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PubMed1977

Fever and behavioural temperature regulation in the frog Rana esculenta.

The skin and colonic temperatures were recorded in frogs (Rana esculenta) which had selected a suitable microenvironment in a box filled with 2-3 cm water. The water temperatures ranged from 0 degrees C to + 40 degrees C. Such measurements were performed before and after intraperitoneal injections of killed pathogenic bacteria (M. xenopi and M. range), killed non-pathogenic bacteria (M. aquae II) and 0.9% sterile saline, intraperitoneal injections of blood plasma from frogs pre-injected with killed M. ranae, injections of PGE1 into the brain. The injections of pathogenic bacterial endotoxin caused, after latencies of 5-120 min, higher preferred water temperatures, which produced an average maximum colonic temperature increase of 6.5 degrees C +/- 1.0 degrees C (S.E.) (p less than 0.001). The non-pathogenic bacteria and sterile saline caused no temperature change. Monophasic hyperthermia of shorter latency was caused by injections of blood plasma from frog preinjected with M. ranae. Monophasic hyperthermia of the shortest latency was observed after diencephalic injections of PGE1. Based on their similarity we suggest that ectothermic and endothermic fever have a common phylogenetic origin.

Animals↗
PubMed1994

Morphology of horseradish peroxidase (HRP)-injected glial cells in the myenteric plexus of the guinea-pig.

Glial cells of the myenteric plexus from guinea pig small intestine were intracellularly filled with horseradish peroxidase (HRP), and histochemically stained. Camera lucida-like drawings of twenty cells were morphologically and morphometrically analyzed. The cells have very small ellipsoid somata (8.5 +/- 0.7 microns equivalent diameter, i.e., about 330 micron3 volume), and send up to 20 thin and short processes (less than 26 to about 110 microns in length). The morphology of the cells appears to depend on their location within the plexus. Glial cells located within the ganglia are similar to CNS protoplasmic astrocytes; they are star-shaped, and their very short processes are irregularly branched. In contrast, glial cells within the interganglionic fiber tracts resemble CNS fibrous astrocytes. They extend longer processes that are parallel to the fiber tracts, and show less tendency to branch. We propose that the morphology of enteric glia is determined by the structure of the microenvironment. Both cell types form several flat endfeet at a basal lamina either surrounding blood vessels or at the ganglionic border. Furthermore, the occurrence of "holes" in the glial cell processes suggests that particular neuronal cell processes may be enwrapped in a specific manner. Fractal analysis of camera lucida-like drawings of the cells showed that the cells have a highly complex surface structure, comparable to that of protoplasmic astrocytes in the brain. These tiny cells may possess a membrane surface area of approximately 2000 micron2, almost 90% of which are contributed by the cell processes.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2002

Irradiation induces neural precursor-cell dysfunction.

In both pediatric and adult patients, cranial radiation therapy causes a debilitating cognitive decline that is poorly understood and currently untreatable. This decline is characterized by hippocampal dysfunction, and seems to involve a radiation-induced decrease in postnatal hippocampal neurogenesis. Here we show that the deficit in neurogenesis reflects alterations in the microenvironment that regulates progenitor-cell fate, as well as a defect in the proliferative capacity of the neural progenitor-cell population. Not only is hippocampal neurogenesis ablated, but the remaining neural precursors adopt glial fates and transplants of non-irradiated neural precursor cells fail to differentiate into neurons in the irradiated hippocampus. The inhibition of neurogenesis is accompanied by marked alterations in the neurogenic microenvironment, including disruption of the microvascular angiogenesis associated with adult neurogenesis and a marked increase in the number and activation status of microglia within the neurogenic zone. These findings provide clear targets for future therapeutic interventions.

Animals↗
PubMed1996

Release of collagen type IV degrading activity from C6 astrocytoma cells and cell density.

