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Results for “Functional differentiation”

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PubMed2006

Nitroglycerin attenuates human endothelial progenitor cell differentiation, function, and survival.

Endothelial progenitor cells (EPCs) participate in angiogenesis and the response to chronic ischemia. Risk factors and cardiovascular disease attenuate EPC number, function, and survival. Continuous therapy with nitroglycerin (glyceryl trinitrate; GTN) is associated with increased vascular oxidative stress, leading to nitrate tolerance and endothelial dysfunction. Thus, GTN therapy may also affect EPCs. The purpose of this study was to determine whether continuous exposure to GTN in vivo or during ex vivo expansion affects the circulating number and functional characteristics of human EPCs. To determine the effects of continuous in vivo GTN exposure, EPCs isolated from 28 healthy males before and after receiving 0.6 mg/h GTN (n=17) or no treatment (n=11) for 1 week were expanded for 6 days and compared. To determine the effects of continuous ex vivo GTN exposure, EPCs isolated before randomization were expanded for 6 days in medium supplemented with 100 nM, 300 nM, or 1 microM GTN. EPCs expanded without GTN served as controls (n=10). In vivo, GTN exposure significantly increased the percentage of circulating cells expressing the EPC marker CD34 and increased the susceptibility of expanded EPCs to apoptosis but had no impact on the phenotypic differentiation or migration of EPCs. Ex vivo, GTN exposure increased apoptosis while decreasing phenotypic differentiation, migration, and mitochondrial dehydrogenase activity of EPCs, compared with EPCs expanded in the absence of GTN. Taken together, these results suggest that continuous GTN therapy might impair EPC-mediated processes, an effect that could be detrimental in the setting of ischemic cardiovascular disease.

Adolescent↗
PubMed1979

REgional functional differentiation in the gut of the grasscarp, Ctenopharyngodon idella (Val.).

A regional differentiation--reflecting structural differences--of the intestine of larval and juvenile grasscarps can be illustrated by studying the activity of alkaline phosphatase and the uptake of orally administered horseradish peroxidase. Pinocytosis takes place in a welldefined area of about 23% of the length of the gut (segment II). Neither the rostral +/- 68% (segment I) nor the caudal +/- 9% (segment III) shows absorption of the enzyme. Alkaline phosphatase activity, mainly localized at the microvilli of the enterocytes is high in the first segment of the gut and low in the second segment. In larvae, the activity decreases sharply at the transition from segment I to segment II. The activity is weak or absent in the caudal third segment. Quantitative histochemical data are confirmed by biochemical analyses. Alkaline phosphatase activity is found all over the mucosal folds of the first segment, with relatively weak activity at the base and at the tip of the folds. This may be related to a renewal of the epithelium. Our results suggest that active absorption of digested food takes place mainly in the rostral first segment, while the uptake of macromolecules by pinocytosis is a function of the second segment. Comparison of the results with information available in literature leads to a rejection of the hypothesis that the uptake of protein macromolecules in Cyprinids is to be attributed to the absence of a stomach and therefore to an inefficient digestion of proteins.

Aging↗
PubMed1971

Intramural neural elements in components of the carotid bifurcation. A histological basis for differential function.

The histology of the specialized region of the carotid bifurcation in man was studied with Orcein stain for elastic tissue, Masson's trichrome for muscle and connective tissue, and Bodian's silver method for neural elements. Four distinct regions exist: the common carotid, which appears to be solely a conduit; the carotid sinus, which is thin and very elastic with its baroreceptors in the medial wall; the external carotid, which is highly muscular and presumably active; and the internal carotid, also highly muscular and presumably active. The transition between zones is abrupt. Prominent clusters of up to 30 or 40 multipolar nerve cells, 15 to 25 microns in diameter, were found in the subintimal region of the internal carotid artery, some in the common, and a few in the external carotid. Occasional rounder cells of similar size with only one process were seen, possibly of sensory type. No cell bodies were seen in the adventitia of any vessel. No relation to the perivascular plexus was established. It is speculated that the neurons may be related to the reported local differential response to environment by the internal and external carotid systems.

Adult↗
PubMed1975

Studies on the persistence of differentiated functions in rat hepatocytes set into primary tissue cultures. Specific binding of 3H-bilirubin after eight days of staying in vitro.

