Satellite glial cells in sensory ganglia play a wider role in chronic pain via multiple mechanisms

Satellite glial cells are unique glial cells that surround the cell body of primary sensory neurons.An increasing body of evidence suggests that in the presence of inflammation and nerve damage,a significant number of satellite glial cells become activated,thus triggering a series of functional changes.This suggests that satellite glial cells are closely related to the occurrence of chronic pain.In this review,we first summarize the morphological structure,molecular markers,and physiological functions of satellite glial cells.Then,we clarify the multiple key roles of satellite glial cells in chronic pain,including gap junction hemichannel Cx43,membrane channel Pannexin1,K channel subunit 4.1,ATP,purinergic P2 receptors,and a series of additional factors and their receptors,including tumor necrosis factor,glutamate,endothelin,and bradykinin.Finally,we propose that future research should focus on the specific sorting of satellite glial cells,and identify genomic differences between physiological and pathological conditions.This review provides an important perspective for clarifying mechanisms underlying the peripheral regulation of chronic pain and will facilitate the formulation of new treatment plans for chronic pain.

Enteric glial cells and their role in gastrointestinal motor abnormalities: Introducing the neuro-gliopathies

The role of enteric glial cells has somewhat changed from that of mere mechanical support elements, gluing together the various components of the enteric nervous system, to that of active participants in the complex interrelationships of the gut motor and inflammatory events. Due to their multiple functions, spanning from supporting elements in the myenteric plexuses to neurotransmitters, to neuronal homeostasis, to antigen presenting cells, this cell population has probably more intriguing abilities than previously thought. Recently, some evidence has been accumulating that shows how these cells may be involved in the pathophysiological aspects of some diseases. This review will deal with the properties of the enteric glial cells more strictly related to gastrointestinal motor function and the human pathological conditions in which these cells may play a role, suggesting the possibility of enteric neuro- gliopathies.

Role of Enteric Glial Cells in Gastric Motility in Diabetic Rats at Different Stages

Summary： Diabetes patients tend to have the gastrointestinal motility disorder. Although the relationship between the motility disorder and both the neurons and Cajal cells in the enteric nervous system （ENS） is well established, little is known about the role of enteric glial cells （EGCs） in gastric motility in diabetes. This study aimed to examine the expression of the glial marker S100B and morphology of EGCs in gastric tissues and the relationship between activated EGCs and the damage of gastric emptying in diabetic models. The diabetic model of rat was induced with 1% streptozotocin （STZ）. The model rats at 7-14 days and at 56-63 days were defined as early diabetic rats and advanced diabetic rats, re- spectively, and normal rats at the two time periods served as their corresponding controls. The gastric emptying rate of the rats was tested by using the phenol red solution. The ultrastructure of EGCs in the gastric antrum was observed by the transmission electron microscopy, and the expression of S100B in the myenteric plexus was immunohistochemically detected. The results showed that the gastric emptying rate was significantly increased in the early diabetic rats and decreased in the advanced diabetic rats when compared with their corresponding control rats （P〈0.01 for both）. The ultrastructure of EGCs was mostly normal in both the early diabetic and control groups. Vacuolization of mitochondria and expan- sion of endoplasmic reticulum occurred in both the advanced diabetic group and its control group, and even the structure of smooth muscle cells and intestinal neurons was destroyed in the advanced diabetic group. The expression level of S100B in the advanced diabetic group was significantly decreased com- pared with its control group （P〈0.05）. It was obviously increased in the early diabetic control group when compared with the advanced diabetic control group （P〈0.05）. However, there was no significant difference in the S 100B expression between the early diabetic group and its control group （P〉0.05）. The findings suggested that the gastric motility dysfunction in diabetes may be associated with the changes of morphology and number of EGCs in the myenteric plexus.

Stem cell therapy for central nerve system injuries: glial cells hold the key

Mammalian adult central nerve system （CNS） injuries are devastating because of the intrinsic difficulties for effective neuronal regeneration. The greatest problem to be overcome for CNS recovery is the poor regeneration of neurons and myelin-forming cells, oligodendrocytes. Endogenous neural progenitors and transplanted exogenous neuronal stem cells can be the source for neuronal regeneration. However, because of the harsh local microenvironment, they usually have very low efficacy for functional neural regeneration which cannot compensate for the loss of neurons and oligodendrocytes. Glial cells （including astrocytes, microglia, oligodendrocytes and NG2 glia） are the majority of cells in CNS that provide support and protection for neurons. Inside the local microenvironment, glial cells largely influence local and transplanted neural stem cells survival and fates. This review critically analyzes current finding of the roles of glial cells in CNS regeneration, and highlights strategies for regulating glial cells＇ behavior to create a permissive microenvironment for neuronal stem cells.