Type IV collagen is a major protein component of the vascular basement membrane and its degradation is crucial to the initiation of tumor-associated angiogenesis. The authors have investigated the influence of cell density on the release of collagen type IV degrading activity by C6 astrocytoma cells in monolayer culture. The release of collagen type IV degrading activity was assessed biochemically, immunocytochemically, and by Western blot analysis. The results demonstrate that increasing plating density and increasing cell density are associated with decreased collagen type IV degrading activity released per tumor cell. These findings indicate the existence of regulatory mechanisms dependent on cell-cell communication, which modulate release of collagen type IV degrading activity. The extrapolation of these results to the in vivo tumor microenvironment would suggest that individual and/or small groups of invading tumor cells, distant from the main tumor mass, would release substantial collagen type IV degrading activity, which may be crucial to their continued invasion and to angiogenesis.

Animals↗
PubMed2005

Functional measurement of local proteolytic activity in living cells of invasive and non-invasive tumors.

Proteolytic cleavage of extracellular matrix (ECM) and disruption of tissue architecture are fundamental features of tumor cell invasion. The proteolytic activity is focused in close proximity to the tumor cells. Here, we describe the possibility to quantify local proteolytic activity in the microenvironment of larger cell populations by the electrical resistance breakdown assay. The assay utilizes the transepithelial electrical resistance (TEER) of an epithelial monolayer as a sensitive indicator of monolayer integrity and permeability. Local destruction of ECM by single tumor cells was demonstrated by a second assay, based on a fluorescent matrix coating on cover slides. Local digestion of the matrix results in a reduction of fluorescence. Primary cells derived from high and low grade brain tumors as well as established cell lines of malignant gliomas and non-neural tumors of different origin (melanoma, cervical carcinoma, and breast carcinoma) were compared. Differences in proteolytic activity between tumor entities were demonstrated in both assays. Primary cells of high grade gliomas and cell lines showed TEER breakdown and local matrix destruction, while low grade brain tumors lacked matrix disintegration and disruption of cell monolayers. Taken together, both assays are capable of demonstrating local proteolytic activity and thus are versatile tools for distinguishing high and low invasive tumor cells with a potential application as diagnostic and prognostic markers in clinical investigations. The advantage of the matrix digestion assay is the requirement of only very low tumor cell numbers, whereas measurement of TEER enables precise quantification of local proteolytic processes in large and even heterogeneous tumor cultures.

Animals↗
PubMed1997

Aromatase cytochrome P450 transcripts are detected in fractured human bone but not in normal skeletal tissue.

Peripheral conversion of gender steroid precursors has been implicated in playing a role in bone turnover in postmenopausal women. It has been reported that aromatase cytochrome P450 (P450arom) is present in primary bone and bone marrow (BM), and that P450arom mRNA has been identified in cultured BM and osteoblast-like cell lines. However, there are no reports that P450arom transcripts have been detected in skeletal tissue that has not been cultured. We therefore elected to test for the presence of P450arom mRNA in primary human bone and BM in normal and fractured necks of femora using the reverse transcription-polymerase chain reaction method. Although the RNA extracted from these tissues was of good quality as demonstrated by the expression of transcripts for interleukin-6, P450arom transcripts failed to be detected in normal primary cortical bone and fatty BM containing trabecular bone. However, P450arom transcripts were detected in the latter when they were cultured. Transcripts for P450arom were also detected in total RNA extracted from six fractured necks of femora and semiquantitative PCR demonstrated that P450arom mRNA was present in similar abundance in the same amount of RNA analyzed from buttock adipose tissue and fractured bone/BM. P450arom mRNA expression was also detected in cultured peripheral blood leukocytes, suggesting that this might be the source of the enzyme. In these cultures no correlation was detected between the expression of P450arom mRNA and cell proliferation. PCR failure was excluded in cases when P450arom transcripts failed to be detected in bone/BM by coamplifying RNA from human and rat brain mRNA, known to express P450arom mRNA, using primers that detect both P450arom mRNA from both species. These products were analyzed by Southern blot using oligonucleotide probes, which label either human or rat P450arom cDNA. The blots confirmed the absence of P450arom in nonfractured human bone and BM and preclude PCR failure. Our results indicate that P450arom mRNA is not detected in either normal human bone or BM, but can be induced in this microenvironment under pathological conditions. We propose that tissue grown in vitro is analogous to a wound and this explains why P450arom transcripts were detected in cultured normal skeletal tissue, whereas they failed to be detected in primary normal bone and BM.