Preliminary experiments were performed which indicate that even after 8 days of staying in primary in vitro tissue culture rat hepatocytes are still able to take up and bind tritiated, unconjugated bilirubin in a specific fashion and much more intensely than do connective tissue cells present in the same cultures. The data are suggestive of the maintenance in 8-day cultured hepatocytes of at least some of the specific pathways bound to bilirubin metabolism.

Animals↗
PubMed1993

Evidence for differential functions of the p50 and p65 subunits of NF-kappa B with a cell adhesion model.

The p50 and p65 subunits of NF-kappa B represent two members of a gene family that shares considerable homology to the rel oncogene. Proteins encoded by these genes form homo- and heterodimers which recognize a common DNA sequence motif. Recent data have suggested that homodimers of individual subunits of NF-kappa B can selectively activate gene expression in vitro. To explore this possibility in a more physiological manner, murine embryonic stem (ES) cells were treated with phosphorothio antisense oligonucleotides to either p50 or p65. Within 5 h after exposure to phosphorothio antisense p65 oligonucleotides, cells exhibited dramatic alterations in adhesion properties. Similar findings were obtained in a stable cell line that expressed a dexamethasone-inducible antisense mRNA to p65. Although antisense oligonucleotides raised against both p50 and p65 elicited a significant reduction in their respective mRNAs, only the cells treated with antisense p50 maintained a normal morphology. However, 6 days following removal of leukemia-inhibiting factor, a growth factor which suppresses embryonic stem cell differentiation, adhesion properties of cells treated with the antisense p50 oligonucleotides were markedly affected. The ability of the individual antisense oligonucleotides to elicit differential effects on cell adhesion, a property dependent upon the stage of differentiation, suggests that the p50 and p65 subunits of NF-kappa B regulate gene expression either as homodimers or as heterodimers with other rel family members. Furthermore, the finding that reduction in p65 expression alone had profound effects on cell adhesion properties indicates that p65 plays an important role in nonstimulated cells and cannot exist solely complexed with the cytosolic inhibitory protein I kappa B.

Animals↗
PubMed1999

Mutant p53 gain of function: differential effects of different p53 mutants on resistance of cultured cells to chemotherapy.

Many tumors overexpress mutant forms of p53. A growing number of studies suggest that the nature of a p53 mutation in a cell can impact upon cellular properties, clinical responses to therapy and prognosis of a tumor. To explore the cellular basis of these observations, experiments were designed to compare the properties of cells with and without p53 mutations within the same cell population. To that end, various tumor-derived human p53 mutants were introduced into p53-null H1299 lung adenocarcinoma cells. Clonogenic survival assays revealed that cells overexpressing the p53His175 mutant, but not the p53His273 mutant, recover preferentially from etoposide treatment. Moreover, p53His175 as well as p53His179 reduced substantially the rate of etoposide-induced apoptosis, whereas p53His273 and p53Trp248 had a much milder protective effect. In contrast, p53His175 and p53His273 exerted very similar effects on the cellular response to cisplatin; both conferred increased resistance to low concentrations of the drug (2.5 microg/ml), but did not protect at all against high concentrations (10 microg/ml). Hence particular p53 mutants may confer upon tumor cells a selective survival advantage during chemotherapy. These findings define a new type of mutant p53 selective gain of function, which may compromise the efficacy of cancer chemotherapy.

Adenocarcinoma↗
PubMed1975

Abnormal neuronal differentiation (functional maturation) in mental retardation.

A review is presented of a variety of human pathologic conditions, including some forms of mental retardation, and of experimental situations involving the nervous system proved (with the Golgi method) to be associated with detectable morphologic abnormalities. The postsynaptic elements (the dendritic spines) have been found to be especially sensitive and frequently they are found to be structurally abnormal. Structural abnormalities involving one of the synaptic components could result in synaptic dysfunction which could explain some degree of mental or motor retardation or incoordination. It is hoped that this review will stimulate and encourage the use of the Golgi method in the study of abnormal conditions (clinical or experimental) affecting the nervous system.

