Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “brain microenvironment”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 343 records · Page 19Linked to original sources
PubMed2001

Identification of a candidate human neurohematopoietic stem-cell population.

It was recently reported that transplantation of clonally derived murine neurosphere cells into sublethally irradiated allogeneic hosts leads to a donor-derived hematopoietic reconstitution. The confirmation of the existence of a common neurohematopoietic stem cell in the human brain will have a significant effect on stem cell research and on clinical transplantation. Here, it is demonstrated that the human fetal brain contains separate but overlapping epidermal growth factor (EGF)-responsive and basic fibroblast growth factor (FGF-2)-responsive neural stem cells. The majority (> 85%) of cells within these EGF- and/or FGF-2-generated neurospheres express characteristic neural stem/progenitor cell markers including nestin, EGF receptor, and FGF-2 receptor. These neural stem cells can be continuously passaged in vitro, and demonstrate a constant 20-fold expansion in every passage for up to the fifth passage (the longest period that has been carried out in the authors' laboratory). These neural stem cells are multipotential for neurons, astrocytes, and oligodendrocytes. After transplantation into SCID-hu mice, all neural stem cells, regardless of passages, culture conditions, and donors, are able to establish long-term hematopoietic reconstitution in the presence of an intact human bone marrow microenvironment.

Abortion, Legal↗
PubMed2003

Is beta-amyloid fibrillogenesis a strict process of deposition inherently interactive in molecular terms?

Amyloid fibrillogenesis as a process of interactive molecular processes of deposition in Alzheimer's disease might function as a phenomenon that transforms intracellular amyloid segregation to a state of equilibration with extracellular deposition. beta-Amyloidosis might dynamically implicate loss of viability of vascular tunica media myofibers as a strict reflection of loss of viability of neurons in such an overall system of equilibration between intracellular and extracellular amyloid fibrillogenesis. In terms beyond simple concepts of strict biophysical equilibration, deposition of beta-amyloid in Alzheimer's disease might constitute a phenomenon of congophilic angiopathy as a strict pathobiologic index of activity of the Alzheimer process; such a correlate would perhaps involve a quantitative index that would qualitatively characterize the Alzheimer process as an interactive series of reactions between the intracellular and extracellular microenvironment.

Alzheimer Disease↗
PubMed2005

Combined inhibition of vascular endothelial growth factor and platelet-derived growth factor signaling: effects on the angiogenesis, microcirculation, and growth of orthotopic malignant gliomas.

OBJECT: The goal of this study was to determine the effects of SU6668, a polyvalent receptor tyrosine kinase inhibitor against vascular endothelial growth factor receptor-2, platelet-derived growth factor receptor-beta, and fibroblast growth factor-1 on tumor growth, angiogenesis, and microcirculation in an orthotopic malignant glioma model. METHODS: Fluorescently labeled C6 malignant glioma cells were implanted into a long-term cranial window, which had been prepared in nude mice. The animals were treated with intraperitoneal injections of SU6668 (75 mg/kg/day) immediately (five animals) or 7 days (five animals) following tumor implantation. Control mice received intraperitoneal injections of vehicle (50 microl dimethylsulfoxide) immediately (five animals) or 7 days (four animals) after tumor implantation. Tumor growth, angiogenesis, and microcirculation were assessed by performing intravital fluorescence videomicroscopy over a 14-day observation period. To assess the effects of SU6668 on overall survival, C6 glioma cells were implanted stereotactically into the brains of 24 additional animals and treatment was initiated on Day 7. In both the immediate and delayed experimental setting, SU6668 treatment resulted in a significant reduction of total and functional tumor vessel densities (both p < 0.05), reflecting a suppression of angiogenesis and impairment of tumor perfusion. As a consequence, tumor growth was significantly inhibited (p < 0.05). Histological analysis demonstrated reduced tumor growth and less mass effect on the adjacent brain of treated animals. The survival experiments confirmed the importance of our results in that survival was significantly prolonged following SU6668 therapy (p < 0.05). CONCLUSIONS: Targeting of multiple angiogenic signaling pathways by polyvalent tyrosine kinase inhibitors represents a promising strategy to interfere with the vascularization, microcirculation, and growth of angiogenesis-dependent tumors. This also applies to malignant gliomas, despite the uniqueness of the cerebral microenvironment and the singular pathobiology of this tumor entity.