Animals↗
PubMed2005

Differentiation of human adult CD34+ stem cells into cells with a neural phenotype: role of astrocytes.

It has recently been reported that adult hematopoietic stem cells can differentiate into neural cells, opening new frontiers in therapy for neurodegenerative diseases. In this study, adult human hematopoietic stem cells (HSCs) were isolated via magnetic bead sorting, using a specific CD34 antibody and cultured with human astrocyte culture conditioned medium (ACM). In order to evaluate their differentiation into neurons and/or astrocytes, ACM-treated cultures were probed for the expression of several neural markers. We observed morphological modifications and, after 20 days of treatment, cell morphology displayed extending processes. Immunocytochemistry, Western blotting and RT-PCR showed the expression of neuronal markers such as neurofilaments, neuron specific enolase (NSE) and NeuN in ACM-treated HSCs cultured in poly-L-lysine-coated dishes. On the contrary, when the same ACM-treated cells were grown on a plastic substrate, they expressed high levels of glial fibrillary acidic protein (GFAP), with only weak expression of neuronal markers. Nestin, a neural progenitor cell marker, was present in treated cells, regardless of the substrate. These results demonstrate that astrocytes can generate a suitable microenvironment for inducing HSCs to differentiate into neural cells. Therefore, adult bone marrow may represent a readily accessible source of cells for treating neurodegenerative diseases.

Antigens, CD34↗
PubMed2004

Cancer therapy with a replicating oncolytic adenovirus targeting the hypoxic microenvironment of tumors.

Hypoxia plays a critical role in driving tumor malignancy and is associated with poor patient survival in many human cancers. Novel therapies targeting hypoxic tumor cells are urgently needed, because these cells hinder tumor eradication. Here we demonstrate than an anticancer strategy based on intratumoral delivery of a novel type of oncolytic adenovirus targeting tumor hypoxia is therapeutically efficient and can augment standard chemotherapy. We used a conditionally replicative adenovirus (HYPR-Ad) to specifically kill hypoxic tumor cells. Viral infection and conditional replication occurred efficiently in hypoxic/hypoxia-inducible factor-active cells in culture and in vivo, prevented tumor formation, and reduced the growth of established tumors. Combining HYPR-Ad with chemotherapy effective against normoxic cells resulted in strongly enhanced antitumor efficacy. These studies demonstrate that targeting the hypoxic microenvironment of tumors rather than an intrinsic gene expression defect is a viable and novel antitumor therapeutic strategy that can be used in combination with existing treatment regimens. The replication and oncolytic potential of this virus was made dependent on hypoxic/hypoxia-inducible factor, a transcription factor activated in the tumor hypoxic microenvironment, broadening its therapeutic use to solid tumors of any genetic make-up or tissue of origin.

Adenoviridae↗
PubMed1995

Relational features of acetylcholine, noradrenaline, serotonin and GABA axon terminals in the stratum radiatum of adult rat hippocampus (CA1).

In a well-defined sector of adult rat hippocampus (CA1, stratum radiatum), the ultrastructural features of acetylcholine (ACh), noradrenaline (NA), serotonin (5-HT) and GABA axon terminals (varicosities) were compared by electron microscopy after immunostaining with antibodies against choline acetyltransferase, NA, 5-HT and glutamic acid decarboxylase. Approximately 100 sectional profiles of each type were analyzed for size, presence of a synaptic membrane specialization (synaptic incidence) and composition of the microenvironment. An equivalent number of immunonegative varicosity profiles selected at random from the same micrographs were similarly examined. ACh, NA and 5-HT varicosity profiles were of comparable size, and significantly smaller than GABA profiles. They exhibited a low frequency of junctional specialization, amounting to 7%, 15% and 21%, respectively, when extrapolated to the whole volume of these terminals. In contrast, GABA varicosities appeared entirely synaptic. The ACh, NA and 5-HT varicosities also differed from their GABA counterparts in being juxtaposed to a greater number of unlabeled axonal varicosities and a lower number of dendritic branches. In addition, the microenvironment of immunostained terminals showed a much lower number of dendritic spines than that of immunonegative varicosities. This latter finding was viewed as another indication that predominantly asynaptic varicosities do not maintain particular relationships with their immediate surround. It was also concluded that volume transmission represents a major mode of transmission for ACh, NA and 5-HT in adult rat hippocampus, thus contributing to the properties and functions assigned to these transmitters in this part of brain.