Cell Differentiation↗
PubMed2004

The generation of functionally differentiated, three-dimensional hepatic tissue from two-dimensional sheets of progenitor small hepatocytes and nonparenchymal cells.

BACKGROUND: The authors' laboratory has investigated tissue engineering of the liver as a novel approach for treating end-stage liver disease. Fabrication of thick, viable, three-dimensional liver tissue is limited by the lack of vascularity in the tissue-engineered constructs. To overcome this limitation, the authors fabricated three-dimensional, vascularized liver tissue in vivo from two-dimensional cell sheets created from small hepatocytes (SHC) and nonparenchymal cells (NPC) implanted into rat omentum. METHODS: SHC and NPC were cultured on a silicon wafer and lifted as monolayer cell sheets. After maximal hepatotrophic stimulation was induced in the host by injecting retrorsine, creating a portacaval shunt, and performing a partial hepatectomy, these sheets were placed onto the omentum and then rolled into a three-dimensional cylinder. RESULTS: New tissue consisting of both hepatocytes and bile duct-like structures formed by 2 weeks, and the mass of hepatocytes increased in size up to 2 months. The hepatocytes in these constructs were immunohistochemically positive for albumin and transferrin, and bile duct-like structures were positive for gamma-glutamyl transpeptidase, which suggests that they possess liver-specific function. Electron microscopy also revealed structures resembling bile canaliculi. CONCLUSIONS: Functional, morphologically complex new tissue was generated from morphologically simple monolayer cell sheets of SHC and NPC. These results represent an essential step toward the design of tissue-engineered complex vascularized thick tissue.

Animals↗
PubMed2004

Differential function of the prolyl hydroxylases PHD1, PHD2, and PHD3 in the regulation of hypoxia-inducible factor.

Hypoxia-inducible factor (HIF) is a transcriptional regulator that plays a key role in many aspects of oxygen homeostasis. The heterodimeric HIF complex is regulated by proteolysis of its alpha-subunits, following oxygen-dependent hydroxylation of specific prolyl residues. Although three HIF prolyl hydroxylases, PHD1, PHD2, and PHD3, have been identified that have the potential to catalyze this reaction, the contribution of each isoform to the physiological regulation of HIF remains uncertain. Here we show using suppression by small interference RNA that each of the three PHD isoforms contributes in a non-redundant manner to the regulation of both HIF-1alpha and HIF-2alpha subunits and that the contribution of each PHD under particular culture conditions is strongly dependent on the abundance of the enzyme. Thus in different cell types, isoform-specific patterns of PHD induction by hypoxia and estrogen alter both the relative abundance of the PHDs and their relative contribution to the regulation of HIF. In addition, the PHDs manifest specificity for different prolyl hydroxylation sites within each HIF-alpha subunit, and a degree of selectively between HIF-1alpha and HIF-2alpha isoforms, indicating that differential PHD inhibition has the potential to selectively alter the characteristics of HIF activation.

Animals↗
PubMed2005

Different regions of the mouse nestin enhancer may function differentially in nestin expression in an NSC-like cell line and astrocytes.

Nestin is a characteristic intermediate filament protein expressed in neural stem cells (NSCs). Evidence has shown that it is also found in reactive astrocytes. Previous studies have demonstrated that the second intron of the human and rat nestin genes harbors the central nervous system (CNS) enhancer and the midbrain enhancer, which regulate nestin expression in different regions of CNS during development. In this study, using an NSC-like cell line C17.2 and primarily cultured astrocytes, we show that both C17.2 cells and astrocytes express nestin. To characterize the nestin enhancer in further detail, we cloned the second intron of the mouse nestin gene, which is homologous to the human and rat counterparts as shown by DNA sequencing. Reporter assay indicated that the full-length nestin enhancer was active in both C17.2 cells and astrocytes, consistent with the immunocytochemistry results. However, in C17.2 cells, the enhancer activity was attributed to the highly conserved 3' part, and the 5' part of the enhancer was suppressive to the transcription activation activity of the full-length enhancer. While in astrocytes, both 3' and 5' parts were able to enhance the reporter gene expression. Our data suggested that different regions of the nestin enhancer might have different functions in C17.2 cells and astrocytes: while the 3' region activates transcription in both cell types, the 5' region suppresses in C17.2 cells but activates in astrocytes nestin expression.

