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PubMed1979

Development of cell-to-cell relationships in the thyroid gland of the chick embryo.

Thyroid glands of 7 to 21 day-old chick embryos were examined by electron microscopy using freeze-fracture and thin-section preparations. The primitive follicle lumen first appears between two adjacent epithelial cells in 8 day-old embryos, and is formed in the region of a focal tight junction (macula occludens). The focal tight junction develops into the zonula occludens when the primitive follicle lumen first forms. The zonula occludens is, at first, composed of 4.6 +/- 2.45 strands, but with increasing embryonic age the number of strands increases to 5.9 +/- 1.41 in 13 day-old, and 8.0 +/- 1.75 in 19 day-old embryos. Thyroglobulin stored within the embryonic gland lumina is isolated from the mesenchymal tissue even at the first appearance of these follicle cavities. Well developed gap junctions already occur in the thyroid gland of the 7 day-old embryo, so that an intimate relationship and communication between these cells already exists at the time of their functional differentiation.

Animals↗

PubMed1998

Self-inhibition in Ca2+ -evoked taste responses: a novel tool for functional dissection of salt taste transduction mechanisms.

Rat chorda tympani (CT) responses to CaCl2 were obtained during simultaneous current and voltage clamping of the lingual receptive field. Unlike most other salts, CaCl2 induced negatively directed transepithelial potentials and gave CT responses that were auto-inhibitory beyond a critical concentration. CT responses increased in a dose-dependent manner to approximately 0.3 M, whereafter they decreased with increasing concentration. At concentrations where Ca2+ was self-inhibitory, it also inhibited responses to NaCl, KCl, and NH4Cl present in mixtures with CaCl2. Ca2+ completely blocked the amiloride-insensitive component of the NaCl CT response, the entire KCl-evoked CT response, and the high-concentration-domain CT responses of NH4Cl (>/=0.3 M). The overlapping Ca2+-sensitivity between the responses of the three Cl- salts (Na+, K+, and NH+4) suggests a common, Ca2+-sensitive, transduction pathway. Extracellular Ca2+ has been shown to modulate the paracellular pathways in different epithelial cell lines by decreasing the water permeability and cation conductance of tight junctions. Ca2+-induced modulation of tight junctions is associated with Ca2+ binding to fixed negative sites. This results in a conversion of ion selectivity from cationic to anionic, which we also observed in our system through simultaneous monitoring of the transepithelial potential during CT recording. The data indicate the paracellular pathway as the stimulatory and modulatory site of CaCl2 taste responses. In addition, they indicate that important transduction sites for NaCl, KCl, and NH4Cl taste reception are accessible only through the paracellular pathways. More generally, they show that modulation of paracellular transport by Ca2+ in an intact epithelium has functional consequences at a systemic level.

Amiloride↗

PubMed1983

The conjunctival epithelium in domestic ruminants. II. Electronmicroscopic investigations.

The basal cells of all types of epithelia in the domestic ruminants have a smooth surface in their proximal part or are furnished with branched cytoplasmic projections. The cytoplasm of many basal cells contains a few or many micropinocytotic vesicles, which can be arranged in a moniliform manner. The intermediate cells as well as the cells of the stratum superficiale - with the exception of the uppermost layers of the stratified squamous epithelium - are characterized by the presence of a great number of membrane-bound granules. Microvilli which project over the uppermost epithelial cells only occasionally contain a filamentous internal structure. The apical closure of the epithelium is preferentially formed by zonulae occludentes (tight junctions) with maximally 2-3 tight junction seals, they are followed proximally by 1-2 desmosomes. Zonulae adhaerentes can only rarely be observed. The nervous supply of the conjunctival epithelium which is best developed in the bulbusfacing side of the nictitating membrane is brought about by sub- and intraepithelial nerve-endings.

Animals↗

PubMed1976

Uptake and transport of exogenous proteins by respiratory epithelium.

The tracer proteins, horseradish peroxidase and ferritin, placed in the trachea of guinea pigs were taken up by epithelial cells and transported to the extracellular space. The interval between the introduction of the tracer proteins into the lumen of the trachea and the morphologic demonstration of the porteins in the extracellular space or within the basal portion of the cells was between 30 and 60 minutes. The proteins were transported in vesicles and no penetration of the epithelial intercellular tight junctions was found. The intercellular tight junctions were made permeable to horseradish peroxidase by anesthetic ether and this permeable epithelium was compared to the vesicle type transport. Transepithelial transport of proteins is a possible mechanism for the introduction of antigenic material into the subepithelial lymphoid tissue and this transport may also be of importance in the late onset type of asthma.