Acetylcholine↗
PubMed2000

The immunological microenvironment in the CNS: implications on neuronal cell death and survival.

Microenvironmental factors have a profound influence on resident cell populations and their ability to modulate an immune response. The unique central nervous system (CNS) microenvironment has important effects in this regard, resulting in the establishment of immune privilege. The immune response in the CNS is under tight control of bipolar regulatory mechanisms. Neurons have a suppressive potential, which prevents and limits the formation of inflammatory responses. In contrast, activated lymphocytes, which can invade the CNS, deposit potentially pro-inflammatory mediators. The balance between pro- and anti-inflammatory factors determines localization, intensity and course of immune responses in the brain. Thus, an overwhelming invasion of activated lymphocytes, which may have emerged from a recent anti-microbial immune response, may create inflammation in intact parts of the CNS. In contrast, in compromised brain areas, much weaker proinflammatory forces are required to create the same effect. Thus, in degenerative brain lesions, inflammatory infiltrates may be formed easily. Immune cell invasion and expression of immune effector molecules in degenerative CNS disease could exert a variety of actions on the neurons. In the first instance, activation of the local immune response could be harmful to resident brain cells, possibly resulting in neuronal cell death. Alternatively, immune cell-derived mediators could protect and support the regeneration of damaged neurons. Recently, it has been realized that normal inflammatory cells (lymphocytes and macrophages) produce neurotrophic factors. In addition, pro-inflammatory cytokines released by invading immune cells may have a role in neuroprotection. Infiltration of degenerative brain areas by inflammatory cells could thus reflect a beneficial process encouraging neuronal survival and local cell regeneration.

Animals↗
PubMed2006

Molecular characterization of retinal stem cells and their niches in adult zebrafish.

BACKGROUND: The persistence in adult teleost fish of retinal stem cells that exhibit all of the features of true 'adult stem cells'--self-renewal, multipotency, and the capacity to respond to injury by mitotic activation with the ability to regenerate differentiated tissues--has been known for several decades. However, the specialized cellular and molecular characteristics of these adult retinal stem cells and the microenvironmental niches that support their maintenance in the differentiated retina and regulate their activity during growth and regeneration have not yet been elucidated. RESULTS: Our data show that the zebrafish retina has two kinds of specialized niches that sustain retinal stem cells: 1) a neuroepithelial germinal zone at the interface between neural retina and ciliary epithelium, called the ciliary marginal zone (CMZ), a continuous annulus around the retinal circumference, and 2) the microenvironment around some Müller glia in the differentiated retina. In the uninjured retina, scattered Müller glia (more frequently those in peripheral retina) are associated with clusters of proliferating retinal progenitors that are restricted to the rod photoreceptor lineage, but following injury, the Müller-associated retinal progenitors can function as multipotent retinal stem cells to regenerate other types of retinal neurons. The CMZ has several features in common with the neurogenic niches in the adult mammalian brain, including access to the apical epithelial surface and a close association with blood vessels. Müller glia in the teleost retina have a complex response to local injury that includes some features of reactive gliosis (up-regulation of glial fibrillary acidic protein, GFAP, and re-entry into the cell cycle) together with dedifferentiation and re-acquisition of phenotypic and molecular characteristics of multipotent retinal progenitors in the CMZ (diffuse distribution of N-cadherin, activation of Notch-Delta signaling, and expression of rx1, vsx2/Chx10, and pax6a) along with characteristics associated with radial glia (expression of brain lipid binding protein, BLBP). We also describe a novel specific marker for Müller glia, apoE. CONCLUSION: The stem cell niches that support multi-lineage retinal progenitors in the intact, growing and regenerating teleost retina have properties characteristic of neuroepithelia and neurogenic radial glia. The regenerative capacity of the adult zebrafish retina with its ability to replace lost retinal neurons provides an opportunity to discover the molecular regulators that lead to functional repair of damaged neural tissue.

