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PubMed1991

Biochemical and ultrastructural evidence for the association of basic fibroblast growth factor with cardiac gap junctions.

Basic fibroblast growth factor (bFGF) is a ubiquitous and multifunctional polypeptide that is believed to have a role in tissue repair and to act as a morphogen in embryonic development. Here, we have used immunohistochemical and biochemical methods with antibodies directed against the amino-terminal domain of bFGF, designated IS2, which recognize native and denatured bFGF, to demonstrate that in addition to its known intracellular and extracellular localization in heart, bFGF is also associated with cardiomyocyte gap junctions. In tissue sections, IS2 labeled regions of intercalated discs, producing an immunofluorescence pattern virtually indistinguishable from that obtained with antibodies against the heart gap junction protein connexin-43. By electron microscopy, gap junctions but not other regions of plasma membrane were heavily immunolabeled with this antibody. By solid phase immunoassay, bFGF was found to be more concentrated in a fraction enriched in cardiac gap junctions than in whole sarcolemmal preparations. Finally, an 18-kDa protein was recognized by several different antibodies specific for bFGF on Western blots of heart subcellular fractions enriched in gap junctions. We suggest that bFGF-like peptides are either an integral part of, or exist in close association with, cardiac gap junctions and thus may play a role in modulating gap junctional intercellular communication.

Animals↗
PubMed1991

Junctional communication of highly and weakly metastatic variant clones from a rat mammary carcinoma in primary and metastatic sites.

We have investigated junctional intercellular communication (JC) in primary and metastatic sites, using two highly and two weakly metastatic variant clones which had been isolated from a rat mammary carcinoma cell line, c-SST-2. After each variant had been subcutaneously inoculated into syngeneic rats, tumor cells were isolated from local tumor (primary tumor) and their metastatic foci (lung, heart and kidney). The cells were then recultured, and we measured their JC in vitro by the dye transfer method with the fluorescent dye Lucifer yellow CH, and found that the homologous (tumor cell-tumor cell) JC of highly metastatic clones were less in recultured tumor cells from primary tumors than that of weakly metastatic clones. At the same time, the heterologous (tumor cell-normal fibroblast) JC of highly metastatic clones was less than that shown by weakly metastatic clones. On the other hand, tumor cells obtained from metastatic foci showed relatively reduced JC (homologous and heterologous) when compared with those from their primary tumors in the weakly metastatic clones. These data suggest that a decrease in and/or a loss of JC may play a role in the expression of metastatic properties.

Animals↗
PubMed1989

Papillary cystic tumor of the pancreas: an immunohistochemical and ultrastructural study of 14 patients.

We report herein the clinicopathological, immunohistochemical and ultrastructural studies on 13 female patients and one male patient with papillary cystic tumors of the pancreas. Their ages ranged from 12 to 60 (mean 25) years. Most patients complained of abdominal mass or abdominal pain. Following complete resection of the tumor, all have remained well for between 3 months and 19 years (maen 5 years). In one patient the tumor was malignant and, 10 years after the initial partial resection, there was a recurrence with involvement of the colon, metastasis to the lymph nodes and venous invasion. Immunohistochemically, most tumor cells were positive for neuron specific enolase, synaptophysin, alpha-1-antitrypsin and vimentin and sometimes for the estrogen receptor related antigen, ER-D5, and the oncogen product of c-Ha-ras, c-Ha-ras P21. Ultrastructurally there were zymogen-like intracytoplasmic granules, intercellular junctions and intercellular spaces. These results support the hypothesis that the tumor originates from undifferentiated cells capable of differentiation toward acinar, endocrine or ductular cells. Estrogen and the c-Ha-ras oncogene presumably are linked to the development.

Adolescent↗
PubMed2006

Regulation of the intestinal epithelial barrier by the apical junctional complex.

PURPOSE OF REVIEW: Epithelial intercellular junctions are important components of the epithelial barrier and are compromised in disorders such as Crohn's disease. We will highlight recent progress in understanding the role of an intercellular junction referred to as the apical junctional complex in regulating small intestinal epithelial permeability in health and disease. RECENT FINDINGS: Recent studies have implicated aberrant regulation of the AJC as an underlying factor contributing to a leaky epithelial barrier in Crohn's patients. Consequences of increased epithelial permeability include exposure of intestinal tissue to luminal antigens/pathogens which in turn influence disease activity. Furthermore, proinflammatory cytokines released into the milieu of the epithelium in patients with Crohn's disease influence apical junctional complex and epithelial barrier function. Such cytokines induce disassembly of the apical junctional complex by promoting differential endocytosis of component proteins. Additionally, apical junctional complex proteins are targeted by pathogens that use the epithelium as a portal of entry to establish disease in the host. SUMMARY: The epithelial apical junctional complex is important in determining epithelial barrier properties. Recent studies have highlighted contribution of proinflammatory cytokines and endocytosis of apical junctional complex proteins to the epithelial barrier defect. Continued advances in understanding of this field will yield new therapeutic targets for intestinal disorders.

