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PubMed2004

Novel neuronal phenotypes from neural progenitor cells.

We report the first isolation of progenitor cells from the hypothalamus, a derivative of the embryonic basal plate that does not exhibit neurogenesis postnatally. Neurons derived from hypothalamic progenitor cells were compared with those derived from progenitor cultures of hippocampus, an embryonic alar plate derivative that continues to support neurogenesis in vivo into adulthood. Aside from their different embryonic origins and their different neurogenic potential in vivo, these brain regions were chosen because they are populated with cells of three different categories: Category I cells are generated in both hippocampus and hypothalamus, Category II cells are generated in the hypothalamus but are absent from the hippocampus, and Category III is a cell type generated in the olfactory placode that migrates into the hypothalamus during development. Stem-like cells isolated from other brain regions, with the ability to generate neurons and glia, produce neurons of several phenotypes including gabaergic, dopaminergic, and cholinergic lineages. In the present study, we extended our observations into neuroendocrine phenotypes. The cultured neural precursors from 7-week-old rat hypothalamus readily generated neuropeptide-expressing neurons. Hippocampal and hypothalamic progenitor cultures converged to indistinguishable populations and produced neurons of all three categories, confirming that even short-term culture confers or selects for immature progenitors with enough plasticity to elaborate neuronal phenotypes usually inhibited in vivo by the local microenvironment. The range of phenotypes generated from neuronal precursors in vitro now includes the peptides found in the neuroendocrine system: corticotropin-releasing hormone, growth hormone-releasing hormone, gonadotropin-releasing hormone, oxytocin, somatostatin, thyrotropin-releasing hormone, and vasopressin.

Animals↗
PubMed1998

Cortical perineuronal nets in the gray short-tailed opossum (Monodelphis domestica): a distribution pattern contrasting with that shown in placental mammals.

Extracellular matrix proteoglycans accumulated in perineuronal nets and in certain neuropil zones have been shown to influence the immediate neuronal microenvironment, and to contribute to the chemoarchitectonic characteristics of neuronal networks. Studies in different placental mammals, including the human, have suggested that the major principles of extracellular matrix distribution remained constant during phylogenesis of the different mammalian strains. However, the comparison of matrix distribution between various species also indicates that striking deviations from the basic pattern may occur, although their functional significance appears unknown as yet. This study examines the extracellular matrix in the forebrain of a basic American marsupial, which has evolved independently of placental mammals for more than 100 million years. Brain sections obtained from adult gray short-tailed opossums (Monodelphis domestica) were stained for extracellular matrix components using the N-acetylgalactosamine-binding lectin Wisteria floribunda agglutinin (WFA), a polyclonal antibody against chondroitin sulfate proteoglycans (CSPG), and biotinylated hyaluronectin for the detection of hyaluronan. In subcortical regions, the distribution patterns of WFA-stained and CSPG-immunoreactive perineuronal nets were similar to those reported previously in placental mammals. In contrast, a unique distribution was found in the neocortex. This distribution was characterized by the presence of perineuronal nets around pyramidal cells and matrix components within the adjacent neuropil that together form a continuously labeled zone in layer V. Weakly stained nets ensheathed less numerous pyramidal cells in the upper layers II/III and a few multipolar cortical neurons. Dual staining experiments showed that cortical net-associated neurons were rarely immunopositive for parvalbumin. This fact, in addition to the predominant association of extracellular matrix components with layer V pyramidal cells, differentiates the neocortex in Monodelphis from that of all placental mammals studied to date. Regarding the basic phylogenetic position of this marsupial species it remains to be shown if these distribution characteristics of extracellular matrix may represent also a basic feature of cortical organization.

Acetylgalactosamine↗
PubMed2005

Adenoviral proteins mimic nutrient/growth signals to activate the mTOR pathway for viral replication.