Aging↗
PubMed2003

Glia maturation factor produced by thymic epithelial cells plays a role in T cell differentiation in the thymic microenvironment.

In order to determine molecules on thymic epithelial cells which play an important role in the process of T cell differentiation, mAb recognizing thymic epithelial cells were made using stromal cells of the embryonic thymus at 15-gestation date. Among many mAb, a specific one was selected in terms of its inhibition of T cell development in an in vitro culture system of the embryonic thymus. cDNA of the protein recognized by one of the mAb was obtained by a panning method. Sequence analysis revealed that the protein was identical to glia maturation factor (GMF)-beta. Northern blot analysis confirmed the expression of GMF-beta mRNA in the thymus and brain. Furthermore, immunoblotting analysis identified the production of GMF-beta protein in the thymus, the brain and a thymic epithelial cell line. GMF-beta protein prepared by a glutathione-S-transferase gene fusion system greatly influenced T cell development in the in vitro culture system of the embryonic thymus in favor of a significant increase of CD4(+) T cells with expression of TCRbeta. These data taken together suggest that GMF-beta protein is produced by thymic epithelial cells and plays a role in T cell development in favor of CD4(+) T cells.

Amino Acid Sequence↗
PubMed2006

Interactions of chromogranin A-derived vasostatins and monolayers of phosphatidylserine, phosphatidylcholine and phosphatidylethanolamine.

Vasostatin-I (CgA1-76) is a naturally occurring and biologically active N-terminal peptide derived from chromogranin A (CgA), produced and secreted at high concentrations by neuroendocrine tissues and also from a range of neuroendocrine tumors. This study aims to examine the hypothesis that in the absence of classical protein receptors CgA1-76 may, like its two derived peptides CgA1-40 and CgA47-66, perturb the lipid microenvironment of other membrane receptors, as a basis for the largely inhibitory activities of these CgA peptides. The nature of the interactions between phospholipids and vasostatin-derived fragments was studied in the Langmuir film balance apparatus at 37 degrees C. The synthetic peptides CgA1-40 and CgA47-66 and a recombinant fragment (VS-I) containing vasostatin-I (Ser-Thr-Ala-CgA1-78) were compared for their effects on monolayers of phosphatidylcholine and phosphatidylethanolamine from pig brain and defined species of phosphatidylserine. Marked differences in surface pressure-area isotherms and phase-transition plateaus were apparent with the three classes of phospholipids on VS-I, CgA1-40 and CgA47-66 in physiological buffer or pure water. The results indicate that VS-I and CgA47-66 at 5-10 nM concentrations may engage in electrostatic as well as hydrophobic interactions with membrane-relevant phospholipids at physiological conditions, VS-I in particular enhancing the fluidity of saturated species of phosphatidylserine.

Animals↗
PubMed1997

Function of metal-ion homeostasis in the cell division cycle, mitochondrial protein processing, sensitivity to mycobacterial infection and brain function.