Animals↗

PubMed1982

Ionic conductive properties and electrophysiology of the rabbit cortical collecting tubule.

The Na, K, and Cl conductive properties and the electrophysiological variability of the rabbit isolated cortical collecting tubule were assessed by evaluating the effect of single-ion substitutions on the transepithelial potential difference, Vte, and the transepithelial conductance, Gte. The Na permeability (and conductance) of the tight junction and basolateral cell membrane appeared to be low. However, a significant but variable amiloride-sensitive Na conductance was identified at the apical cell membrane. Although this Na conductance accounts for less than 10% of the Gte, variations in this conductance caused major alterations in the active transepithelial Na current and the Vte. A highly variable K permeability (and conductance) was also identified at the apical cell border and may account for some of the variability in Vte and Gte. This probably provides a pathway for K secretion from cell to lumen. The K permeability of the tight junction and basolateral cell membrane appeared to be relatively low. In contrast, the Cl permeability (and conductance) of the tight junction, and perhaps of the basolateral cell membrane, appeared to be high but variable and to account for the major fraction of the Gte and its variability. It is concluded that variations in the Na and K conductance of the apical cell membrane and the Cl conductance of the tight junction and basolateral cell membrane predominantly account for the variations in the electrophysiological properties of the cortical collecting tubule.

Amphotericin B↗

PubMed2000

Epithelial barrier defects in HT-29/B6 colonic cell monolayers induced by tumor necrosis factor-alpha.

The barrier function of intestinal epithelia relies upon the continuity of the enterocyte monolayer and intact tight junctions. After incubation with tumor necrosis factor-alpha TNF-alpha, however, the number of strands that form the tight junctions decreases, and apoptosis is induced in intestinal epithelial cells. These morphological changes lead to a rise of transepithelial ion permeability, because the paracellular ion permeability increases and leaks associated with sites of apoptosis increase by number and magnitude. Thus apoptosis and degradation of tight junctions contribute to the increased permeability observed after exposure to TNF-alpha. These mechanisms explain clinical manifestations in the inflamed intestinal wall containing cytokine-secreting macrophages--for example, leak flux diarrhea and invasion of bacterial enterotoxins.

Apoptosis↗

PubMed2004

Glioblastoma cells release factors that disrupt blood-brain barrier features.

The blood-brain barrier (BBB), mediated by endothelial tight junctions, is defective in malignant gliomas such as glioblastoma, resulting in cerebral edema and contrast enhancement upon neuroradiological examination. The mechanisms underlying BBB breakdown are essentially unknown. Since non-neoplastic astrocytes are required to induce BBB features of cerebral endothelial cells, it is conceivable that malignant astrocytes have lost this ability due to dedifferentiation. Alternatively, glioma cells might actively degrade previously intact BBB tight junctions. To examine the latter hypothesis, we have employed a transepithelial electrical resistance breakdown assay using monolayers of the C7 subclone of Madin-Darby canine kidney (MDCK-C7) cells forming tight junctions similar to those of BBB endothelial cells. We found that glioblastoma primary cells co-cultured with the MDCK-C7 monolayer (without direct contact of the two cell types) resulted in marked breakdown of electrical resistance, whereas primary cultures derived from low-grade gliomas (fibrillary astrocytoma, oligoastrocytoma) showed delayed or no effects. These results suggest that malignant gliomas have acquired the ability to actively degrade tight junctions by secreting soluble factors, eventually leading to BBB disruption within invaded brain tissue.

Animals↗

PubMed1988

Neuronal and glial gap junctions in the goldfish preoptic area, a thin section and freeze-fracture study.

In freeze-fracture, both large macular gap junctions and long thin gap junctions surrounded by a strand of tight junction were found on neurosecretory cells. Preoptic neurons show large areas of soma-to-soma apposition, but thin section showed no evidence for gap junctions between neuronal somata. Neurosecretory cell neurites formed parallel bundles in neuropil lateral to the nucleus, and gap junctions were found between the neurites. These junctions apparently correspond to macular junctions seen on neurosecretory elements in freeze-fracture. Some large macular gap junctions found in freeze-fracture presumably correspond to junctions seen between glial cells in thin section. However, glial membranes lacked characteristics distinguishing them from neuronal membranes. In one instance, a large apparent glial sheet process formed both macular and long thin gap junctions on different surfaces. The long thin gap junctions that were surrounded by a strand of tight junction were formed with a large neurosecretory cell soma. Extensive pinocytosis was observed at some membranes forming gap junctions.