Like tumor cells, DNA viruses have had to evolve mechanisms that uncouple cellular replication from the many intra- and extracellular factors that normally control it. Here we show that adenovirus encodes two proteins that activate the mammalian target of rapamycin (mTOR) for viral replication, even under nutrient/growth factor-limiting conditions. E4-ORF1 mimics growth factor signaling by activating PI3-kinase, resulting in increased Rheb.GTP loading and mTOR activation. E4-ORF4 is redundant with glucose in stimulating mTOR, does not affect Rheb.GTP levels and is the major mechanism whereby adenovirus activates mTOR in quiescent primary cells. We demonstrate that mTOR is activated through a mechanism that is dependent on the E4-ORF4 protein phosphatase 2A-binding domain. We also show that mTOR activation is required for efficient S-phase entry, independently of E2F activation, in adenovirus-infected quiescent primary cells. These data reveal that adenovirus has evolved proteins that activate the mTOR pathway, irrespective of the cellular microenvironment, and which play a requisite role in viral replication.

Adenoviridae↗
PubMed2005

Using peripheral blood mononuclear cells to determine a gene expression profile of acute ischemic stroke: a pilot investigation.

BACKGROUND: Direct brain biopsy is rarely indicated during acute stroke. This study uses peripheral blood mononuclear cells (PBMCs) to determine whether a systemic gene expression profile could be demonstrated in patients with acute ischemic stroke. METHODS AND RESULTS: Using oligonucleotide microarrays, we compared the gene expression profile of an index cohort of 20 patients with confirmed ischemic stroke on neuroimaging studies with that of 20 referent subjects. Validation studies used quantitative real-time polymerase chain reaction to measure the levels of 9 upregulated genes in the index cohort, and an independent cohort of 9 patients and 10 referent subjects was prospectively studied to determine the accuracy of the Prediction Analysis for Microarrays list to classify stroke. After correction for multiple comparisons with the Bonferroni technique, 190 genes were significantly different between the stroke and referent groups. Broad classes of genes included white blood cell activation and differentiation (approximately 60%), genes associated with hypoxia and vascular repair, and genes potentially associated with an altered cerebral microenvironment. Real-time polymerase chain reaction confirmed increased mRNA expression in 9 of 9 upregulated stroke-associated genes in the index cohort. A panel of 22 genes derived from the Prediction Analysis for Microarrays algorithm in the index cohort classified stroke in the validation cohort with a sensitivity of 78% and a specificity of 80%. Control for the Framingham stroke risk score revealed only a partial dependence of the stroke gene expression profile in PBMCs on vascular risk. CONCLUSIONS: This study demonstrated an altered gene expression profile in PBMCs during acute ischemic stroke. Some genes with altered expression were consistent with an adaptive response to central nervous system ischemia.

Acute Disease↗
PubMed1992

Characterization of murine CD10, an endopeptidase expressed on bone marrow adherent cells.

The CD10/neutral endopeptidase (NEP) gene was identified in murine genomic DNA using a human CD10 cDNA probe. It is transcribed most abundantly in kidneys resulting in RNA transcripts of 3.4, 6.0, and 6.2 kb. The activity of the murine CD10/NEP shows identical kinetic parameters, Km and Ki, to those observed for this enzyme in other species. Two mAbs raised against rabbit NEP detect a 100 kDa protein by Western blot analysis; the antigen immunoprecipitated from extracts of lung shows specific NEP activity. CD10/NEP, as analyzed by Western blot and enzymatic activity, is expressed at high levels in kidney and lung, and at lower levels in liver, brain, thymus, spleen, and bone marrow. Analysis of bone marrow subpopulations indicate that the majority of CD10/NEP is associated with cells adherent to plastic and with subpopulations that do not express the surface markers AA4.1, B220, Mac-1, and Gr-1. These results suggest that CD10 is primarily associated with the stromal elements in murine bone marrow. A bone marrow stromal line, BMS 2.2, also expresses high levels of CD10/NEP. This peptidase activity on the surface of stromal cells may influence lymphopoiesis or other hematopoietic processes through the hydrolysis of regulatory peptides in the microenvironment.

Animals↗
PubMed2001

[Stromal cell-derived factor 1 (SDF-1). Its structure and function].