Adherens Junctions↗
PubMed1993

An improved long-term culture of rat hepatocytes to detect liver tumour-promoting agents: results with phenobarbital.

Among various cocultures of hepatocytes with other cell types, we found that mouse embryonal cells (BALB/c 3T3) are more effective in maintaining rat hepatocytes in vitro. Because most human cancers are epithelial in origin, we thought that such a hepatocyte culture system could be used for the detection of tumour-promoting agents, most of which are inhibitors of gap-junctional intercellular communication. We, therefore, have examined the effect of the strong rat liver tumour promoter, phenobarbital, on the gap-junctional intercellular communication capacity of hepatocytes in long-term cultures. A single application of phenobarbital drastically inhibited the gap-junctional intercellular communication between hepatocytes in a coculture for only several hours, but treatment for 3 weeks provoked a constant decrease of gap-junctional intercellular communication (50%) throughout the treatment period. This type of long-term culture of rat hepatocytes may be usable in a rapid in vitro assay to detect tumour-promoting agents.

Albumins↗
PubMed1980

Cell junctions and intercellular communication.

We have compared intercellular communication in normal and regenerating rat liver. Gap junctions are greatly reduced in size and numbers 29 to 35 hr after hepatectomy, but we still find some 90% of hepatocytes coupled by electrophysiological criteria. The spread of dyes such as carboxyfluorescein however is very limited in the regenerating organs as compared to the situation in the controls. We show how the apparent discrepancies between morphological and physiological data can be reconciled. We also present a summary of preliminary findings on the biosynthesis of gap junction protein and some of the conclusions one can draw from the sequence of 58 amino acids at the amino terminal of the protein.

Animals↗
PubMed1970

The fine structure and electrophysiology of heart muscle cell injury.

Injured frog heart cells electrically uncouple from their uninjured neighbors within 30 min after injury. This uncoupling process can be shown by the disappearance of an injury potential measured between such injured and uninjured cells. In the present study, the time course of the decline of injury potentials, and thus of electrical uncoupling, in bullfrog atrial trabeculae was determined. Tissue was fixed with glutaraldehyde and osmium tetroxide at various times after injury to determine the morphological changes which accompany this uncoupling process. In some cases, ruthenium red was included in the fixatives. Normal atrial cells are long and narrow, with intercellular junctions located along the lateral surfaces of the cells. Two types of intercellular junctions have been observed: cardiac adhesion plaques (CAPs), and close junctions. Close junctions occur only infrequently. Ruthenium red penetrates all around the cells, leaving only small areas within the CAPs unstained. After injury, the cells are very dense and the myofilaments disarranged. Both types of intercellular junction remain intact, and only slight changes within CAPs are observed. The results are discussed in relation to current concepts of intercellular communication.

Action Potentials↗
PubMed1986

Ultrastructural studies of intercellular contacts (junctions) in bone marrow. A review.

This paper reviews ultrastructural studies of the intercellular contacts or junctions between cells of the bone marrow. Studies using tannic acid and glutaraldehyde as a fixative have shown pentalaminar complexes between many types of cells in marrow of mice and chicks. These intercellular contacts occur between adjacent stromal cells, between stromal cells and developing blood cells and, in marrow of mice, between migrating blood cells and cells of the sinusoidal wall. Because of their location and widespread occurrence, it is believed these contacts may represent a type of adherent junction helping to maintain an orderly arrangement of blood cells and stromal cells in the marrow. Migrating blood cells may use these contacts as anchoring sites during locomotion toward the sinusoids and in crossing the sinusoidal wall. On the other hand, since these junctions resemble gap junctions of other tissues, one should not exclude the possibility that they are involved in cellular communication. Freeze-fracture and lanthanum impregnation studies have failed to demonstrate these junctions in marrow. Studies using ruthenium red have shown apparent sites of attachment between cells of the marrow, but it is not known whether these sites correspond to the intercellular contacts seen in tannic acid preparations.