Animals↗
PubMed1997

Functionally differentiating two neuronal nitric oxide synthase isoforms through antisense mapping: evidence for opposing NO actions on morphine analgesia and tolerance.

Several isoforms of neuronal nitric oxide synthase (nNOS) have been identified. Antisense approaches have been developed which can selectively down-regulate nNOS-1, which corresponds to the full-length nNOS originally cloned from the brain, and nNOS-2, a truncated form lacking two exons which is generated by alternative splicing, as demonstrated by decreases in mRNA levels. Antisense treatment also lowers nNOS enzymatic activity. Down-regulation of nNOS-1 prevents the development of morphine tolerance. Whereas morphine analgesia is lost in control and mismatch-treated mice given daily morphine injections for 5 days, mice treated with antisense probes targeting nNOS-1 show no decrease in their morphine sensitivity over the same time period. Conversely, an antisense probe selectively targeting nNOS-2 blocks morphine analgesia, shifting the morphine dose-response curve over 2-fold to the right. Both systems are active at the spinal and the supraspinal levels. An antisense targeting inducible NOS is inactive. Studies with NG-nitro-L-arginine, which does not distinguish among NOS isoforms, indicate that the facilitating nNOS-2 system predominates at the spinal level while the inhibitory nNOS-1 system is the major supraspinal nNOS system. Thus, antisense mapping distinguishes at the functional level two isoforms of nNOS with opposing actions on morphine actions. The ability to selectively down-regulate splice variants opens many areas in the study of nNOS and other proteins.

Analgesia↗
PubMed2006

Differential functions of tumor necrosis factor receptor 1 and 2 signaling in ischemia-mediated arteriogenesis and angiogenesis.

We have previously shown that tumor necrosis factor (TNF) acts via its two receptors TNFR1 and TNFR2 to elicit distinct signaling pathways in vascular endothelial cells (ECs). Here we used a femoral artery ligation model to demonstrate that TNFR1-knockout (KO) mice had enhanced, whereas TNFR2-KO had reduced, capacity in clinical recovery, limb perfusion, and ischemic reserve capacity compared with the wild-type mice. Consistently, ischemia-initiated collateral growth (arteriogenesis) in the upper limb and capillary formation and vessel maturation (angiogenesis) in the lower limb were enhanced in TNFR1-KO but were reduced in TNFR2-KO mice. Furthermore, our results suggest that vascular proliferation, but not infiltration of macrophages and lymphocytes, accounted for the phenotypic differences between the TNFR1-KO and TNFR2-KO mice. In wild-type animals TNFR2 protein in vascular endothelium was highly up-regulated in response to ischemia, leading to increased TNFR2-specific signaling as determined by the formation TNFR2-TRAF2 complex and activation of TNFR2-specific kinase Bmx/Etk. In isolated murine ECs, activation of TNFR2 induced nuclear factor-kappaB-dependent reporter gene expression, EC survival, and migration. In contrast, activation of TNFR1 caused inhibition of EC migration and EC apoptosis. These data demonstrate that TNFR1 and TNFR2 play differential roles in ischemia-mediated arteriogenesis and angiogenesis, partly because of their opposite effects on EC survival and migration.

Amino Acid Sequence↗
PubMed2001

Bidirectional modulation of basal forebrain N-methyl-D-aspartate receptor function differentially affects visual attention but not visual discrimination performance.