SDF-1, a novel cytokine from alpha-chemokine family, plays a key role in regulation of haematopoiesis. It exists in two forms (alpha and beta) that originate from alternative splicing. Its high expression in the bone marrow microenvironment accounts for the release of progenitor cells in the circulation and represents a prevention of uncontrolled leak of CD34+ cells. Notably significant is its stimulation of proliferation of B-lineage progenitors, in other haematopoietic lineages it functions as a facilitating factor of other cytokines. Ability of induction of platelet aggregation reveals the role of SDF-1 in thrombogenesis and vascular lumen obliteration in vessels affected by atherosclerosis. The only receptor for SDF-1 is CXCR4, whose presence was proved in great numbers of tissues and organs. Their presence was also verified in brain tumours, whereas degree of their expression raises with grading, angiogenesis and occurrence of necrotic changes in tumour. Thanks to this feature it will probably be possible to estimate the prognosis of the patients. SDF-1 is also a suppressor of immune response via its facilitating activity on the interaction of the macrophages and CD8+ T lymphocytes. Affinity of the T-lymphocytotropic HIV to CXCR4 holds out hopes for a possible modulation of the infection with SDF-1. The significance of SDF-1 and its receptor CXCR4 is supported by morphological and functional abnormalities of new-born mice in their absence, especially disorders in haematopoiesis, angiogenesis and development of cardiac and nervous tissues.

B-Lymphocytes↗
PubMed1997

Unique spindle cells in the involved ileal segment of rats with congenital aganglionosis.

Protein gene product (PGP) 9.5 is a newly characterized brain-specific protein originally detected by high-resolution two-dimensional electrophoresis of soluble human brain proteins. Immunoreactivity for PGP9.5 was investigated in the small and large intestine of aganglionic mutant and control rats with light microscopy, electron microscopy, and confocal laser scanning microscopy. Immunoreactive spindle-shaped cells were seen in the inner circular muscle layer of the aganglionic ileal segment. The long axes of these spindle cells paralleled the inner circular muscle fibers. PGP9.5-positive spindle cells were positive for enteric actin, and some of them were also positive for vimentin, a relatively specific marker for the special smooth muscle (pacemaker cells). These cells may prove to be a maldeveloped microenvironment of aganglionic segment. However, it is necessary to investigate expression of PGP9.5 in embryonal tissue with an abnormal environment to test this hypothesis. This study showed PGP9.5-positive pacemaker cells in the aganglionic ileal segment in the first time.

Animals↗
PubMed1994

Neurotrophin-3 induces neural crest-derived cells from fetal rat gut to develop in vitro as neurons or glia.

The precursor cells that form the enteric nervous system (ENS) are multipotent when they arrive in the gut from the neural crest. Their differentiation thus depends on signals from the enteric microenvironment. Crest-derived cells were isolated from the fetal rat bowel by immunoselection at E14 with NC-1/HNK-1 antibodies and secondary antibodies coupled to magnetic beads. NC-1/HNK-1-immunoreactive cells were enriched approximately 36-fold. The NC-1/HNK-1-selected population and the residual population were plated at equal cell density and maintained in a defined medium for 6-7 d. The total number of cells found in the cultures of the residual cells was three- to fourfold that in cultures of immunoselected cells. Neurotrophin-3 (NT-3), but not nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), or neurotrophin-4/5 (NT-4/5), was found to increase the proportion of neurons (neurofilament-immunoreactive or neuron-specific enolase-immunoreactive) or glia (S-100-immunoreactive) (from 6.6 +/- 0.9% to 15.2 +/- 1.4%; p < 0.001). This effect was concentration dependent (from 1 to 40 ng/ml) and observed only in the cultures of immunoselected cells. NT-3 also enhanced neurite outgrowth. NT-3 increased neither cell number nor bromodeoxyuridine incorporation and thus was not mitogenic. Exposure of immunoselected cells to NT-3 rapidly and transiently induced the appearance of nuclear Fos immunoreactivity. Transcripts coding for TrkC, the transducing receptor for NT-3, were identified in the fetal rat gut (E14-E16) and in the immunoselected population of cells using reverse transcriptase and the polymerase chain reaction. It is concluded that NT-3 specifically promotes the differentiation of enteric crest-derived cells as neurons or glia and may thus play a role in the development and/or maintenance of the ENS.

Animals↗
PubMed1990

Embryonic expression of a haematopoietic growth factor encoded by the Sl locus and the ligand for c-kit.

