deposition of amyloid plaques and hyperphosphorylated tau containing neurofibrillary tangles.The disease presents clinically with progressive memory loss and disruption of cognitive function.Currently,there is no cure for AD;recent advances in the therapeutics aimed at clearing the amyloid protein from the brain have led to potential disease stabilization,however,this does not prevent eventual disease progression(Cummings et al.,2024).
基金MGS from the Alzheimer Society(#384,AS-PG-17-026,Alzheimer’s Research UK(ART-PG2011-20 and ARUK-EXT2015B-2)the BBSRC(BB/T509085/1)+1 种基金The Fondation Recherche Alzheimer(G112606)the Scholl Foundation,and to MGS and AMT from the National Center for the Replacement,Refinement,&Reduction of Animals in Research(NC3R)(#NC/L000741/1).
文摘Astrocytes have important neurosupportive functions in the brain that are altered in neurodegenerative diseases by unresolved mechanisms.We showed previously that astrocytes cultured from mice transgenic for human P301S-tau(P301S-mice)recapitulate the deficit in production and secretion of thrombospondin1 found in symptomatic P301S mouse brains,causing both reduced synapse formation and survival of cultured neurons.To further characterize how P301S-derived astrocytes differ from controls,we have compared the astrocyte-conditioned media of cultured astrocytes from postnatal day 7/8 P301S mice(P301S-astrocyte-conditioned media)versus controls(C57-astrocyte-conditioned media)using label-free liquid chromatography-mass spectrometry.We verified that thrombospondin1 secretion was significantly reduced in the P301S-astrocyte-conditioned media versus C57-astrocyte-conditioned media,demonstrating the robustness of the analysis.The most notable distinction was that~57%of the P301S-astrocyte-conditioned media-enriched proteins were cytoplasmic proteins linked to cellular metabolism that are not predicted to be secreted via classical or non-classical secretion pathways,whereas~88%of C57-astrocyte-conditioned media-enriched proteins comprised classically secreted proteins enriched in extracellular matrix components.These differences are associated with the finding that P301S-derived cultured astrocytes were smaller and in vivo appeared less mature in the cortex of P301S mice.The unconventional secretion pathway that P301S-astrocyte-conditioned media display shares similarities with several amyloid-β-exposed astrocyte-conditioned media,indicating that stimuli induced by tau and amyloid-βmay induce a common adverse response pathway.Altogether,members of this adverse pathway may serve as a potential set of biomarkers to aid the clinical diagnosis of Alzheimer’s disease and other tauopathies,while the list of reduced neurosupportive factors could indicate new approaches to enhance neuronal survival by factor supplementation in tauopathies.
基金National Natural Science Foundation of China,Nos.82371405(to HZ),82203683(to YH)the Hubei Provincial Key Research Projects,No.2022BCA027.
文摘Inflammasomes,a category of protein complexes,recognize exogenous pathogens and endogenous tissue damage.In response,they induce inflammatory responses and pyroptosis,and are involved in both innate immunity and the regulation of adaptive immunity,with significant effects in disease and health.Neuroinflammation is closely related to neurological disorders.Nervous system homeostasis is primarily regulated by glial cells,with microglia and astrocytes playing a dual role in both neuroprotection and neurotoxicity.Recent studies highlight the importance of microglia and astrocytes within the central nervous system in mediating neuroinflammation associated with neuropsychiatric diseases.In particular,the role of inflammasomes in glial cells and neuroinflammation has garnered growing attention.This review classifies inflammasomes and their activation mechanisms as well as explores their involvement in the activation of microglia and astrocytes in various neurological diseases,aiming to contribute a deeper understanding of the pathogenesis of neurodegenerative disease and brain injury and identification of novel therapeutic targets.
基金funded in part by the STI2030-Major Projects(2022ZD0212200)Hainan Province Key Area R&D Program(KJRC2023C30)+1 种基金Project of Collaborative Innovation Center of One Health(XTCX2022JKB02)Sanya Yazhou Bay Science and Technology City(SKJC-JYRC-2024-38).
