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Results for “brain microenvironment”

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PubMed1994

Normal and abnormal development of the blood-brain barrier.

The blood-brain barrier is responsible for the maintenance of the neuronal microenvironment. This is accomplished by isolation of the brain from the blood by the tight junctions that join endothelial cells in cerebral microvessels, and by selective transport and metabolism of substances from blood or brain by the endothelial cells. This review describes the growth and maturation of the brain vasculature, and the development of the special properties of the endothelia at the blood-brain interface. Evidence suggests that the development of the unique properties of the brain microvasculature is a consequence of tissue-specific interactions between endothelial cells of extraneural origin and developing brain cells. The cellular and molecular mechanisms that control these processes are as yet unknown but this review will include experimental studies which have used in vivo and in vitro systems to investigate what factors may be involved, and some pathological conditions in which abnormal barrier development is thought to be an important aspect of the disease process.

Animals↗
PubMed1972

Age changes in the neuronal microenvironment.

The extracellular space of the rat brain was visualized by electron roscopy in sections of cerebral cortex fixed by freeze-substitution. The volume tissue occupied by the extracellular space was estimated stereomnetrically, and found to decrease from 20.8 percent in 3-month-old rats to 9.6 percent in escent animals, 26 months of age. This decrease in extracellular space indicates age-associated change in the microenvironment of nerve cells.

Aging↗
PubMed2000

Hexokinase 'binding sites' of normal and tumoral human brain mitochondria.

Interaction of type I hexokinase (HK-I) with the mitochondria obtained from the biopsy specimens of normal and tumoral human brain tissues was studied in the present investigation. This effort was undertaken with the aim of exploring possible differences in the mode of association of the enzyme with the outer mitochondrial membrane in the described sources. Results indicate that the two 'sites' for binding of HK-I suggested in the literature, based on extensive studies carried out on rat brain mitochondria, are similarly present in the human brain mitochondria. Differences in the microenvironments of HK binding, as reflected by the presented data, are suggested to be of importance in regulation of the catalytic potential of the bound enzyme. The real metabolic significance of this association in relation to cancer and its practical importance would need further investigation.

Amino Acid Sequence↗
PubMed2006

Murine mesenchymal stem cells transplanted to the central nervous system of neonatal versus adult mice exhibit distinct engraftment kinetics and express receptors that guide neuronal cell migration.

Mesenchymal stem cells (MSCs) have demonstrated efficacy as cellular vectors for treating a variety of nervous system disorders. Nevertheless, few studies have quantified MSC engraftment levels or explored the mechanisms that promote their survival and migration in nervous tissue. In this study, we compared the engraftment kinetics and anatomical distribution of murine, male MSCs injected intracranially into neonatal versus adult female mice using a real-time PCR assay that targets the mouse SRY gene. These analyses revealed that MSCs exhibited low but equivalent engraftment levels in the central nervous system (CNS) of neonatal and adult transplant recipients at 12 days post-injection. However, MSC engraftment levels were significantly greater at 60 and 150 days post-transplantation in neonates as compared to adults. Despite these differences, engrafted MSCs were widely distributed along the neuraxis of the CNS in both transplant groups. Collectively, these data indicate that proliferation, but not engraftment and migration, of MSCs in brain are regulated by the host microenvironment. Using a genomics approach, we also identified MSC subpopulations that express neural adhesion proteins and receptors that regulate neuronal cell migration in brain, including cadherin 2, neurexin 1, ninjurin 1, neogenin 1, neuropilin 2, and roundabout homolog 1 and 4. Functional studies indicate these proteins confer cell adhesion and migration of MSCs in response to the appropriate chemoattractant. On the basis of these findings, we conclude that the unique molecular composition of MSC subpopulations imparts to them an inherent capacity to engraft and migrate in brain. These subpopulations may represent more potent cellular vectors for treating CNS disorders.

Aging↗
PubMed2002

Tight junctions of the blood-brain barrier: development, composition and regulation.

1. The blood-brain barrier is essential for the maintenance and regulation of the neural microenvironment. The main characteristic features of blood-brain barrier endothelial cells are an extremely low rate of transcytotic vesicles and a restrictive paracellular diffusion barrier. 2. Endothelial blood-brain barrier tight junctions differ from epithelial tight junctions, not only by distinct morphological and molecular properties, but also by the fact that endothelial tight junctions are more sensitive to microenvironmental than epithelial factors. 3. Many ubiquitous molecular tight junction components have been identified and characterized including claudins, occludin, ZO-1, ZO-2, ZO-3, cingulin and 7H6. Signaling pathways involved in tight junction regulation include G-proteins, serine-, threonine- and tyrosine-kinases, extra and intracellular calcium levels, cAMP levels, proteases and cytokines. Common to most of these pathways is the modulation of cytoskeletal elements and the connection of tight junction transmembrane molecules to the cytoskeleton. Additionally, crosstalk between components of the tight junction- and the cadherin-catenin system of the adherens junction suggests a close functional interdependence of the two cell-cell contact systems. 4. Important new molecular aspects of tight junction regulation were recently elucidated. This review provides an integration of these new results.