Animals↗

PubMed2005

Regulation of the polarity protein Par6 by TGFbeta receptors controls epithelial cell plasticity.

The transition of cells from an epithelial to a mesenchymal phenotype is a critical event during morphogenesis in multicellular organisms and underlies the pathology of many diseases, including the invasive phenotype associated with metastatic carcinomas. Transforming growth factor beta (TGFbeta) is a key regulator of epithelial-to-mesenchymal transition (EMT). However, the molecular mechanisms that control the dissolution of tight junctions, an early event in EMT, remain elusive. We demonstrate that Par6, a regulator of epithelial cell polarity and tight-junction assembly, interacts with TGFbeta receptors and is a substrate of the type II receptor, TbetaRII. Phosphorylation of Par6 is required for TGFbeta-dependent EMT in mammary gland epithelial cells and controls the interaction of Par6 with the E3 ubiquitin ligase Smurf1. Smurf1, in turn, targets the guanosine triphosphatase RhoA for degradation, thereby leading to a loss of tight junctions. These studies define how an extracellular cue signals to the polarity machinery to control epithelial cell morphology.

Activin Receptors, Type I↗

PubMed1982

Intercellular junctions in the developing arachnoid membrane in the chick.

The arachnoid membrane of chick embryos was prepared for electron microscopic study by means of thin sections and freeze-fracture replicas. Particular attention was given to the relationships among junctional complexes during arachnoid maturation. By 14 days of incubation, the arachnoid had differentiated into morphologically distinct inner and outer zones. Both desmosomes and gap junctions were present among the cells of both layers at this time. Desmosomes were most numerous in the inner arachnoid layer and their structure remained constant. Gap junctions showed a great variation in structure. The large gap junctions contained a particle packing pattern in which rows of intramembranous particles were separated by particle-free zones. Arched gap junctions were also present. Smaller arrays of gap junctions exhibited a variety of configurations on the membrane P-face. The first tight-junctional stands clearly identifiable in freeze-fractured preparations appeared at 15-17 days. These were closely associated with the particles of gap junctions and consisted of single stands on the P-face. By hatching age (21 days) a "mature" pattern of tight-junctional strands was interwoven in several layers. In the interim, more complex arrangements of tight-junctional strands were in intimate relation with gap junctions.

Animals↗

PubMed2001

Succession of events in desquamation of superficial urothelial cells as a response to stress induced by prolonged constant illumination.

The effect of moderate stress induced by prolonged illumination was analysed on urothelial cells of female mouse urinary bladders at ultrastructural and cytochemical levels. This study demonstrates that the urothelium responds to moderate stress with desquamation which involves two subsequent steps. The first step includes a local detachment of tight junctions and consequently the loss of the permeability barrier leading to expanded intercellular spaces among urothelial cells. During the second step, the disjunction of desmosomes accompanied by exocytosis of lysosomal enzymes (NADPase) in the intercellular space results in exfoliation of superficial cells. It is evident that moderate stress elicits an enhanced desquamation of only superficial cells by a subsequent dysfunction of first tight junctions and after that adherens-type junctions. A rapid restoration of the new tight junctions prevents a long-term malfunction of the blood-urine barrier.

Animals↗

PubMed2006

ESAM supports neutrophil extravasation, activation of Rho, and VEGF-induced vascular permeability.

Endothelial cell-selective adhesion molecule (ESAM) is specifically expressed at endothelial tight junctions and on platelets. To test whether ESAM is involved in leukocyte extravasation, we have generated mice carrying a disrupted ESAM gene and analyzed them in three different inflammation models. We found that recruitment of lymphocytes into inflamed skin was unaffected by the gene disruption. However, the migration of neutrophils into chemically inflamed peritoneum was inhibited by 70% at 2 h after stimulation, recovering at later time points. Analyzing neutrophil extravasation directly by intravital microscopy in the cremaster muscle revealed that leukocyte extravasation was reduced (50%) in ESAM(-/-) mice without affecting leukocyte rolling and adhesion. Depletion of >98% of circulating platelets did not abolish the ESAM deficiency-related inhibitory effect on neutrophil extravasation, indicating that it is only ESAM at endothelial tight junctions that is relevant for the extravasation process. Knocking down ESAM expression in endothelial cells resulted in reduced levels of activated Rho, a GTPase implicated in the destabilization of tight junctions. Indeed, vascular permeability stimulated by vascular endothelial growth factor was reduced in ESAM(-/-) mice. Collectively, ESAM at endothelial tight junctions participates in the migration of neutrophils through the vessel wall, possibly by influencing endothelial cell contacts.