文摘Neuroinflammation plays an important role in the occurrence and development of neurological diseases.In addition to microglia,the role of astrocytes in neuroinflammation has gradually attracted attention.Photobiomodulation(PBM),as a non-invasive treatment,has been shown potential to alleviate inflammation of microglia or astrocytes.In this study,the spatiotemporal regulation and molecular mechanism of PBM on astrocytes were deeply explored by analyzing the effects and genomics at different time points.The results showed that PBM significantly attenuated the upregulation of inflammatory factors and mitochondrial dysfunction in astrocytes under LPS stimulation for 4 h and 24 h.RNA-seq analysis showed that the JAK-STAT pathway played an important role in the early stage of both LPS-induced astrocytic neuroin-flammation and PBM-alleviated astrocytic neuroinflammation.Under PBM treatment,Stat5a translocation to the nucleus and upregulated Socs3 expression were observed in LPS-treated astrocytes,which may inhibit the overactivation of the JAK-STAT inflammatory signaling pathway and thus alleviate astrocyte inflammation.Taken together,this study provides new insight into the molecular mechanism of the potential application of PBM in the treatment of neuroinflammation.
文摘Cell function has a tight relationship with cell architecture.Distribution of proteins to the correct compartment is one of the functions of the traffic pathway through the Golgi apparatus.The others are to ensure proper protein folding,the addition of post-translational modifications,and delive ring to intracellular and extracellular destinations.Astrocytes are fundamental homeostatic cells,controlling multiple aspects of the central nervous system physiology,such as ion balance,nutrients,blood flow,neurotransmitte rs,and responses to insults.Astrocytes are polarized cells,and,such as neurons,extensively use the secretory pathway for secreting factors and exposing functional receptors,channels,and transporte rs on the plasma membrane.In this review,we will underline the importance of studying the Golgi apparatus and the secretory pathway in astrocytes,based on the possible tight connection between the Golgi apparatus and astrocytes'homeostatic function.Given the topic of this review,we will provide examples mostly about the Golgi apparatus structure,function,localization,and its involvement in astrocytes'homeostatic response,with an insight into congenital glycosylation disorders,as an example of a potential future field in the study of astrocyte homeostatic failu re and Golgi apparatus alteration.
基金supported by the National Natural Science Foundation of China,No.U21A20400(to QW)the National Natural Science Foundation of China,No.82104560(to CL)+1 种基金the Natural Science Foundation of Beijing,No.7232279(to XW)the Project of Beijing University of Chinese Medicine,Nos.2024-JYB-JBZD-043(to CL),2022-JYB-JBZR-004(to XW)。
文摘Ischemic stroke,a frequently occurring form of stroke,is caused by obstruction of cerebral blood flow,which leads to ischemia,hypoxia,and necrosis of local brain tissue.After ischemic stroke,both astrocytes and the blood–brain barrier undergo morphological and functional transformations.However,the interplay between astrocytes and the blood–brain barrier has received less attention.This comprehensive review explores the physiological and pathological morphological and functional changes in astrocytes and the blood–brain barrier in ischemic stroke.Post-stroke,the structure of endothelial cells and peripheral cells undergoes alterations,causing disruption of the blood–brain barrier.This disruption allows various pro-inflammatory factors and chemokines to cross the blood–brain barrier.Simultaneously,astrocytes swell and primarily adopt two phenotypic states:A1 and A2,which exhibit different roles at different stages of ischemic stroke.During the acute phase,A1 reactive astrocytes secrete vascular endothelial growth factor,matrix metalloproteinases,lipid carrier protein-2,and other cytokines,exacerbating damage to endothelial cells and tight junctions.Conversely,A2 reactive astrocytes produce pentraxin 3,Sonic hedgehog,angiopoietin-1,and other protective factors for endothelial cells.Furthermore,astrocytes indirectly influence blood–brain barrier permeability through ferroptosis and exosomes.In the middle and late(recovery)stages of ischemic stroke,A1 and A2 astrocytes show different effects on glial scar formation.A1 astrocytes promote glial scar formation and inhibit axon growth via glial fibrillary acidic protein,chondroitin sulfate proteoglycans,and transforming growth factor-β.In contrast,A2 astrocytes facilitate axon growth through platelet-derived growth factor,playing a crucial role in vascular remodeling.Therefore,enhancing our understanding of the pathological changes and interactions between astrocytes and the blood–brain barrier is a vital therapeutic target for preventing further brain damage in acute stroke.These insights may pave the way for innovative therapeutic strategies for ischemic stroke.