Mice carrying mutations at the W (Dominant white spotting) and Sl (Steel) loci develop abnormalities in three independent systems: neural crest-derived melanocytes, primordial germ cells and haematopoietic stem cells. Consequently, homozygotes of viable mutant alleles have white coats and are sterile and severely anaemic. Tissue recombination studies predict that the W gene is expressed cell autonomously, whereas the product of the Sl locus affects the microenvironment in which the stem cells migrate, proliferate and differentiate. The W locus encodes the protoncogene c-kit, a member of the tyrosine kinase receptor family. The haematopoietic growth factor SCF (stem cell factor) has been identified as the product of the Sl locus and a ligand for c-kit. Here, we report that SCF is expressed during embryogenesis in cells associated with both the migratory pathways and homing sites of melanoblasts, germ cells and haematopoietic stem cells. Both SCF and c-kit are also expressed in a variety of other tissues, including the brain and spinal cord, suggesting that the receptor-ligand system has additional roles in embryogenesis.

Animals↗
PubMed1997

Amyloid beta-peptide induces cell monolayer albumin permeability, impairs glucose transport, and induces apoptosis in vascular endothelial cells.

Amyloid beta-peptide (A beta) is deposited as insoluble fibrils in the brain parenchyma and cerebral blood vessels in Alzheimer's disease (AD). In addition to neuronal degeneration, cerebral vascular alterations indicative of damage to vascular endothelial cells and disruption of the blood-brain barrier occur in AD. Here we report that A beta25-35 can impair regulatory functions of endothelial cells (ECs) from porcine pulmonary artery and induce their death. Subtoxic exposures to A beta25-35 induced albumin transfer across EC monolayers and impaired glucose transport into ECs. Cell death induced by A beta25-35 was of an apoptotic form, characterized by DNA condensation and fragmentation, and prevented by inhibitors of macromolecular synthesis and endonucleases. The effects of A beta25-35 were specific because A beta1-40 also induced apoptosis in ECs with the apoptotic cells localized to the microenvironment of A beta1-40 aggregates and because astrocytes did not undergo similar changes after exposure to A beta25-35. Damage and death of ECs induced by A beta25-35 were attenuated by antioxidants, a calcium channel blocker, and a chelator of intracellular calcium, indicating the involvement of free radicals and dysregulation of calcium homeostasis. The data show that A beta induces increased permeability of EC monolayers to macromolecules, impairs glucose transport, and induces apoptosis. If similar mechanisms are operative in vivo, then A beta and other amyloidogenic peptides may be directly involved in vascular EC damage documented in AD and other disorders that involve vascular amyloid accumulation.

Amyloid beta-Peptides↗
PubMed2001

Cell encapsulation technology as a therapeutic strategy for CNS malignancies.

Gene therapy using viral vectors has to date failed to reveal its definitive clinical usefulness. Cell encapsulation technology represents an alternative, nonviral approach for the delivery of biologically active compounds to tumors. This strategy involves the use of genetically engineered producer cells that secrete a protein with therapeutic potential. The cells are encapsulated in an immunoisolating material that makes them suitable for transplantation. The capsules, or bioreactors, permit the release of recombinant proteins that may assert their effects in the tumor microenvironment. During the last decades, there has been significant progress in the development of encapsulation technologies that comprise devices for both macro- and microencapsulation. The polysaccharide alginate is the most commonly used material for cell encapsulation and is well tolerated by various tissues. A wide spectrum of cells and tissues has been encapsulated and implanted, both in animals and humans, indicating the general applicability of this approach for both research and medical purposes, including CNS malignancies. Gliomas most frequently recur at the resection site. To provide local and sustained drug delivery, the bioreactors can be implanted in the brain parenchyma or in the ventricular system. The development of comprehensive analyses of geno- and phenotypic profiles of a tumor (genomics and proteomics) may provide new and important guidelines for choosing the optimal combination of bioreactors and recombinant proteins for therapeutic use.

Alginates↗
PubMed2007

Cancer stem cells: models and concepts.