Animals↗

PubMed1998

Hot spices influence permeability of human intestinal epithelial monolayers.

Indirect evidence suggests that hot spices may interact with epithelial cells of the gastrointestinal tract to modulate their transport properties. Using HCT-8 cells, a cell line from a human ileocoecal carcinoma, we studied the effects of spices on transepithelial electrical resistance (TER), permeability for fluorescein isothiocyanate (FITC)-labeled dextrans with graded molecular weight, and morphological alterations of tight junctions by immunofluorescence using an anti-ZO-1 antibody, a marker for tight junction integrity. Two different reactivity patterns were observed: paprika and cayenne pepper significantly decreased the TER and increased permeability for 10-, 20- and 40-kDa dextrans but not for -70 kDa dextrans. Simultaneously, tight junctions exhibited a discontinuous pattern. Applying extracts from black or green pepper, bay leaf or nutmeg increased the TER and macromolecular permeability remained low. Immunofluorescence ZO-1 staining was preserved. In accordance with the above findings, capsaicin transiently reduced resistance and piperine increased resistance, making them candidates for causing the effects seen with crude spice extracts. The observation that Solanaceae spices (paprika, cayenne pepper) increase permeability for ions and macromolecules might be of pathophysiological importance, particularly with respect to food allergy and intolerance.

Cells, Cultured↗

PubMed1984

Junction formation in aggregated embryonal carcinoma cells.

Under the action of supplemental calcium, H6 mouse embryonal carcinoma cell aggregates undergo compaction, a morphological phenomenon similar to mouse embryonic compaction. Formation of various types of cell junctions, especially gap junctions, is associated with compaction of the embryo and we sought to analyze the pattern of junction formation during aggregation and compaction of H6 cells. At 24 hr of aggregation, gap junctions were abundant in both uncompacted and compacted aggregates but quantitative analysis of freeze fracture replicas of these junctions showed a 20-fold increase in the size of the largest gap junctions in compacted aggregates. Such a difference in size could even be detected at 12 hr of aggregation. Tight junctions were not normally formed in 12 hr aggregates but initial stages of tight junction formation could be noticed in 12 hr compacted aggregates. More definitive tight junctions and desmosomes were evident only after 48 hr of aggregation. Thus we have observed that both uncompacted and compacted aggregates can form gap junctions at similar frequencies, suggesting that cell flattening, which contributes to the compacted morphology, is not a requisite for gap junctions. Likewise, generation of the compacted morphology seems to be independent of gap junction formation. This supports the idea that compaction in embryonal carcinoma cells results from calcium-induced cell flattening, probably through the mobilization of cytoskeletal elements. Calcium-dependent features of H6 cell aggregation and compaction enables the independent analysis of separate steps in compaction.

Animals↗

PubMed1997

Maturation of the blood-retina barrier in the developing pecten oculi of the chicken.

The major interest in the development of the blood-brain barrier and its underlying induction mechanisms is given by the crucial role they play in the maturation of the central nervous system in general. Whilst it is believed that it is the microenvironment in the brain that destines the endothelial cells to become committed to barrier properties, the analysis of the multitude of factors probably responsible for this commitment is extremely difficult. Therefore, in a previous study, we inaugurated the pecten oculi of the avian eye as a relatively simple in vivo model of the blood-brain barrier [Gerhardt, S. et al, Cell Tissue Res., 285 (1996) 91-100]. In the present study, we demonstrate data on the development of the pecten which allow us to understand better the commitment of barrier properties in endothelial cells in an environment which is considerably less complex than that realized in the brain. The pecten is built up by mainly two cell types, the pigmented glial cells and the endothelial cells. The pigmented cells, which are believed to originate from the retinal pigment epithelium, lose their tight junctions in the microenvironment of the vitreous body, whereas the endothelial cells, which originate from the permeable choroidal vessels, gain tight junctions and other barrier properties in the microenvironment of the vitreous body. On embryonic day 7 (E7), tight and gap junctions between epithelial-like glial cells line the vitreal border of the developing pecten. By E16, these junctions disappear, and the endothelial cells gradually acquire barrier characteristics (continuous and P-face associated tight junctions, no extravasation of lanthanum nitrate, and the exclusive expression of the glucose transporter isoform 1 and the barrier specific antigen HT7 in their luminal and abluminal membranes). The results are discussed considering the switch from an epithelial (glial) to an endothelial barrier.

Animals↗

PubMed1991

Histogenesis of the mucosa of the descending colon in mouse fetuses.