文摘The concept of the brain cognitive reserve is derived from the well-acknowledged notion that the degree of brain damage does not always match the severity of clinical symptoms and neurological/cognitive outcomes.It has been suggested that the size of the brain(brain reserve) and the extent of neural connections acquired through life(neural reserve) set a threshold beyond which noticeable impairments occur.In contrast,cognitive reserve refers to the brain's ability to adapt and reo rganize stru cturally and functionally to resist damage and maintain function,including neural reserve and brain maintenance,resilience,and compensation(Verkhratsky and Zorec,2024).
文摘Cell function has a tight relationship with cell architecture.Distribution of proteins to the correct compartment is one of the functions of the traffic pathway through the Golgi apparatus.The others are to ensure proper protein folding,the addition of post-translational modifications,and delivering to intracellular and extracellular destinations.Astrocytes are fundamental homeostatic cells,controlling multiple aspects of the central nervous system physiology,such as ion balance,nutrients,blood flow,neurotransmitters,and responses to insults.Astrocytes are polarized cells,and,such as neurons,extensively use the secretory pathway for secreting factors and exposing functional receptors,channels,and transporters on the plasma membrane.In this review,we will underline the importance of studying the Golgi apparatus and the secretory pathway in astrocytes,based on the possible tight connection between the Golgi apparatus and astrocytes’homeostatic function.Given the topic of this review,we will provide examples mostly about the Golgi apparatus structure,function,localization,and its involvement in astrocytes’homeostatic response,with an insight into congenital glycosylation disorders,as an example of a potential future field in the study of astrocyte homeostatic failure and Golgi apparatus alteration.
文摘Spared regions of the damaged central nervous system undergo dynamic remodelling and exhibit a remarkable potential for therapeutic exploitation1.Lesion-remote astrocytes(LRAs),which interact with viable neurons and glia,undergo reactive transformations whose molecular and functional properties are poorly understood2.Here,using multiple transcriptional profiling methods,we investigated LRAs from spared regions of mouse spinal cord following traumatic spinal cord injury.
基金National Natural Science Foundation of China,No.32271148(to JW)the National Key Research and the Development Program of China,No.2023M740625(to ML)+1 种基金the Natural Science Foundation of Guangdong Province,Nos.2021B1515120050(to HW)and 2023A1515110782(to ML)and Key R&D Program of Ningxia Hui Autonomous Region,No.2024BEG02027(to JW).
文摘Astrocytes are the most abundant glial cells in the central nervous system.They perform a diverse array of functions,with a critical role in structural integrity,synapse formation,and neurotransmission.These cells exhibit substantial regional heterogeneity and display variable responses to different neurological diseases.Such diversity in astrocyte morphology and function is essential for understanding both normal brain function and the underlying mechanisms of neurological disorders.To investigate this heterogeneity,we developed a novel method for the selective and sparse labeling of astrocytes in various brain regions.This technique utilizes a dual adeno-associated virus system that allows for the expression of Cre recombinase and enhanced green fluorescent protein under the control of the glial fibrillary acidic protein(GfaABC1D)promoter.The system was tested in C57BL/6J mice and successfully labeled astrocytes across multiple brain regions.The method enabled the detailed visualization of individual astrocytes-including their intricate peripheral processes-through three-dimensional reconstructions from confocal microscopy images.Furthermore,the labeling efficiency of this dual adeno-associated virus technology was validated by examining astrocyte function in a spared nerve injury model and through chemogenetic modulation.This innovative approach holds great promise for future research because it enables a more comprehensive understanding of astrocyte variation not only in spared nerve injury but also in a broad spectrum of neurological diseases.The ability to selectively label and study astrocytes in different brain regions provides a powerful tool for exploring the complexities of these essential cells and their roles in physiological and pathological conditions.