Although monoclonal in origin, most tumors appear to contain a heterogeneous population of cancer cells. This observation is traditionally explained by postulating variations in tumor microenvironment and coexistence of multiple genetic subclones, created by progressive and divergent accumulation of independent somatic mutations. An additional explanation, however, envisages human tumors not as mere monoclonal expansions of transformed cells, but rather as complex tridimensional tissues where cancer cells become functionally heterogeneous as a result of differentiation. According to this second scenario, tumors act as caricatures of their corresponding normal tissues and are sustained in their growth by a pathological counterpart of normal adult stem cells, cancer stem cells. This model, first developed in human myeloid leukemias, is today being extended to solid tumors, such as breast and brain cancer. We review the biological basis and the therapeutic implications of the stem cell model of cancer.

Humans↗
PubMed2006

Three-dimensional visualization of microvessel architecture of whole-mount tissue by confocal microscopy.

The three-dimensional architecture of the nascent microvascular network is a critical determinant of vascular perfusion in the setting of regenerative growth, vasculopathies and cancer. Current methods for microvessel visualization are limited by insufficient penetration and instability of endothelial immunolabels, inadequate vascular perfusion by the high-viscosity polymers used for vascular casting, and destruction of tissue stroma during the processing required for scanning electron microscopy. The aim of this study was to develop whole-mount tissue processing methods for 3D in situ visualization of the microvasculature that were also compatible with supplementary labeling for other structures of interest in the tissue microenvironment. Here, we present techniques that allow imaging of the microvasculature by confocal microscopy, to depths of up to 1500 mum below the specimen surface. Our approach includes labeling luminal surfaces of endothelial cells by i.v. injection of fluorescently conjugated lectin and filling the microvasculature with carbon or fluorescent nanoparticles/Mercox, followed by optical clearing of thick tissue sections to reduce light scatter and permit 3D visualization of microvessel morphology deep into the sample. Notably, tissue stroma is preserved, allowing simultaneous labeling of other structures by immunohistochemistry or nuclear dyes. Results are presented for various murine tissues including fat, muscle, heart and brain under conditions of normal health, as well as in the setting of a glioma model growing in the subcutaneous space or orthotopically in the brain parenchyma.

Animals↗
PubMed2005

Construction of a novel constitutively active chimeric EGFR to identify new targets for therapy.

Tumor cells and tumor-associated endothelial cells express activated epidermal growth factor receptor (EGFR) due to production of EGF-related ligands in the tumor microenvironment. To investigate the effect of perpetual EGFR activation on endothelial cells, we developed a novel method to generate constitutively active EGFR. We fused the entire intracellular domain of the EGFR to the N-terminus of the CD3zeta component of the T-cell receptor signaling complex. Expression of the chimeric receptor CD3-EGFR in EGFR-deficient human embryonic kidney cells resulted in ligand-independent sustained EGFR phosphorylation and in the induction of Akt, mitogen-activated protein kinase, and signal transducer and activator of transcription 3 (Stat3). Next, CD3-EGFR was stably expressed in murine brain endothelial cells where it signaled for the initiation of angiogenic programs, Stat3 activation, and continuous proliferation. A comparison between brain endothelial cells encoding CD3zeta and CD3-EGFR revealed that proangiogenic phenotype was modulated by the intracellular effector Stat3 and that suppression of this downstream target with the EGFR tyrosine kinase inhibitor PKI166 could revert this phenotype. Thus, our results validate the use of chimeric constitutively active receptors to replicate critical features observed in pathophysiological processes that can expedite the identification of novel therapeutic agents targeting EGFR activation and function.

Animals↗
PubMed2006

The high integration and differentiation potential of autologous neural stem cell transplantation compared with allogeneic transplantation in adult rat hippocampus.

Cell therapy is thought to have a central role in restorative therapy, which aims to restore function to the damaged nervous system. The purpose of this study was to establish an autologous neural stem cell (NSC) transplantation model using adult rats and to compare survival, migration, and differentiation between this system and allogeneic NSC transplantation. Furthermore, we compared the immunologic response of the host tissue between autologous and allogeneic transplantation. NSCs were removed from the subventricular zone of adult Fischer 344 rats using stereotactic methods. NSCs were expanded and microinjected into normal hippocampus in the autologous brain. Allogeneic NSC (derived from adult Wistar rats) transplantation was performed using the same procedure, and hippocampal sections were analyzed immunohistologically 3 weeks post-transplantation. The cell survival and migration rate were higher for autologous transplantation than for allogeneic transplantation, and the neuronal differentiation rate in the autologous transplanted cells far exceeded that of allogeneic transplantation. Furthermore, there was less astrocyte and microglia reactivity in the host tissue of the autologous transplantation compared with allogeneic transplantation. These findings demonstrate that immunoreactivity of the host tissue strongly influences cell transplantation in the CNS as the autologous transplantation did not induce host tissue immunoreactivity; the microenvironment was essentially maintained in an optimal condition for the transplanted cells.