Animals↗
PubMed1994

Cadherin function is required for human keratinocytes to assemble desmosomes and stratify in response to calcium.

Elevation of the calcium concentration in keratinocyte culture induces the rapid organization of adherens junctions and desmosomes. Formation of these intercellular junctions is accompanied by reorganization of the cytoskeleton and, with a more delayed timecourse, stratification of the culture into a multilayered epithelial cell sheet. Keratinocytes express two cadherins, known as E- and P-cadherin, which are the cell-cell adhesion molecules of the adherens junction. Antibody that blocks E-cadherin function delays the calcium-induced formation of both adherens junctions and desmosomes and leads to an abnormally stratified cultured. In the present study, we show that anti-E-cadherin plus anti-P-cadherin antibodies inhibit the formation of adherens junctions and desmosomes, prevent reorganization of the cytoskeleton, and block stratification. These studies indicate that cadherin function is required for the calcium-induced intercellular junction organization and stratification of human keratinocytes in vitro.

Antibodies, Monoclonal↗
PubMed1999

Identification and characterisation of human Junctional Adhesion Molecule (JAM).

It is widely believed that migrating immune cells utilise the intercellular junctions as routes of passage, and in doing so cause the transient disruption of junctional structures. Thus there is much interest in the molecules that have been identified at cell-cell contact points and their potential involvement in the control of leukocyte diapedesis. In this report we describe the human orthologue to Junctional Adhesion Molecule (JAM), a recently identified member of the immunoglobulin superfamily expressed at intercellular junctions (Martin-Padura et al., 1998). The human protein shares a highly conserved structure and sequence with the murine protein. However it is distinct in that it is constitutively expressed on circulating neutrophils, monocytes, platelets and lymphocyte subsets. This broad expression pattern is similar to another IgSF molecule, CD31, expressed at intercellular junctions, and may indicate further complexities in the control of leukocyte/ endothelial interactions.

Amino Acid Sequence↗
PubMed1978

Cellular junctions in human oesophageal epithelium.

The appearances of this intercellular junctions in normal and in inflamed oesophageal epithelium are described. Typical hemidesmosomes occur along the abluminat aspect of the basal cells. Desmosomes are most frequent in the prickle cell layer, where desmosome fields may occur, and in the lower functional cell layer. Their fate in the upper layers is not known. Gap junctions are few in the basal cell layer and rare in the most superficial layers. They are maximal in the prickle cell layer. Tight junctions only occur in inflamed tissue between the most superficial cells usually as part of a lateral intercellular junctional complex that also contains belt desmosomes. They may represent attempts by a non-keratinised epithelium to increase its defences against toxic luminal contents.

Cell Membrane↗
PubMed1988

Topography and ultrastructure of kidney lymphatics in some hibernating bats.

The kidney lymphatic system of some bats consists of intraparenchymal (interlobar, arcuate, and interlobular) and extraparenchymal vessels (capsular and prehilar connective). These vessels drain lymph via precollecting and prenodal collecting lymphatics into a hilar lymph node. There are no lymphatics in the renal medulla. The lymphatic vasculature (precollecting vessels excluded) is characterized by an endothelial wall lacking basal lamina and fenestrations. The endothelial cells, mostly rectangular in shape, are joined together by overlapping, end-to-end, and complex interdigitating junctions. Cytoplasmic expansions profile and thickness, intercellular junctions and particularly the different categories of uncoated vesicles (free or opened on luminal or abluminal surface) show qualitative and quantitative seasonal variations. Luminal and abluminal cytoplasmic processes appear (when analyzed in tridimensional reconstructions) as "intraendothelial channels." The increased number of these structures during summer characterizes them as dynamic elements and supports the concept of an active role played by them in transendothelial transport. Nevertheless, the main functional role is still ascribed (in addition to membrane transport mechanisms) to the vesicular system, also defined as the "vesicular route." We did not find any open intercellular junctions.

Animals↗
PubMed2003

Gap junction-mediated intercellular communication in a long-term primary mouse hepatocyte culture system.