Animals↗
PubMed1986

Distant blood-brain barrier opening in subfields of the rat hippocampus after intrastriatal injections of kainic acid but not ibotenic acid.

Blood-brain barrier (BBB) permeability towards proteins was determined in rats 4 h after intrastriatal kainic or ibotenic acid application, using Evans blue as indicator. Whereas, with the exception of the unspecific damage in cortex, after ibotenic acid BBB remained intact in deep brain areas. Evans blue leakage was found ipsilateral to the kainic acid injection, occasionally in striatum, thalamus and amygdala and regularly in hippocampus. There it was confined to the fimbria and the CA3 field. Only rarely a mirror focus-like staining was present in the contralateral hippocampus. The ultrastructural investigation revealed that BBB opening in CA3 is due to increased transendothelial pinocytosis; the tight junctions were intact. Thus, changes in the microenvironment around vessels, elicited by kainic acid and/or seizures, might be responsible for BBB opening.

Animals↗
PubMed1998

Coexpression of erythropoietin and vascular endothelial growth factor in nervous system tumors associated with von Hippel-Lindau tumor suppressor gene loss of function.

Hemangioblastomas are highly vascular tumors of the central nervous system that overexpress the hypoxia-inducible gene, vascular endothelial growth factor (VEGF), as a consequence of mutational inactivation of the von Hippel-Lindau tumor suppressor gene (VHL). Previous reports showed that hemangioblastomas can also express erythropoietin (Epo), which is also hypoxia-inducible. However, Epo expression in hemangioblastomas was observed only in individual cases, and the analyses were mainly based on indirect determination of erythropoiesis-stimulating activity. Therefore, we analyzed a series of 11 hemangioblastomas for Epo, VEGF, and VHL expression by Northern blot analysis and compared the results with normal brain and glioblastomas. Surprisingly, we observed Epo mRNA expression in all hemangioblastoma specimens analyzed, but in none of four glioblastomas. In contrast, VEGF mRNA was expressed in all hemangioblastomas and all glioblastomas. In situ hybridization revealed neoplastic stromal cells as Epo- and VEGF-producing cells in hemangioblastomas. These results suggest that in the nonhypoxic microenvironment of hemangioblastoma, Epo, similar to VEGF, might be negatively regulated by the VHL gene product.

Adult↗
PubMed1999

Transcriptional expression of tissue factor pathway inhibitor, thrombomodulin and von Willebrand factor in normal human tissues.

Under normal physiologic conditions, tissue factor pathway inhibitor (TFPI) is synthesized primarily by the microvascular endothelium. Using Northern blotting, we studied its transcriptional expression in different organs and compared it with the expression of two other endothelial specific proteins, namely thrombomodulin (TM) and von Willebrand factor (vWF). The order of mRNA expression for each protein was: TFPI-placenta>lung>liver>kidney>heart>skeletal muscle> or =pancreas>brain; TM-heart>pancreas>lung>skeletal muscle>kidney> or =liver>placenta>brain; and vWF-heart>skeletal muscle>pancreas>lung> or =kidney>placenta>brain>liver. Notably, heart expressed TM and vWF mRNA in large amounts and only small amounts of TFPI whereas lung expressed all three mRNAs in significant amounts. Placenta, on the contrary, expressed large amounts of TFPI but only small amounts of TM and vWF mRNAs. Brain by this technique was found to express undetectable amounts of TFPI and TM mRNAs but small amounts of vWF mRNA. The expression of TFPI mRNA in the brain was however detected by RT/PCR and the antigen was localized to the endothelium of microvessels as well as to the astrocytes and oligodendrocytes. Since ultimate expression of proteins is linked to the expression of their mRNAs, our data support a concept that vascular endothelium is made up of phenotypically diverse groups of cells and that endothelial cells of different vascular beds express specific sets of genes that enable them to carry out tissue-specific functions. Importantly, since astrocytes are known to express tissue factor, the TFPI expression by these cells may control coagulation in their microenvironment and their response to injury and inflammation.

Brain↗
PubMed1989

Activation of a flavoprotein by proteolysis.