Animals↗
PubMed2006

Signaling pathways in self-renewing hematopoietic and leukemic stem cells: do all stem cells need a niche?

Many adult tissue stem cells, such as the cells of the hematopoietic system, gastrointestinal epithelium, brain, epidermis, mammary gland and lung have now been identified, all of them fulfilling a crucial role in supplying organisms with mature cells during normal homeostasis as well as in times of tissue generation or repair. Two unique features characterize adult stem cells: the ability to generate new pluripotent stem cells (to self-renew) and the ability to give rise to differentiated progeny that has lost its self-renewal capacity. Our understanding of the mechanisms that determine whether, where and when a stem cell will self-renew or differentiate is still limited, but recent advances have indicated that the stem cell microenvironment, or niche, provides essential cues that direct these cell fate decisions. Moreover, loss of control over these cell fate decisions might lead to cellular transformation and cancer. This review addresses the current understandings of the molecular mechanisms that regulate hematopoietic stem cell self-renewal in the niche and how leukemic transformation might change the dependency of leukemic stem cells on their microenvironment for self-renewal and survival.

Animals↗
PubMed2006

Effects of acidosis on brain capillary endothelial cells and cholinergic neurons: relevance to vascular dementia and Alzheimer's disease.

Alzheimer's disease is a progressive brain disorder which is neuropathologically characterized by an increased number of beta-amyloid plaques, tau pathology and synapse loss. Recent research suggests that vascular pathology may be also important for the development and progression of Alzheimer's disease. It is still unknown whether there is a relation between damage of brain capillary endothelial cells (BCEC) and subsequent cholinergic cell death. The aim of this study was to examine the effects of acidosis on cell death of BCEC and cholinergic neurons in an organotypic brain slice model. We show that BCEC were heavily damaged in medium at pH<6.6. Cholinergic neurons incubated in medium pH 6.0 degenerated within 2-3 days and were not rescued by nerve growth factor (NGF). Lactate did not affect the survival of BCEC or cholinergic neurons. Both BCEC and cholinergic cells were not affected at pH 7.4, 7.0 or 6.6. It is concluded that both endothelial cells and cholinergic neurons have a high capacity to compensate for pH changes. At a certain pH, however, the vascular and neuronal cells show the same vulnerability, indicating that a low pH is deleterious for the cerebral microenvironment. Future studies are necessary to explore whether temporary pH changes could be responsible for cerebrovascular damage and cholinergic cell death. Acidosis may play an important role in the development of vascular dementia and Alzheimer's disease.

Acetylcholine↗
PubMed1980

Alpha adrenoreceptor mediated alteration of ethanol effects on (Na+ + K+)-ATPase of rat neuronal membranes.

Noradrenaline (NA) sensitizes rat brain (Na+ + K+)-ATPase to inhibition by ethanol (EtOH). This effect of NA increases with the degree of enrichment of the enzyme: 0.1 mM NA + 0.05 M EtOH produced 27% inhibition in whole brain homogenates, 40% in 2.5-fold purified P2 fractions, and 45% in 5-fold purified microsomal fractions. The sensitization by NA was prevented by 0.1 microM phentolamine but not by 100 microM propranolol. Adrenaline and phenylephrine also sensitized the enzyme to EtOH inhibition in all of the fractions but isoproterenol did not. For all three alpha agonists the degree of sensitization was concentration dependent and the degree of reversal of this effect varied with the concentration of phentolamine added. These findings suggest that the NA + EtOH interaction is a direct effect on the membrane, probably mediated by an alpha receptor modified perturbation of the membrane microenvironment of the enzyme.

Animals↗