Regulatory effects of inhibiting the activation of glial cells on retinal synaptic plasticity

Various retinal injuries induced by ocular hypertension have been shown to induce plastic changes in retinal synapses, but the potential regulatory mechanism of synaptic plasticity after retinal injury was still unclear. A rat model of acute ocular hypertension was established by injecting saline intravitreally for an hour, and elevating the intraocular pressure to 14.63 kPa （110 mmHg）. Western blot assay and immunofluorescence results showed that synaptophysin expression had a distinct spatiotemporal change that increased in the inner plexiform layer within 1 day and spread across the outer plexiform layer after 3 days. Glial fibrillary acidic protein expression in retinae was greatly increased after 3 days, and reached a peak at 7 days, which was also consistent with the peak time of synaptophysin expression in the outer plexiform layer following the increased intraocular pressure. Fluorocitrate, a glial metabolic inhibitor, was intravitreally injected to inhibit glial cell activation following high intraocular pressure. This significantly inhibited the enhanced glial fibrillary acidic protein expression induced by high intraocular pressure injury. Synaptophysin expression also decreased in the inner plexiform layer within a day and the widened distribution in the outer plexiform layer had disappeared by 3 days. The results suggested that retinal glial cell activation might play an important role in the process of retinal synaptic plasticity induced by acute high intraocular pressure through affecting the expression and distribution of synaptic functional proteins, such as synaptophysin.

Mycobacterium avium subspecies paratuberculosis infects and multiplies in enteric glial cells

AIM: To establish the role of enteric glial cells during infection with Mycobacterium avium subspecies paratuberculosis (MAP) in Crohn's disease. METHODS: In order to establish the role of enteric glial cells during infection with M. avium subspecies paratuberculosis (MAP) in Crohn's disease, Map adhesion experiments on enteric glial cells were performed as well as expression analysis of Map sigma factors during infection. RESULTS: In this study, for the first time, we found a high affinity of MAP to enteric glial cells and we analyzed the expression of MAP sigma factors under different conditions of growth. CONCLUSION: The fact that Map showed a high affinity to the glial cells raises concerns about the complicated etiology of the Crohn's disease. Elucidation of the mechanisms whereby inflammation alters enteric neural control of gut functions may lead to novel treatments for Crohn's disease.

Impact of SARS-CoV-2 infection during pregnancy on postnatal brain development:The potential role of glial cells

Glial cells are crucial for maintaining central nervous system(CNS)homeostasis.They actively participate in immune responses,as well as form functional barriers,such as blood-brain barrier(BBB),which restrict the entry of pathogens and inflammatory mediators into the CNS.In general,viral infections during the gestational period can alter the embryonic and fetal environment,and the related inflammatory response may affect neurodevelopment and lead to behavioral dysfunction during later stage of life,as highlighted by our group for Zika virus infection.Severe acute respiratory syndrome coronavirus-2(SARS-CoV-2)induces a cytokine storm and,during pregnancy,may be related to a more severe form of the coronavirus disease-19(COVID-19)and also to higher preterm birth rates.SARS-CoV-2 can also affect the CNS by inducing neurochemical remodeling in neural cells,which can compromise neuronal plasticity and synaptic function.However,the impact of SARS-CoV-2 infection during pregnancy on postnatal CNS,including brain development during childhood and adulthood,remains undetermined.Our group has recently highlighted the impact of COVID-19 on the expression of molecular markers associated with neuropsychiatric disorders,which are strongly related to the inflammatory response.Thus,based on these relationships,we discussed the impact of SARS-CoV-2 infection either during pregnancy or in critical periods of neurodevelopment as a risk factor for neurological consequences in the offspring later in life,focusing on the potential role of glial cells.Thus,it is important to consider future and long-term public health concerns associated with SARS-CoV-2 infection during pregnancy.

Regulation of neuroinflammatory properties of glial cells by T cell effector molecules

Multiple sclerosis （MS） is a chronic inflammatory and neurodegenerative disorder that is thought to be mediated by autoreactive T lymphocytes that find their way into the central nervous system （CNS）. The pathological mechanism of MS is still being elucidated but it involves complex interactions between infiltrating immune cells and resi- dent glial cells within the CNS that culminate into strong neuroinflammation and axonal damage.