The present study clarify intraepithelial events occurring during the formation of intestinal crypts in the descending colon. In early stage, the mucosa is lined with a simple columnar epithelium consisting of undifferentiated cells which are mutually joined by the junctional complex surrounding the intestinal lumen. The epithelium becomes thickened and stratified, and secondary junctional complexes are formed in the abluminal part of the epithelium. An intracellular cavity opens to the focal tight junction of the secondary junctional complex to form an intraepithelial (intercellular) cavity surrounded by the tight junction. The intraepithelial cavity grows by the fusion of intracellular cavities and vesicles as well as by the division of surrounding cells. Intraepithelial cavities fuse with each other and with the main intestinal lumen. This, together with mesenchymal invasion, results in the formation of intestinal crypts lined with a simple columnar epithelium, where various cell types begin to differentiate. These processes seem essentially similar to those occurring in the developing small intestine except that villi, not crypts, are formed in the small intestine. It is suggested that the formation site and elongation of the tight junction provide for the location and fusion of intraepithelial cavities and eventually result in the formation of villi or crypts, alternatively.

Animals↗

PubMed2003

Endothelin-1 synthesis and secretion in human retinal pigment epithelial cells (ARPE-19): differential regulation by cholinergics and TNF-alpha.

PURPOSE: Endothelin (ET)-1 can produce nerve damage analogous to that in optic neuropathies such as glaucoma. The precise source of endothelin in the posterior segment of the eye remains unclear. The present study was conducted to determine whether the retinal pigment epithelium (RPE), which helps maintain the outer blood-retinal barrier, is a local source for ET-1 and whether the amount of ET-1 secreted by the RPE is be differentially regulated by cholinergics and the cytokine TNF-alpha. METHODS: Human retinal pigment epithelial cells (ARPE-19) were cultured either to a mature state (mRPE) for 4 weeks, with well-defined tight junctions, or to a young state (yRPE) for 4 days, with incompletely formed tight junctions. ET-1-like immunoreactivity was determined by immunocytochemistry, and secreted ET-1 was quantified by radioimmunoassay in both cell types. Cells were stimulated with the cholinergic agonist carbachol or with the cytokine TNF-alpha for specific periods. The expression of muscarinic receptor subtypes M1 and M3 and the peripheral membrane protein ZO-1 were analyzed by immunoblot and immunocytochemistry, respectively. Expression of preproendothelin-1 (ppET-1) mRNA after application of different stimuli at specific time points was determined by real-time RT-PCR. Carbachol-mediated elevation in intracellular calcium ([Ca2+]i) was also measured in the presence or absence of a selective muscarinic receptor antagonist. RESULTS: Constitutive synthesis and secretion of ET-1 was greater in mRPE than in yRPE cells. TNF-alpha caused a significant increase in ppET-1 mRNA levels and ET-1 secretion in both phenotypes. The disruption and subsequent breakdown of the tight junction barrier was evident in either phenotype after treatments with TNF-alpha. There was a concentration-dependent increase in [Ca2+]i in both y- and mRPE cells in response to CCh. CCh at 1 microM significantly increased ET-1 secretion, a response observed in yRPE but not in mRPE cells. This effect may be mediated primarily by the M3 receptor subtype and is phospholipase C (PLC) dependent. CONCLUSIONS: Regulation of ET-1 release in ARPE-19 cells was differentially regulated by TNF-alpha and CCh and was dependent on the age of the culture. RPE may be a source for ET-1 in the retina, and its increased release may become more important during breakdown of the blood-retinal barrier, as seen after TNF-alpha treatment.

Calcium↗

PubMed1985

Large particles associated with gap junctions of pancreatic exocrine cells during embryonic and neonatal development.

The formation of gap junctions was studied in pancreatic exocrine cells of rats and mice during late embryonic and neonatal development by the freeze-fracture replica method. Small gap junctions were present in association with tight junctional strands near the cell apex during embryonic development. Independently of tight junctions, small gap junctions were sometimes seen more basally on day 13 to 15 of gestation. The gap junctions increased in number and were rapidly enlarged by day 18 to 20 of gestation. Large particles 12-13 nm in diameter were frequently associated with the gap junction, which consisted of 10 nm particles. The large particles were either irregularly distributed or arranged in hexagonal patterns. The number of large particles decreased with time, so that they sparsely rimmed the gap junction in postnatal animals. This suggests that large particles are precursors of typical gap junctional particles, and that they participate in rapid growth of the gap junction during late embryonic development. It may be also possible that large particles represent functionally different gap junctions.

Animals↗