基金supported by the National Natural Science Foundation of China(82474625)Zhejiang Provincial Natural Science Funds(LZ23H270001).
文摘In a recent work published in Neuron,Xu et al.identified a novel contribution of G protein-coupled receptor 37-like 1(GPR37L1),which is identified to be expressed by spinal astrocytes,to the regulation of neuropathic pain[1].By interacting and enhancing the activity of glutamate transporter-1(GLT-1)in spinal astrocytes,GPR37L1 promotes glutamate uptake by spinal astrocytes and reduces excitatory synaptic transmission in the spinal dorsal horn,all of which contribute to the resolution of chronic neuropathic pain.
基金supported by the National Natural Science Foundation of China,No.82201460(to YH)Nanjing Medical University Science and Technology Development Fund,No.NMUB20210202(to YH).
文摘Neurotoxic astrocytes are a promising therapeutic target for the attenuation of cerebral ischemia/reperfusion injury.Low-density lipoprotein receptor,a classic cholesterol regulatory receptor,has been found to inhibit NLR family pyrin domain containing protein 3(NLRP3)inflammasome activation in neurons following ischemic stroke and to suppress the activation of microglia and astrocytes in individuals with Alzheimer’s disease.However,little is known about the effects of low-density lipoprotein receptor on astrocytic activation in ischemic stroke.To address this issue in the present study,we examined the mechanisms by which low-density lipoprotein receptor regulates astrocytic polarization in ischemic stroke models.First,we examined low-density lipoprotein receptor expression in astrocytes via immunofluorescence staining and western blotting analysis.We observed significant downregulation of low-density lipoprotein receptor following middle cerebral artery occlusion reperfusion and oxygen-glucose deprivation/reoxygenation.Second,we induced the astrocyte-specific overexpression of low-density lipoprotein receptor using astrocyte-specific adeno-associated virus.Low-density lipoprotein receptor overexpression in astrocytes improved neurological outcomes in middle cerebral artery occlusion mice and reversed neurotoxic astrocytes to create a neuroprotective phenotype.Finally,we found that the overexpression of low-density lipoprotein receptor inhibited NLRP3 inflammasome activation in oxygen-glucose deprivation/reoxygenation injured astrocytes and that the addition of nigericin,an NLRP3 agonist,restored the neurotoxic astrocyte phenotype.These findings suggest that low-density lipoprotein receptor could inhibit the NLRP3-meidiated neurotoxic polarization of astrocytes and that increasing low-density lipoprotein receptor in astrocytes might represent a novel strategy for treating cerebral ischemic stroke.
基金supported by the National Natural Science Foundation of China(82171386,81971161,and 82201536)the Shanghai Science and Technology Development Foundation(22YF1458600)+1 种基金the Scientifc Foundation from Naval Medical University(2021QN08)the STI2030-Major Projects from Ministry of Science and Technology of China(2022ZD0204700).
文摘In the mammalian central nervous system(CNS),astrocytes are the ubiquitous glial cells that have complex morphological and molecular characteristics.These fascinating cells play essential neurosupportive and homeostatic roles in the healthy CNS and undergo morphological,molecular,and functional changes to adopt so-called‘reactive’states in response to CNS injury or disease.In recent years,interest in astrocyte research has increased dramatically and some new biological features and roles of astrocytes in physiological and pathological conditions have been discovered thanks to technological advances.Here,we will review and discuss the wellestablished and emerging astroglial biology and functions,with emphasis on their potential as therapeutic targets for CNS injury,including traumatic and ischemic injury.This review article will highlight the importance of astrocytes in the neuropathological process and repair of CNS injury.
基金supported by the Science and Technology Innovation(STI)2030-Major Projects(2025ZD0214900-02 and 2021ZD0203200-05)the National Natural Science Foundation of China(82130032)+1 种基金the Natural Science Foundation of Shanghai(24ZR1413900 and 25ZR1402460)and the China Postdoctoral Science Foundation(2021M690685).