A novel Saccharomyces cerevisiae mutant, unable to grow in the presence of 12.5 mmol l-1 EGTA, was isolated. The phenotype of the mutant is caused by a single amino acid change (Gly149 to Arg) in the essential yeast cell division cycle gene CDC1. The mutant could be suppressed by overexpression of the SMF1 gene, which codes for a plasma membrane Mn2+ transporter. We observed that the yeast SMF1 gene shares homology with the mouse Nramp gene. Nramp (Bcg) was cloned as a gene responsible for mouse resistance to infection with mycobacteria and is identical with the Ity and the Lsh genes conferring resistance to infection by Salmonella typhimurium and Leishmania donovani, respectively. Although the cloning of Nramp identified the gene responsible for the resistance of mice to mycobacteria, its function is unknown. We propose that the mammalian protein, like the yeast transporter, is a Mn2+ and/or Zn2+ transporter. Following the phagocytosis of a parasite into the phagosome, the macrophage produces reactive oxygen and/or nitrogen intermediates that are toxic for the internalized bacteria. The survival of the pathogen during the burst of macrophage respiratory activity is thought to be partly mediated by microbial superoxide dismutase (SOD), which contains Mn2+ or Fe2+ in its active centre. Nramp may transport Mn2+ from the extracellular milieu into the cytoplasm of a macrophage and, after the generation of the phagosome, remove Mn2+ from the organelle. Thus, the Mn(2+)-depletion of the phagosome microenvironment by the Nramp gene product may be a rate-limiting step in the metalloenzyme's production by the engulfed bacteria. This limitation will restrict the mycobacterial ability to produce active enzymes such as SOD and prevent the propagation of the ingested microorganisms. Conversely, an increased concentration of Mn2+ in the phagosome caused by a defective Nramp transporter (Bcgs) may promote the growth of the mycobacteria and render the organism sensitive to the pathogen. We use a similar approach to identify, clone and study other metal-ion transporters.

Animals↗
PubMed2026

Spatial Total RNA Sequencing of Formalin-Fixed Paraffin-Embedded Tissue by spRandom-seq.

The molecular pathogenesis of infectious diseases and cancer is orchestrated by nanoscale of host and microbial RNA transcripts within the tissue microenvironment. Nevertheless, spatially resolving the comprehensive transcriptional landscape within complex clinical tissues, like formalin-fixed paraffin-embedded (FFPE) specimens, still poses a formidable challenge. Here, we present spRandom-seq, a random primer-based spatial total RNA sequencing technology designed to spatially resolve complete transcriptomes from host, bacteria, and even nanoscale viruses in FFPE tissues. Capitalizing on the random primer design, our technology not only facilitated the discovery of specific lncRNAs and alternative splicing events in mouse brain and olfactory bulb, but also delineated pronounced spatial heterogeneity in clinical FFPE sections-across distinct tumor regions in breast cancer and microbial infection sites in Klebsiella pneumoniae-infected tissues. Importantly, integrated analysis of host and viral RNAs in FFPE samples from hepatitis B virus (HBV)‑positive hepatocellular carcinoma (HCC) demonstrated that complement and coagulation pathways were specifically activated across expansive HBV‑infected tumor areas, which also exhibited an increased burden of copy number variations (CNVs). Owing to its compatibility with existing spatial transcriptomics platforms and minimal operational complexity, spRandom-seq represents a practical and scalable approach for clinical pathology applications and infection diagnostics.

Paraffin Embedding↗
PubMed2006

AMP-dependent protein kinase alpha 2 isoform promotes hypoxia-induced VEGF expression in human glioblastoma.

Tumor cells respond to hypoxic stress by upregulating a variety of genes involved in glucose uptake, glycolysis, and angiogenesis, all essential to maintaining nutrient availability and intracellular ATP levels. Adenosine monophosphate-dependent kinase (AMPK) is a key sensor for cellular homeostasis and is highly sensitive to changes in AMP:ATP ratios. The two catalytic AMPK alpha isoforms (AMPKalpha1, AMPKalpha2) were investigated with respect to their expression, cellular distribution, and contribution to VEGF expression under hypoxic stress in human U373 glioblastoma cells. Quantitative real-time PCR analysis showed AMPKalpha1 mRNA to be constitutively expressed in normoxia and hypoxia, whereas AMPKalpha2 mRNA levels were low in normoxia and significantly induced in hypoxia. Fluorescent immunohistochemistry showed that AMPKalpha2 protein redistributed to the nucleus under hypoxia, whereas AMPKalpha1 remained distributed throughout the cell. The AMPK chemical inhibitor, 5-iodotubericidin, effectively repressed the hypoxic induction of VEGF mRNA levels and hypoxia inducible factor-1 dependent transcription. AMPKalpha2 repression with RNA interference reduced hypoxia-induced VEGF mRNA and HIF-1 transcription, whereas AMPKalpha1 repression did not. Human glioblastoma cell lines U118 and U138 also showed hypoxia-induction of AMPKalpha2 as well as VEGF. Immunohistochemistry analysis of human astrocytoma/glioma samples revealed AMPKalpha2 present in high grade gliomas within hypoxic pseudopalisading microenvironments. These data suggest that prolonged hypoxia promotes the expression and functional activation of AMPKalpha2 and VEGF production in glioma cell lines and glioblastoma multiform tumors, thus contributing to tumor survival and angiogenesis in high grade human gliomas.