Chymotryptic digestion of brain pyridoxine-5-P oxidase brings about a 4-fold enhancement of the catalytic power (Vmax/KM) using pyridoxine-5-P as substrate in the assay mixtures. The chymotrypsin-treated enzyme is less susceptible to inhibition by pyridoxal-5-P than the native enzyme. Fragments arising from limited proteolysis were separated by affinity chromatography using P-pyridoxal-Sepharose as supporting matrix. Catalytically active fractions, eluted by pyridoxine-5-P (5mM), displayed three bands when analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The molecular masses of the three protein bands are considerably lower than 28 kDa, the molecular mass of monomeric pyridoxine-5-P oxidase. Spectroscopic studies, absorption, fluorescence, and circular dichroism revealed that the microenvironment surrounding the cofactor flavin mononucleotide is not perturbed by limited proteolysis.

Animals↗
PubMed2003

Fetal human hematopoietic stem cells can differentiate sequentially into neural stem cells and then astrocytes in vitro.

In some rodent models, there is evidence that hematopoietic stem cells (HSC) can differentiate into neural cells. However, it is not known whether humans share this potential, and, if so, what conditions are sufficient for this transdifferentiation to occur. We addressed this question by assessing the ability of fetal human liver CD34(+)/CD133(+)/CD3(-) hematopoietic stem cells to generate neural cells and astrocytes in culture. We cultured fetal liver-derived hematopoietic stem cells in human astrocyte culture-conditioned medium or using a method wherein growing human astrocytes were separated from cultured, nonadherent hematopoietic stem cells by a semipermeable membrane in a double-chamber co-culture system. Hematopoietic stem cell cultures were probed for neural progenitor cell marker expression (nestin and bone morphogenic protein-2 [BMP-2]) during growth in both culture conditions. RT-PCR, western blotting, and immunocytochemistry assays showed that cells cultured in either condition expressed nestin mRNA and protein and BMP-2 mRNA. HSC similarly cultured in nonconditioned medium or in the absence of astrocytes did not express either marker. Cells expressing these neural markers were transferred and cultured on poly-D-lysine-coated dishes with nonconditioned growth medium for further study. Immunocytochemistry demonstrated that these cells differentiated into astrocytes after 8 days in culture as indicated by their morphology and expression of the astrocytic markers glial fibrillary acidic protein (GFAP) and S100, as well as by their rate of proliferation, which was identical to that of freshly isolated fetal brain astrocytes. These findings demonstrate that neural precursor gene expression can be induced when human hematopoietic stem cells are exposed to a suitable microenvironment. Furthermore, the neural stem cells generated in this environment can then differentiate into astrocytes. Therefore, human hematopoietic stem cells may be an alternative resource for generation of neural stem cells for therapy of central nervous system defects resulting from disease or trauma.

AC133 Antigen↗
PubMed2006

The aging neurogenic subventricular zone.

In the adult mouse brain, the subventricular zone (SVZ) is a neurogenic stem cell niche only 4-5 cell diameters thick. Within this narrow zone, a unique microenvironment supports stem cell self-renewal, gliogenesis or neurogenesis lineage decisions and tangential migration of newly generated neurons out of the SVZ and into the olfactory bulb. However, with aging, SVZ neurogenesis declines. Here, we examine the dynamic interplay between SVZ cytoarchitecture and neurogenesis through aging. Assembly of high-resolution electron microscopy images of corresponding coronal sections from 2-, 10- and 22-month-old mice into photomontages reveal a thinning of the SVZ with age. Following a 2-h BrdU pulse, we detect a significant decrease in cell proliferation from 2 to 22 months. Neuroblast numbers decrease with age, as do transitory amplifying progenitor cells, while both SVZ astrocytes and adjacent ependymal cells remain relatively constant. At 22 months, only residual pockets of neurogenesis remain and neuroblasts become restricted to the anterior dorsolateral horn of the SVZ. Within this dorsolateral zone many key components of the younger neurogenic niche are maintained; however, in the aged SVZ, increased numbers of SVZ astrocytes are found interposed within the ependyma. These astrocytes co-label with markers to ependymal cells and astrocytes, form intercellular adherens junctions with neighboring ependymal cells, and some possess multiple basal bodies of cilia within their cytoplasm. Together, these data reveal an age-related, progressive restriction of SVZ neurogenesis to the dorsolateral aspect of the lateral ventricle with increased numbers of SVZ astrocytes interpolated within the ependyma.