Basal forebrain neuronal circuits, specifically the corticopetal cholinergic system, mediate attentional abilities. The effects of infusions of N-methyl-D-aspartate (NMDA) and the competitive NMDA receptor antagonist DL-2-amino-5-phosphonovaleric acid (APV) into the basal forebrain were assessed in rats trained in an operant task designed to generate measures of sustained attention performance. Control animals were trained in a cued visual discrimination task devoid of explicit demands on attentional performance, but involving similar basic operant components as the sustained attention task. The effects of intrabasalis infusions of NMDA (1, 3 and 6nmol) and APV (3, 10 and 20nmol) were tested in separate groups of animals. Infusion of neither drug affected the animals' response accuracy in the cued visual discrimination task, indicating that performance in this task remains insufficient to activate basal forebrain NMDA receptors. Infusions of APV in sustained attention task-performing animals selectively decreased the animals' ability to detect visual signals, but spared their ability to reject non-signal events. Conversely, infusions of NMDA into the basal forebrain did not affect the animals' hit rate but increased their number of false alarms, i.e. "claims" for signals in non-signal trials. The concentrations of NMDA infused into the basal forebrain did not result in neurotoxic effects as demonstrated by a separate experiment, which indicated neurodegeneration following the infusion of 30 nmol NMDA as visualized by the Fluoro-Jade method.The effects of APV correspond with the attentional consequences of other manipulations known to impair the functions of cortical cholinergic input. Conversely, the effects of NMDA infusions agree with the hypothesis that overactivity of cortical cholinergic inputs mediates an abnormal overprocessing of the stimulus situation. Basal forebrain NMDA receptor manipulations assist in determining the role of this neuronal system in cognitive processes.

2-Amino-5-phosphonovalerate↗
PubMed1999

Differential function of N-cadherin and cadherin-7 in the control of embryonic cell motility.

Similar amounts of N-cadherin and cadherin-7, the prototypes of type I and type II cadherin, induced cell-cell adhesion in murine sarcoma 180 transfectants, Ncad-1 and cad7-29, respectively. However, in the initial phase of aggregation, Ncad-1 cells aggregated more rapidly than cad7-29 cells. Isolated Ncad-1 and cad7-29 cells adhered and spread in a similar manner on fibronectin (FN), whereas aggregated cad7-29 cells were more motile and dispersed than aggregated Ncad-1 cells. cad7-29 cells established transient contacts with their neighbors which were stabilized if FN-cell interactions were perturbed. In contrast, Ncad-1 cells remained in close contact when they migrated on FN. Both beta-catenin and cadherin were more rapidly downregulated in cad7-29 than in Ncad-1 cells treated with cycloheximide, suggesting a higher turnover rate for cadherin-7-mediated cell-cell contacts than for those mediated by N-cadherin. The extent of FN-dependent focal adhesion kinase phosphorylation was much lower if the cells had initiated N-cadherin-mediated rather than cadherin-7-mediated cell adhesion before plating. On grafting into the embryo, Ncad-1 cells did not migrate and remained at or close to the graft site, even after 48 h, whereas grafted cad7-29 cells dispersed efficiently into embryonic structures. Thus, the adhesive phenotype of cadherin-7-expressing cells is regulated by the nature of the extracellular matrix environment which also controls the migratory behavior of the cells. In addition, adhesions mediated by different cadherins differentially regulate FN-dependent signaling. The transient contacts specifically observed in cadherin- 7-expressing cells may also be important in the control of cell motility.

Animals↗
PubMed1982

Characterization of biochemical properties of melanosomes for structural and functional differentiation: analysis of the compositions of lipids and proteins in melanosomes and their subfractions.

Two types of melanosomes were isolated from B16 and Harding Passey (HP) mouse melanomas to elucidate whether there are any features of melanosomal lipids and proteins related to the differences in morphology of melanosomes and in the biological activities of melanoma cells. Biochemical analyses were made to clarify (a) the lipid components of the 2 melanosomes and (b) the lipid and polypeptide compositions of their subfractions, i.e., the outer surface and inner core, resolved by a detergent, Brij-35, separately. We found (a) that the lipid contents in B16 melanosomes were much higher than those in HP, (b) that the B16 and HP melanosomes could be fractionated into a phospholipid-rich outer surface and phospholipid-poor core, (c) that both outer surface and core subfractions of HP were distinct from the corresponding subfractions of B16 with respect to phospholipid contents, (d) that the outer surface of B16 and HP revealed a polypeptide composition similar to each other, although the protein contents of the outer surface were much lower than those of core and (e) that the total melanosomes showed a marked difference in polypeptides between B16 and HP. In addition, both B16 and HP melanosomes revealed the alteration of lipid compositions, e.g., fatty acid acyl chain, similar to that observed during malignant transformation. There was not, however, any significant difference in acyl compositions between B16 and HP. It is likely that melanosomal lipid and protein not only affect the different morphogenesis of melanosomes but also reflect the different biological activities of whole cells, and that lipids, primarily located in the outer surface, regulate the functional aspects of melanosomes.