Animals↗
PubMed2026

FZD5 drives macrophage-mediated immunomodulation and predicts prognosis in glioma: evidence from single-cell sequencing.

BACKGROUND: Gliomas are highly malignant brain tumors characterized by an immunosuppressive microenvironment, which limits therapeutic efficacy and contributes to poor clinical outcomes. The WNT/β-catenin signaling pathway is critically involved in tumor progression, and FZD5, a key receptor within this pathway, may participate in immune regulation. However, its specific role and underlying mechanisms in glioma remain unclear. METHODS: RNA-seq and microarray datasets from the Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA), together with single-cell RNA sequencing (scRNA-seq) datasets from GEO, were comprehensively analyzed. The Seurat package was used to identify macrophage-related clusters and mitophagy-associated pathways. Cox and LASSO regression analyses, along with a prognostic nomogram, were applied to evaluate the prognostic significance of FZD5. Immune infiltration, functional enrichment, and immunotherapy response analyses were conducted, followed by validation using spatial transcriptomics, immunohistochemistry, and in vitro assays. RESULTS: In bulk glioma transcriptomes, FZD5 emerged as an independent predictor of poor prognosis. Crucially, single-cell and spatial analyses revealed that the biologically significant FZD5 signal originated predominantly within tumor-associated macrophages (TAMs), where it colocalized with the M2 marker CD163. Consistently, elevated FZD5 levels correlated with increased myeloid infiltration and an immunosuppressive tumor microenvironment. Functionally, macrophage-expressed FZD5 was associated with mitophagy-related programs and promoted an M2-skewed phenotype, thereby enhancing glioma cell proliferation, migration, and invasion via macrophage-glioma crosstalk. CONCLUSION: FZD5 is a TAM-enriched marker in glioma tissues and a potential regulator of macrophage-associated immunosuppressive programs, supporting its utility as a prognostic biomarker and a candidate target for microenvironment-oriented interventions in glioma.

Humans↗
PubMed2002

Differentiation of the RN33B cell line into forebrain projection neurons after transplantation into the neonatal rat brain.

The rat neural cell line RN33B has a remarkable ability to undergo region-specific neuronal differentiation after transplantation into the CNS. To further study its neurogenic properties in vivo, we used a recombinant lentiviral vector to genetically label the cells with the Green Fluorescent Protein (GFP) gene before implantation into the striatum/cortex, hippocampus, or mesencephalon of newborn rats. Three weeks after implantation, about 1-2% of the GFP-expressing cells had developed morphologies typical of neurons, astrocytes, or oligodendrocytes, the rest remained as either immature or undifferentiated nestin-positive cells. At 15-17 weeks postgrafting, the immature cells had disappeared in most graft recipients and only cells with neuronal or glial morphologies remained in similar numbers as at 3 weeks. The GFP distributed throughout the expressing cells, revealing fine morphological details, including dendrites with spines and extensive axonal projections. In all forebrain regions, the grafted cells differentiated into neurons with morphologies characteristic for each site, including large numbers of pyramidal-like cells in the cortex and the hippocampus, giving rise to dense projections to normal cortical target regions and to the contralateral hippocampus, respectively. In lower numbers, it was also possible to identify GFP-positive granulelike cells in the hippocampus, as well as densely spiny neurons in the striatum. In the mesencephalon by contrast, cells with astrocytic features predominated. The ability of the grafted RN33B cells to undergo region-specific differentiation into highly specialized types of forebrain projection neurons and establish connections with appropriate targets suggests that cues present in the microenvironment of the neonatal rat brain can effectively guide the development of immature progenitors, also in the absence of ongoing neurogenesis.

Animals↗
PubMed2002

The adhesion molecule ICAM-1 and its regulation in relation with the blood-brain barrier.

The blood-brain barrier (BBB) is formed by high resistance tight junctions within the capillary endothelium perfusing the vertebrate brain. Normal BBB maintains a unique microenvironment within the central nervous system (CNS). In neurodegenerative disorders (for example multiple sclerosis, MS), the BBB becomes impaired. Perivascular cells (astrocytes, macrophages and microglial cells) and brain microvascular endothelial cells (BMEC) produce various inflammatory factors that affect the BBB permeability and the expression of adhesion molecules. Indeed, cytokines can stimulate the expression of several adhesion molecules on brain microvascular endothelial cells. Among these adhesion molecules, the intercellular adhesion molecule-1 (ICAM-1) binds to its leukocyte ligands and allows activated leukocytes entry into the CNS. This review is dealing with the expression and regulation of ICAM-1 in relation with several properties of the BBB. Particularly, the role of ICAM-1 in the control of the leukocyte traffic into the CNS, as well as in cerebral malaria and in CNS infection by viruses, is discussed.