Aging↗
PubMed2002

Emerging patterns in tumor systems: simulating the dynamics of multicellular clusters with an agent-based spatial agglomeration model.

Brain cancer cells invade early on surrounding parenchyma, which makes it impossible to surgically remove all tumor cells and thus significantly worsens the prognosis of the patient. Specific structural elements such as multicellular clusters have been seen in experimental settings to emerge within the invasive cell system and are believed to express the systems' guidance toward nutritive sites in a heterogeneous environment. Based on these observations, we developed a novel agent-based model of spatio-temporal search and agglomeration to investigate the dynamics of cell motility and aggregation with the assumption that tumors behave as complex dynamic self-organizing biosystems. In this model, virtual cells migrate because they are attracted by higher nutrient concentrations and to avoid overpopulated areas with high levels of toxic metabolites. A specific feature of our model is the capability of cells to search both globally and locally. This concept is applied to simulate cell-surface receptor-mediated information processing of tumor cells such that a cell searching for a more growth-permissive place "learns" the information content of a brain tissue region within a two-dimensional lattice in two stages, processing first the global and then the local input. In both stages, differences in microenvironment characteristics define distinctions in energy expenditure for a moving cell and thus influence cell migration, proliferation, agglomeration, and cell death. Numerical results of our model show a phase transition leading to the emergence of two distinct spatio-temporal patterns depending on the dominant search mechanism. If global search is dominant, the result is a small number of large clusters exhibiting rapid spatial expansion but shorter lifetime of the tumor system. By contrast, if local search is dominant, the trade-off is many small clusters with longer lifetime but much slower velocity of expansion. Furthermore, in the case of such dominant local search, the model reveals an expansive advantage for tumor cell populations with a lower nutrient-depletion rate. Important implications of these results for cancer research are discussed.

Algorithms↗
PubMed1982

Relative halothane accumulation in brain subcellular membranes in vitro.

The accumulation of halothane in brain homogenates was compared with halothane accumulation in brain during inhalation at anesthetic and subanesthetic levels. Anesthesia is achieved at a tissue concentration well below the halothane solubility in brain tissue. Analysis of halothane in the particulate solids of brain homogenate and in purified subcellular membranes indicates that a membrane constituent (presumably the lipids) acts as an ideal solvent in which halothane is fully miscible. Therefore, membranes offer a local microenvironment in which halothane accumulation deviates from Henry's law. Specifically, we observe that even slight increases of halothane in a saline medium result in a relatively large increase in the concentration of halothane in subcellular membranes suspended in the medium, eventually leading to solvation of the membrane in halothane. This observation offers a ready explanation for the high degree of positive correlation between MAC and lipid solubility and the small difference between anesthetic and lethal concentrations of halothane during inhalation. The rate of halothane increase in myelin exceeded the rate in other brain subcellular membranes, indicating that a major site of halothane localization is within this subcellular membrane.

Animals↗
PubMed2002

Dynamic contrast-enhanced magnetic resonance imaging as a surrogate marker of tumor response to anti-angiogenic therapy in a xenograft model of glioblastoma multiforme.

PURPOSE: To evaluate the effects of a neutralizing anti-vascular endothelial growth factor (anti-VEGF) antibody on tumor microvascular permeability, a proposed indicator of angiogenesis, and tumor growth in a rodent malignant glioma model. MATERIALS AND METHODS: A dynamic contrast-enhanced magnetic resonance imaging (MRI) technique, permitting noninvasive in vivo and in situ assessment of potential therapeutic effects, was used to measure tumor microvascular characteristics and volumes. U-87, a cell line derived from a human glioblastoma multiforme, was implanted orthotopically into brains of athymic homozygous nude rats. RESULTS: Treatment with the monoclonal antibody A4.6.1, specific for VEGF, significantly inhibited tumor microvascular permeability (6.1 +/- 3.6 mL min(-1)100 cc(-1)), compared to the control, saline-treated tumors (28.6 +/- 8.6 mL min(-1)100 cc(-1)), and significantly suppressed tumor growth (P <.05). CONCLUSION: Findings demonstrate that tumor vascular permeability and tumor growth can be inhibited by neutralization of endogenous VEGF and suggest that angiogenesis with the maintenance of endothelial hyperpermeability requires the presence of VEGF within the tissue microenvironment. Changes in tumor vessel permeability and tumor volumes as measured by contrast-enhanced MRI provide an assay that could prove useful for clinical monitoring of anti-angiogenic therapies in brain tumors.