Neurotrophins and their receptors in satellite glial cells following nerve injury

Peripheral neuropathy is a condition where damage resulting from mechanical or pathological mechanisms is inflicted on nerves within the peripheral nervous system （PNS）. Physical injury is the most common cause and may result in nerves being partially or completely severed, crushed, compressed or stretched. Other causes include metabolic or endocrine disorders, with e.g.,

The emerging roles of transplanted radial glial cells in regenerating the central nervous system

Scientists conclude that a combination of treatments involving rehabilitation,drug delivery,surgery and cell transplantation are necessary to achieve significant progress in regenerating the injured central nervous system（CNS）.

Axotomy induces damage to glial cells remote from the transection site in the peripheral nervous system

Traumatic cerebral or spinal cord injury induced by military,traffic,and sports accidents,falls or environmental and anthropogenic catastrophes are among main causes of people mortality and disability,especially in young and middle age men（Kobeissy,2015）.Axon transection,or axotomy,occurs in wounds and during surgery.

Seeing the wood for the trees:towards improved quantification of glial cells in central nervous system tissue

The following mini-review attempts to guide researchers in the quantification of fluorescently-labelled proteins within cultured thick or chromogenically-stained proteins within thin sections of brain tissue.It follows from our examination of the utility of Fiji Image J thresholding and binarization algorithms.Describing how we identified the maximum intensity projection as the best of six tested for two dimensional（2 D）-rendering of three-dimensional（3 D） images derived from a series of z-stacked micrographs,the review summarises our comparison of 16 global and 9 local algorithms for their ability to accurately quantify the expression of astrocytic glial fibrillary acidic protein（GFAP）,microglial ionized calcium binding adapter molecule 1（IBA1） and oligodendrocyte lineage Olig2 within fixed cultured rat hippocampal brain slices.The application of these algorithms to chromogenically-stained GFAP and IBA1 within thin tissue sections,is also described.Fiji’s Bio Voxxel plugin allowed categorisation of algorithms according to their sensitivity,specificity accuracy and relative quality.The Percentile algorithm was deemed best for quantifying levels of GFAP,the Li algorithm was best when quantifying IBA expression,while the Otsu algorithm was optimum for Olig2 staining,albeit with over-quantification of oligodendrocyte number when compared to a stereological approach.Also,GFAP and IBA expression in 3,3′-diaminobenzidine（DAB）/haematoxylin-stained cerebellar tissue was best quantified with Default,Isodata and Moments algorithms.The workflow presented in Figure 1 could help to improve the quality of research outcomes that are based on the quantification of protein with brain tissue.

Effect of glial cells on remyelination after spinal cord injury

Remyelination plays a key role in functional recovery of axons after spinal cord injury.Glial cells are the most abundant cells in the central nervous system.When spinal cord injury occurs,many glial cells at the lesion site are immediately activated,and different cells differentially affect inflammatory reactions after injury.In this review,we aim to discuss the core role of oligodendrocyte precursor cells and crosstalk with the rest of glia and their subcategories in the remyelination process.Activated astrocytes influence proliferation,differentiation,and maturation of oligodendrocyte precursor cells,while activated microglia alter remyelination by regulating the inflammatory reaction after spinal cord injury.Understanding the interaction between oligodendrocyte precursor cells and the rest of glia is necessary when designing a therapeutic plan of remyelination after spinal cord injury.

Glial cell line-derived neurotrophic factor and brain-derived neurotrophic factor regulate the interaction between astrocytes and Schwann cells at the trigeminal root entry zone