文摘Astrocytes in the spinal dorsal horn(SDH)exhibit diverse reactive phenotypes under neuropathic conditions,yet the mechanisms driving this diversity and its implications in chronic pain remain unclear.Here,we report that spared nerve injury(SNI)induces marked upregulation of both complement component 3(C3⁺,A1-like)and S100 calcium-binding protein A10(S100A10⁺,A2-like)astrocyte subpopulations in the SDH,with elevated microglial cytokines including interleukin-1α,tumor necrosis factor-α,and complement component 1q.Transcriptomic,immunohistochemical,and Western blot analyses reveal co-activation of multiple reactive astrocyte states over a unidirectional shift toward an A1-like phenotype.Fibroblast growth factor 8(FGF8),a neuroprotective factor via FGFR3,mitigated microglia-induced C3⁺astrocyte reactivity in vitro and suppressed spinal C3 expression and mechanical allodynia following intrathecal administration in SNI mice.These findings reveal a microglia–astrocyte signaling axis that promotes A1 reactivity and position FGF8 as a promising therapeutic candidate for neuropathic pain by modulating astrocyte heterogeneity.
基金supported by grants PICT 2019-08512017-2203,UBACYT and PIP CONICET(to AJR).
文摘Traumatic brain injury is a global health crisis,causing significant death and disability worldwide.Neuroinflammation that follows traumatic brain injury has serious consequences for neuronal survival and cognitive impairments,with astrocytes involved in this response.Following traumatic brain injury,astrocytes rapidly become reactive,and astrogliosis propagates from the injury core to distant brain regions.Homeostatic astroglial proteins are downregulated near the traumatic brain injury core,while pro-inflammatory astroglial genes are overexpressed.This altered gene expression is considered a pathological remodeling of astrocytes that produces serious consequences for neuronal survival and cognitive recovery.In addition,glial scar formed by reactive astrocytes is initially necessary to limit immune cell infiltration,but in the long term impedes axonal reconnection and functional recovery.Current therapeutic strategies for traumatic brain injury are focused on preventing acute complications.Statins,cannabinoids,progesterone,beta-blockers,and cerebrolysin demonstrate neuroprotective benefits but most of them have not been studied in the context of astrocytes.In this review,we discuss the cell signaling pathways activated in reactive astrocytes following traumatic brain injury and we discuss some of the potential new strategies aimed to modulate astroglial responses in traumatic brain injury,especially using cell-targeted strategies with miRNAs or lncRNA,viral vectors,and repurposed drugs.
基金supported by the National Natural Science Foundation of China,No.8227050826(to PL)Tianjin Science and Technology Bureau Foundation,No.20201194(to PL)Tianjin Graduate Research and Innovation Project,No.2022BKY174(to CW).
文摘Cerebral edema caused by blood-brain barrier injury after intracerebral hemorrhage is an important factor leading to poor prognosis.Human-induced pluripotent stem cell-derived neural stem cell exosomes(hiPSC-NSC-Exos)have shown potential for brain injury repair in central nervous system diseases.In this study,we explored the impact of hiPSC-NSC-Exos on blood-brain barrier preservation and the underlying mechanism.Our results indicated that intranasal delivery of hiPSC-NSC-Exos mitigated neurological deficits,enhanced blood-brain barrier integrity,and reduced leukocyte infiltration in a mouse model of intracerebral hemorrhage.Additionally,hiPSC-NSC-Exos decreased immune cell infiltration,activated astrocytes,and decreased the secretion of inflammatory cytokines like monocyte chemoattractant protein-1,macrophage inflammatory protein-1α,and tumor necrosis factor-αpost-intracerebral hemorrhage,thereby improving the inflammatory microenvironment.RNA sequencing indicated that hiPSC-NSC-Exo activated the PI3K/AKT signaling pathway in astrocytes and decreased monocyte chemoattractant protein-1 secretion,thereby improving blood-brain barrier integrity.Treatment with the PI3K/AKT inhibitor LY294002 or the monocyte chemoattractant protein-1 neutralizing agent C1142 abolished these effects.In summary,our findings suggest that hiPSC-NSC-Exos maintains blood-brain barrier integrity,in part by downregulating monocyte chemoattractant protein-1 secretion through activation of the PI3K/AKT signaling pathway in astrocytes.