Animals↗
PubMed1987

Blood-brain barrier permeability to horseradish peroxidase in twitcher and cuprizone-intoxicated mice.

The status of blood-brain barrier (BBB) permeability was investigated in the twitcher, an authentic murine model of globoid cell leukodystrophy (GLD, Krabbe disease) and cuprizone-intoxicated mice. Although extensive demyelination was noted in the CNS of both mice and additionally, macrophage infiltration was pronounced in the twitcher, BBB remained intact to horseradish peroxidase. Thus, the change of microenvironment caused by demyelination is not necessarily a responsible factor for increased BBB permeability in the inflammatory demyelinating conditions.

Animals↗
PubMed1987

Effects of ethanol on the activity of brain enzymes.

Ethanol alters, in a selective manner, the activity of several membrane-bound enzymes in the central nervous system (CNS) which are important for neuronal transmission of information. Ethanol inhibits Na+/K+-transporting ATPase activity, while adenylate cyclase (AC) activity is stimulated by ethanol added in vitro. Ethanol's effects on AC activity are mediated primarily via effects on proteins that regulate AC activity. Ethanol has selective effects on monoamine oxidase activity, in that the B form of the enzyme is more sensitive to inhibition by ethanol added in vitro. The selective effects of ethanol on different membrane-bound CNS enzymes may result from differing membrane lipid microenvironments of the enzymes, or from differences in the enzyme proteins per se.

Adenylyl Cyclases↗
PubMed2005

Stem cells: from epigenetics to microRNAs.

The complexity and cellular diversity of the adult brain arises from the proliferation and differentiation of a small number of stem cells. The intrinsic state of stem cells depends on their spatial and temporal history and affects their responsiveness to extrinsic signals from the microenvironment. Stem cell self-renewal and differentiation along neuronal and glial lineages are defined by the dynamic interplay between transcription, epigenetic control, and posttranscriptional regulators, including microRNAs, whose key role in stem cell biology is just emerging.

Animals↗
PubMed2005

Neurogenesis in the adult ischemic brain: generation, migration, survival, and restorative therapy.

This article reviews current data on the induction of neurogenesis after stroke in the adult brain. The discussion of neurogenesis is divided into production, migration, and survival of these newly formed cells. For production, the subpopulations and the types of cell division are presented. Discussion of cell migration entails presenting data on both the pathways as well as the molecular targeting of newly formed neural progenitor cells to sites of injury. The role of the vascular and the astrocytic microenvironment in promoting the survival and integration of progenitor cells is also presented. Cell-based and pharmacological therapies designed to restore neurological function that promote neurogenesis are described. These therapies also induce angiogenesis and astrocytic changes that brain tissue, which prime the ischemic brain to foster the survival of the newly formed progenitor cells. Signaling pathways that regulate neurogenesis and angiogenesis are also addressed. This review summarizes recent data on neurogenesis and provides insight into the potential for restorative treatments of stroke.

Animals↗
PubMed1990

Modulation of respiration during brain hypoxia.

This review is a summary of the effects of brain hypoxia on respiration with a particular emphasis on those studies relevant to understanding the cellular basis of these effects. Special attention is given to mechanisms that may be responsible for the respiratory depression that appears to be the primary sequela of brain hypoxia in animal models. Although a variety of potential mechanisms for hypoxic respiratory depression are considered, emphasis is placed on changes in the neuromodulator constituency of the respiratory neuron microenvironment during hypoxia as the primary cause of this phenomenon. Hypoxia is accompanied by a net increase in neuronal inhibition due to both decreased excitatory and increased inhibitory neuromodulator levels. A survey of hypoxia-tolerant cellular systems and organisms suggests that hypoxic respiratory depression may be a manifestation of the depression of cellular metabolism, which appears to be a major adaptation to limited oxygen availability in these systems.

Animals↗