The trigeminal root entry zone is the zone at which the myelination switches from peripheral Schwann cells to central oligodendrocytes.Its special anatomical and physiological structure renders it susceptible to nerve injury.The etiology of most primary trigeminal neuralgia is closely related to microvascular compression of the trigeminal root entry zone.This study aimed to develop an efficient in vitro model mimicking the glial environment of trigeminal root entry zone as a tool to investigate the effects of glial cell line-derived neurotrophic factor and brain-derived neurotrophic factor on the structural and functional integrity of trigeminal root entry zone and modulation of cellular interactions.Primary astrocytes and Schwann cells isolated from trigeminal root entry zone of postnatal rats were inoculated into a two-well silicon culture insert to mimic the trigeminal root entry zone microenvironment and treated with glial cell line-derived neurotrophic factor and brain-derived neurotrophic factor.In monoculture,glial cell line-derived neurotrophic factor promoted the migration of Schwann cells,but it did not have effects on the migration of astrocytes.In the co-culture system,glial cell line-derived neurotrophic factor promoted the bidirectional migration of astrocytes and Schwann cells.Brain-derived neurotrophic factor markedly promoted the activation and migration of astrocytes.However,in the co-culture system,brain-derived neurotrophic factor inhibited the migration of astrocytes and Schwann cells to a certain degree.These findings suggest that glial cell line-derived neurotrophic factor and brain-derived neurotrophic factor are involved in the regulation of the astrocyte-Schwann cell interaction in the co-culture system derived from the trigeminal root entry zone.This system can be used as a cell model to study the mechanism of glial dysregulation associated with trigeminal nerve injury and possible therapeutic interventions.

Inhibition of Foxp4 Disrupts Cadherin-based Adhesion of Radial Glial Cells,Leading to Abnormal Differentiation and Migration of Cortical Neurons in Mice

Heterozygous loss-of-function variants of FOXP4 are associated with neurodevelopmental disorders(NDDs)that exhibit delayed speech development,intellectual disability,and congenital abnormalities.The etiology of NDDs is unclear.Here we found that FOXP4 and N-cadherin are expressed in the nuclei and apical end-feet of radial glial cells(RGCs),respectively,in the mouse neocortex during early gestation.Knockdown or dominant-negative inhibition of Foxp4 abolishes the apical condensation of N-cadherin in RGCs and the integrity of neuroepithelium in the ventricular zone(VZ).Inhibition of Foxp4 leads to impeded radial migration of cortical neurons and ectopic neurogenesis from the proliferating VZ.The ectopic differentiation and deficient migration disappear when N-cadherin is over-expressed in RGCs.The data indicate that Foxp4 is essential for N-cadherin-based adherens junctions,the loss of which leads to periventricular heterotopias.We hypothesize that FOXP4 variant-associated NDDs may be caused by disruption of the adherens junctions and malformation of the cerebral cortex.

Exploring the vital role of microglial membrane receptors in Alzheimer’s disease pathogenesis: a comprehensive review

Neurodegenerative diseases constitute a broad category of diseases caused by the degeneration of the neurons.They are mainly manifested by the gradual loss of neuron structure and function and eventually can cause death or loss of neurons.As the global population ages rapidly,increased people are being diagnosed with neurodegenerative diseases.It has been established that the onset of Alzheimer’s disease(AD)is closely linked with increasing age and its major pathological features include amyloid-beta plaques(Aβ),Tau hyperphosphorylation,Neurofibrillary tangles(NFTs),neuronal death as well as synaptic loss.The involvement of microglia is crucial in the pathogenesis and progression of AD and exhibits a dual role.For instance,in the early stage of AD,microglia surface membrane proteins or receptors can participate in immunophagocytosis,and anti-inflammatory functions and act as a physical barrier after recognizing various ligands such as Aβand NFTs.However,in the later stage of the disease,membrane receptors on the surface of microglia can cause its activation to release a substantial quantity of pro-inflammatory factors.Which can amplify the neuroinflammatory response.The rapid decline of normal immune phagocytosis can result in the continuous accumulation of abnormal proteins,leading to neuronal dysfunction and destruction of the formed physical barrier as well as the neurovascular microenvironment.It can also increase the transformation of microglia from anti-inflammatory phenotype M2 to pro-inflammatory phenotype M1,induce severe neuronal injury or apoptosis,and aggravate the progression of AD.Due to few articles have focused on the AD-related membrane protein receptors on microglia,thus in this paper,we have reviewed several representative microglial membrane proteins or receptors about their specific roles and functions implicated in AD,and expect that there will be more in-depth research and scientific research results in the treatment of AD by targeted regulation of microglia membrane protein receptors in the future.