Animals↗
PubMed1993

Differential effects of transforming growth factor-beta 1 and bone morphogenetic protein 4 on gene expression and differentiated function of preosteoblasts.

Transforming growth factor-beta (TGF-beta) and bone morphogenetic protein 4 (BMP 4) are both able, under certain circumstances, to induce endochondral bone formation in vivo. This study compared the effects of TGF-beta 1 and BMP 4 on the gene expression of a retinoic acid (RA) responsive rat clonal preosteoblast cell line, UMR 201, as well as the way in which these proteins interact with RA in these cells. Both similarities as well as differences between the effects and mechanism of action of TGF-beta 1 and BMP 4 were demonstrated. TGF-beta 1 (0.1 ng/ml) strongly induced matrix gla protein (MGP) mRNA and increased the steady state osteonectin (ON) mRNA level. Cotreatment with TGF-beta 1 and RA did not result in a further increase in MGP mRNA expression. In contrast, BMP 4 alone had no influence on MGP or ON mRNA expression but it significantly enhanced the RA induction of MGP mRNA. Pro-alpha 1(l) collagen mRNA was increased by TGF-beta 1 (1 ng/ml) and BMP 4 (50 ng/ml). The addition of either TGF-beta 1 or BMP 4 together with RA resulted in a further increase in pro-alpha 1 (l) collagen mRNA levels. Both RA and TGF-beta 1, but not BMP 4, increased the transcriptional rate of the pro-alpha 1 (l) collagen gene. TGF-beta 1 reduced the constitutive as well as RA-induced expression of osteopontin (OP) mRNA while BMP 4 reduced only the constitutive expression of OP mRNA. RA increased the transcriptional rate of the OP gene. Since the responses of UMR 201 cells to these structurally related factors were not identical, the results lend support to the concept that the coordinated expression of members of the TGF-beta 1 superfamily may be necessary to control the progression of specific cell types through their differentiation pathways.

Animals↗
PubMed1990

Brain-derived neurotrophic factor increases survival and differentiated functions of rat septal cholinergic neurons in culture.

Brain-derived neurotrophic factor (BDNF) was found to promote the survival of E17 rat embryo septal cholinergic neurons in culture, as assessed by a histochemical stain for acetylcholinesterase (AChE). A 2.4-fold increase in neuronal survival was achieved with 10 ng/ml BDNF. After initial deprivation of growth factor for 7 days, BDNF failed to bring about this increase, strongly suggesting that BDNF promotes cell survival and not just induction of AChE. BDNF was also found to increase the levels of cholinergic enzymes; choline acetyltransferase (ChAT) and AChE activities were increased by approximately 2-fold in the presence of 50 ng/ml BDNF. BDNF produced a 3-fold increase in the number of cells bearing the NGF receptor, as detected by the monoclonal antibody IgG-192. Although NGF had no additive effect with BDNF in terms of neuronal survival, suggesting that both act on a similar neuronal population, the combination of both produced an additive response, approximately a 6-fold increase, in ChAT activity.

Acetylcholinesterase↗
PubMed1982

The culture of chick embryo chondrocytes and the control of their differentiated functions in vitro. I. Characterization of the chondrocyte-specific phenotypes.

We have maintained chick embryo chondrocytes in culture for more than 2 months, passaging the floating cells in the absence of ascorbic acid. Throughout the culture period some of the cells attached to the dish, assuming an epithelial-like morphology and subsequently giving rise to new floating cells. The interconversion of the two cell populations was highest in primaries and decreased with the aging of the culture. Cartilage cells synthesized pro-alpha 1 (II) collagen and sulphated proteoglycans in vitro; compared with floaters, the epithelial-like cells secreted relatively large amounts of fibronectin. When ascorbic acid was added to the medium, all cells attached, maintaining their rounded shape; in this condition the pro-alpha, (II) collagen was matured and collagen fibres were detectable outside the cells. Other specific proteins synthesized by the chondrocytes in culture were also identified. One of these, a 64 K collagenase-sensitive protein, was not related to the type II collagen and may represent a new collagen type.

Animals↗