AMP-Activated Protein Kinases↗
PubMed1993

Myelination by mature ovine oligodendrocytes in vivo and in vitro: evidence that different steps in the myelination process are independently controlled.

The ability of isolated mature post-myelination ovine oligodendrocytes to myelinate was investigated in tissue culture and in vivo. In culture, although the cells adhered preferentially to rat dorsal root ganglia (DRG) axons, sent out processes that encircled and wrapped them, proliferated, and synthesised myelin proteins (MBP), no myelination was found. This failure to find myelination occurred despite the fact that the oligodendrocytes both in the present experiments and in previous studies elaborated membranous structures that have been shown chemically and structurally to be similar to normal central nervous system myelin. These findings contrasted with those seen when neonatal rodent glial cells were added to similar DRG neuron cultures, in which myelination readily occurred. When the same adult ovine oligodendrocytes were transplanted into the brains of Shiverer mice, normal compact myelin was formed, proving that the cells were capable of myelination and suggesting that cross-species incompatibility was probably not a major factor in the lack of myelination in vitro. It is possible that the failure of ovine oligodendrocytes to myelinate DRG axons is due either to the relatively low number of supporting glial cells, such as astrocytes or microglia which may be necessary for satisfactory myelination, or that some other factor in the microenvironment is lacking; in any event, these results point to the complexity of oligodendrocyte-axon interactions. It is clear that each of the events, from adherence to proliferation to wrapping and the myelin compaction may be under the control of a different signal and may operate through a distinct mechanism, even though each process is dependent on the other. The results also point to the potential usefulness of this model system for deciphering such signals and mechanisms.

Animals↗
PubMed2005

Hypoxia and the hypoxia-inducible-factor pathway in glioma growth and angiogenesis.

Glioblastomas, like other solid tumors, have extensive areas of hypoxia and necrosis. The importance of hypoxia in driving tumor growth is receiving increased attention. Hypoxia-inducible factor 1 (HIF-1) is one of the master regulators that orchestrate the cellular responses to hypoxia. It is a heterodimeric transcription factor composed of alpha and beta subunits. The alpha subunit is stable in hypoxic conditions but is rapidly degraded in normoxia. The function of HIF-1 is also modulated by several molecular mechanisms that regulate its synthesis, degradation, and transcriptional activity. Upon stabilization or activation, HIF-1 translocates to the nucleus and induces transcription of its downstream target genes. Most important to gliomagenesis, HIF-1 is a potent activator of angiogenesis and invasion through its upregulation of target genes critical for these functions. Activation of the HIF-1 pathway is a common feature of gliomas and may explain the intense vascular hyperplasia often seen in glioblastoma multiforme. Activation of HIF results in the activation of vascular endothelial growth factors, vascular endothelial growth factor receptors, matrix metalloproteinases, plasminogen activator inhibitor, transforming growth factors alpha and beta, angiopoietin and Tie receptors, endothelin-1, inducible nitric oxide synthase, adrenomedullin, and erythropoietin, which all affect glioma angiogenesis. In conclusion, HIF is a critical regulatory factor in the tumor microenvironment because of its central role in promoting proangiogenic and invasive properties. While HIF activation strongly promotes angiogenesis, the emerging vasculature is often abnormal, leading to a vicious cycle that causes further hypoxia and HIF upregulation.

Brain Neoplasms↗