Animals↗
PubMed2002

The cerebromicrovasculature: a key player in the pathogenesis of Alzheimer's disease.

Neuronal cell death is the primary underlying pathogenic lesion in Alzheimer's disease (AD). Despite intense research efforts, the mechanisms that contribute to neuronal cell death have not been clarified. In this debate we address the question, Is AD a vascular or metabolic disorder? Here we defend the hypothesis that the cerebromicrovasculature is a key player in the pathogenesis of AD. Evidence is presented that vascular amyloid beta (Abeta) is more closely associated with tau pathology than the distribution of diffuse or neuritic plaque Abeta. Furthermore, brain endothelial cells are identified as important regulators of the neuronal microenvironment, including Abeta levels. Finally, evidence is presented that brain endothelial cells undergo cellular and biochemical changes in AD and that the release of neurotoxic factors from these dysfunctional cells contributes to the neuronal cell loss characteristic of AD.

Aged↗
PubMed2006

Cyclooxygenase-2 inhibitor, celecoxib, inhibits the altered hippocampal neurogenesis with attenuation of spontaneous recurrent seizures following pilocarpine-induced status epilepticus.

Recent evidences suggest key roles of abnormal neurogenesis and astrogliosis in the pathogenesis of epilepsy. Alterations in the microenvironment of the stem cell, such as microglial activation and cyclooxygenase-2 induction may cause ectopic neurogenesis or astrogliosis. Here, we examined if inflammatory blockade with celecoxib, a selective cyclooxygenase-2 inhibitor, could modulate the altered microenvironment in the epileptic rat brain. Celecoxib attenuated the likelihood of developing spontaneous recurrent seizures after pilocarpine-induced prolonged seizure. During the latent period, celecoxib prevented neuronal death and microglia activation in the hilus and CA1 and inhibited the generation of ectopic granule cells in the hilus and new glia in CA1. The direct inhibition of precursor cells by celecoxib was further demonstrated in human neural stem cells culture. These findings raise the evidence of COX-2 induction to act importantly on epileptogenesis and suggest a potential therapeutic role for COX-2 inhibitors in chronic epilepsy.

Animals↗
PubMed1988

Endothelial cell-astrocyte interactions. A cellular model of the blood-brain barrier.

Microvascular endothelial cells in the brain have a number of special properties that underlie formation of the blood-brain barrier (BBB) and contribute to control of the neuronal microenvironment. Evidence from transplantation experiments indicates that signals arising within brain rather than a programmed commitment of the endothelial cells are responsible for the expression of blood-brain barrier properties. The close anatomic relationship between brain endothelial cells and the foot processes of astrocytes suggests a role for astrocytes as a source of the differentiation signals. It is now possible to isolate and separately culture populations of brain-derived endothelial cells and astrocytes. When the two cell types are grown together, a characteristic morphologic organization occurs that is associated with induction of enzymes and tight junctions similar to those found in vivo. Endothelial cells and astrocytes in culture differ in their production of and response to specific polypeptide growth factors. These findings provide the basis for a model of endothelial cell-astrocyte interaction that may explain several aspects of BBB behavior.

Animals↗
PubMedDate not supplied

Neuroimmunomodulation in immune privilege: role of neuropeptides in ocular immunosuppression.

The microenvironments of the eye and brain are physiologically adapted to protect their delicate structures and functions from damaging immunogenic inflammation (delayed-type hypersensitivity). This adaptation is immune privilege. Aqueous humor, the fluid filling the ocular anterior chamber, suppresses antigen-stimulated primed T cells from mediating inflammation by inhibiting the production of the proinflammatory lymphokine interferon gamma. This suppression is mediated by immunosuppressive cytokines and neuropeptides constitutively produced in the eye and released into aqueous humor. Cerebrospinal fluid has similar immunosuppressive activities, cytokines, and neuropeptides as aqueous humor, indicating that similar mechanisms may mediate immune privilege in the eye and brain. The importance of neuropeptides in mediating immunosuppression indicates that immunosuppressive neuroimmunomodulation has a role in preventing induction of immunogenic inflammation within immune-privileged tissues.

Adaptation, Physiological↗
PubMed2025

Microbial signals in primary and metastatic brain tumors.