Overexpression of lentivirus-mediated glial cell line-derived neurotrophic factor in bone marrow stromal cells and its neuroprotection for the PC12 cells damaged by lactacystin

Objective To construct recombinant lentiviral vectors for gene delivery of the glial cell line-derived neurotropnic factor （GDNF）, and evaluate the neuroprotective effect of GDNF on lactacystin-damaged PC12 cells by transfecting it into bone marrow stromal cells （BMSCs）. Methods pLenti6/V5-GDNF plasmid was set up by double restriction enzyme digestion and ligation, and then the plasmid was transformed into Top10 cells. Purified pLenti6/V5-GDNF plasmids from the positive clones and the packaging mixture were cotransfected to the 293FT packaging cell line by Lipofectamine2000 to produce lentivirus, then the concentrated virus was transduced to BMSCs. Overexpression of GDNF in BMSCs was tested by RT-PCR, ELISA and immunocytochemistry, and its neuroprotection for lactacystin-damaged PC12 cells was evaluated by MTT assay. Results Virus stock of GDNF was harvested with the titer of 5.6×10^5 TU/mL. After tmnsduction, GDNF-BMSCs successfully secreted GDNF to supematant with nigher concentration （800 pg/mL） than BMSCs did （less than 100 pg/mL）. The supematant of GDNF-BMSCs could significantly alleviate the damage of PC12 cells induced by lactacystin （10 μmol/L）. Conclusion Overexpression of lentivirus-mediated GDNF in the BMSCs cells can effectively protect PC12 cells from the injury by the proteasome inhibitor.

Effects of estrogen on collagen gel contraction by human retinal glial cells

Background There are definite gender differences in patients with macular holes. Menopausal women over 50 years are most affected. We aimed to observe the effect of estrogen on collagen gel contraction by cultured human retinal glial cells. It is speculated that estrogen could strengthen the tensile stress of the macula by maintaining the correct morphology and contraction. Methods Estrogen was used to determine its effects on collagen gel contraction, and its function was measured using morphological changes in cells. Human retinal glial cells were cultured in collagen solution. The cells were then exposed to collagen gels and the degree of contraction of the gel was determined. Results Estrogen at differing concentrations had no effect on the growth of human retinal glial cells. However, after exposed to collagen gel block, less contraction was noted in the estrogen-treated group than in the control group. Conclusions Estrogen can inhibit collagen gel contraction by glial cells. These results suggest a mechanism for macular hole formation, which is observed in menopausal females.

Connecting Malfunctioning Glial Cells and Brain Degenerative Disorders

The DNA damage response（DDR） is a complex biological system activated by different types of DNA damage.Mutations in certain components of the DDR machinery can lead to genomic instability disorders that culminate in tissue degeneration,premature aging,and various types of cancers.Intriguingly,malfunctioning DDR plays a role in the etiology of late onset brain degenerative disorders such as Parkinson＇s,Alzheimer＇s,and Huntington＇s diseases.For many years,brain degenerative disorders were thought to result from aberrant neural death.Here we discuss the evidence that supports our novel hypothesis that brain degenerative diseases involve dysfunction of glial cells（astrocytes,microglia,and oligodendrocytes）.Impairment in the functionality of glial cells results in pathological neuro-glial interactions that,in turn,generate a ‘‘hostile＂ environment that impairs the functionality of neuronal cells.These events can lead to systematic neural demise on a scale that appears to be proportional to the severity of the neurological deficit.

Possible role of microparticles in neuroimmune signaling of microglial cells

Aim:Submicron fragments termed microparticles(MPs),derived from all major central nervous system cell types including neurons and glia(microglia,astrocytes,oligodendrocytes),have emerged as novel intercellular signaling agents.This study tested the hypothesis that MPs derived from activated microglia,which represent the mononuclear phagocyte system in the brain,could induce pro-inflammatory and cytotoxic responses of microglia in an autocrine or paracrine manner.Methods:Human THP-1 monocytic cells were used to model human microglia.MPs derived from these cells were reapplied to THP-1 cells and their secretion of neurotoxins and cytokines was measured.Results:When exposed to lipopolysaccharide(LPS)or mitochondrial transcription factor A in combination with interferon(IFN)-γ,THP-1 cells released MPs.When reapplied to THP-1 cells,MPs induced the release of secretions that were toxic to human SH-SY5Y neuroblastoma cells,as well as monocyte chemoattractant protein-1.The cytotoxicity of THP-1 cells induced by MPs derived from IFN-γplus LPS-treated THP-1 donor cells was enhanced in the presence of IFN-γ.The MPs released by THP-1 cells were not directly toxic towards SH-SY5Y cells.Conclusion:Our data support the hypothesis that activated microglia-derived MPs could act as signaling agents that are recognized by microglia to cause pro-inflammatory and cytotoxic responses.