Gliomas and brain metastases are associated with poor prognosis, necessitating a deeper understanding of brain tumor biology and the development of effective therapeutic strategies. Although our group and others have demonstrated microbial presence in various tumors, recent controversies regarding cancer-type-specific intratumoral microbiota emphasize the importance of rigorous, orthogonal validation. This prospective, multi-institutional study included a total of 243 samples from 221 patients, comprising 168 glioma and brain metastases samples and 75 non-cancerous or tumor-adjacent tissues. Using stringent fluorescence in situ hybridization, immunohistochemistry and high-resolution spatial imaging, we detected intracellular bacterial 16S rRNA and lipopolysaccharides in both glioma and brain metastases samples, localized to tumor, immune and stromal cells. Custom 16S and metagenomic sequencing workflows identified taxa associated with intratumoral bacterial signals in the tumor microenvironment; however, standard culture methods did not yield readily cultivable microbiota. Spatial analyses revealed significant correlations between bacterial 16S signals and antimicrobial and immunometabolic signatures at regional, neighborhood and cellular levels. Furthermore, intratumoral 16S bacterial signals showed sequence overlap with matched oral and gut microbiota, suggesting a possible connection with distant communities. Together, these findings introduce microbial elements as a component of the brain tumor microenvironment and lay the foundation for future mechanistic and translational studies.

Humans↗
PubMed2025

m6A regulator-based molecular classification and hub genes associated with immune infiltration characteristics and clinical outcomes in diffuse gliomas.

BACKGROUND: m6A methylation modification is a new regulatory mechanism involved in tumorigenesis and tumor-immunity interaction. However, its impact on glioma immune microenvironment and clinical outcomes remains unclear. METHODS: Comprehensive expression profiles of 18 m6A regulators were used to identify molecular subtypes exhibiting distinct m6A modification patterns in 1673 glioma samples sourced from public datasets. A multi-genes signature was constructed for predicting clinical outcomes and response to immunotherapy in glioma patients. Immunohistochemistry and cellular experiments were performed for validation. RESULTS: Two m6A subtypes of gliomas were identified. The m6A-low-risk subtype was characterized by paucity of immune infiltrates; While the m6A-high-risk subtype had higher abundances of multiple immune cells including lymphocyte and macrophage as well as increased expression of PD-L1, corresponding to an immunosuppressive phenotype. The m6A-high-risk subtype had poorer survival than the m6A-low-risk subtype in both the glioblastoma and lower grade gliomas cohorts. Eight m6A-related hub genes of high prognostic significances were identified and selected for developing a scoring signature termed as m6Ascore. Elevated m6Ascore indicated worse survival for glioma patients under standard care, but showed enhanced response to immunotherapy. Moreover, we demonstrated that overexpression of FTO, a m6A demethylase, inhibited the expressions of m6A-related hub genes (PTX3, SPAG4), impaired glioma cell viability and reduced macrophage chemotaxis. CONCLUSION: This work develops an immune- and clinical-relevant m6A subtyping and a scoring model, which enhances our understanding of the role of m6A modification in regulating immune infiltration microenvironment in gliomas and helps to identify patients who are more likely to benefit from immunotherapy.

Humans↗
PubMed1986

Alcohol, in a single pharmacological dose, decreases brain gangliosides.

Alcohol penetrates into cell membranes, fluidizing and disordering the microenvironment. Here we report that associated with the disordering is a reduction of the normal level of brain gangliosides of adult male rats. The maximum decrement occurred in all major classes of gangliosides at 4 to 8 hours after a single pharmacological dose (3 gm/kg, IP). Because gangliosides have diverse, important functions in cell membranes, this effect of alcohol might be a basis for some of its intoxicating and addicting properties.

Animals↗
PubMed1998

Host TIMP-1 overexpression confers resistance to experimental brain metastasis of a fibrosarcoma cell line.

Within the tumor-stromal microenvironment a disrupted balance between matrix metalloproteinases (MMPs) and their inhibitors compromises the integrity of the extracellular matrix and promotes malignancy. Tissue inhibitors of metalloproteinases (TIMPs) have been linked to tumor suppression in studies of genetically altered tissue culture cells and in analyses of clinical specimens in situ. We generated transgenic mice as a model system to test the relationship between TIMP-1 levels in a host organ and susceptibility to experimentally targeted metastasis. Ectopically overexpressed TIMP-1 in the brain resulted in a tissue microenvironment with elevated protein levels of this natural MMP inhibitor. Metastatic challenge provided by lacZ-tagged fibrosarcoma cells permitted high-resolution analysis of metastatic load and pattern. We found that elevated host TIMP-1 imposed resistance to experimental metastasis of fibrosarcoma: In TIMP-1 overexpressing mice, brain metastases were significantly reduced by 75% compared to wild-type littermates. Our findings demonstrate that ectopic TIMP-1 expression efficiently exerts a suppressive effect on metastasizing tumor cells.

Animals↗