Gap junction-mediated intercellular communication (GJIC) is critical for maintaining integral cellular processes including differentiation and growth control. The disruption of GJIC has been correlated with aberrant function in many cell types, including hepatocytes in vivo; therefore it is imperative that cellular model systems support intercellular communication to simulate normal cellular functions. Functional GJIC has been shown in long-term primary rat hepatocyte cultures, which have been implemented widely to study various aspects of hepatocellular function; however, the onset of transgenic technology in murine species has necessitated the development of a primary mouse hepatocyte system. In this report, we analyze GJIC in a dimethylsulfoxide (DMSO)-containing long-term primary mouse hepatocyte culture system. The cells retain morphologic and biochemical characteristics of differentiated hepatocytes through day 30 post plating, including liver-specific gene expression. We further show that connexin32 and connexin26 expression and gap junction plaque formation increase over time in culture concomitant with an increase in GJIC between adjoining primary mouse hepatocytes. In conclusion, the findings described in this study make it possible to maintain differentiated primary mouse hepatocytes that also show GJIC in long-term culture for 30 days. In addition, this system has the potential to be extended to study primary mouse hepatocytes isolated from genetically engineered mice.

Animals↗
PubMed1991

Inhibition of gap junction-mediated intercellular communication by alpha-linolenate.

The purpose of this investigation was to assess whether alterations in the fatty acid composition of rat liver epithelial (WB-F344) cell phospholipids would modulate gap junction-mediated intercellular communication (GJIC). WB-F344 cells were grown to confluency in culture medium supplemented with one of seven different fatty acids at a concentration of 50 microM for 48 h. Only alpha-linoleate (18:3 n-3) significantly inhibited GJIC. Saturated fatty acids (12:0, 16:0, and 18:0), a monounsaturated fatty acid (18:1 n-9), and n-6 polyunsaturated fatty acids (18:2 and 20:4) did not affect GJIC. The alpha-linolenate-induced inhibition of GJIC was not due to the activation of protein kinase C or intracellular hydroperoxide production, two lipid-dependent parameters previously shown to inhibit GJIC. In addition, alpha-linolenate did not alter membrane fluidity. Although the mechanism by which alpha-linolenate inhibits GJIC is unclear, changes in the fatty acid composition of cell phospholipids may be of critical importance. Subsequent to supplementation with alpha-linolenate, WB-F344 cell phospholipids had reduced 20:4 n-6 and elevated n-3 fatty acids. The results of this investigation emphasize the importance of current research into the influence of lipids on cell function and identify a new mechanism by which gap junctions can be modulated.

Animals↗
PubMed1994

Spatiotemporal relation between gap junctions and fascia adherens junctions during postnatal development of human ventricular myocardium.

BACKGROUND: The growing postnatal human heart maintains electromechanical function while undergoing substantial changes of cellular topology and myocardial architecture. The capacity for growth and remodeling of ventricular myocardium in adaptation to the hemodynamic changes of early infancy later declines. This decline is associated with changes in electromechanical properties of the myocardium, which suggest that the electrical and mechanical interactions between the myocytes may change in an age-dependent manner. Thus, reduction in the capacity for myocardial growth and adaptability may relate to age-dependent alterations in the patterns of the intercellular junctions that mediate electrical and mechanical coupling. We therefore examined the hypotheses that (1) age-dependent changes in the distribution patterns of gap junctions and fasciae adherentes, the intercellular junctions responsible, respectively, for electrical and mechanical coupling, accompany postnatal development in the human heart and that (2) such changes continue into the first few years of childhood. Further, the spatial relation between the two types of junction, for which a close association has been hypothesized as necessary, was explored. METHODS AND RESULTS: Ventricular myocardial gap-junction distribution was investigated in 23 pediatric surgical patients (4 weeks to 15 years old) by quantitative immunohistochemical localization of the principal cardiac gap-junctional protein, connexin43, using confocal microscopy. Immunolocalization of fascia adherens junctions by labeling N-cadherin, and correlative immunogold and standard electron microscopy, were performed in parallel. In the neonate, connexin43 gap junctions have a punctate distribution over the entire surface of the ventricular myocytes. With advancing age, gap junctions become progressively confined to the transverse terminals of the cell, ie, toward the distribution within the intercalated disk characteristic of the adult ventricle. The transversely arrayed proportion of gap-junctional label showed a linear increase with age (R = .88, P < .001), reaching the adult pattern at about 6 years, and the fascia adherens junctions showed a similar progression. Electron microscopy confirmed the changing pattern of junctional contacts and demonstrated that initially gap junctions and adhering junctions are frequently not closely adjacent but become increasingly so with maturation of the intercalated disk. CONCLUSIONS: Changes in the spatiotemporal patterns of the intercellular junctions responsible for electrical and mechanical coupling are closely coordinated in postnatal human ventricular myocardium and continue to about 6 years of age. Over this period there is a close and increasing association between the gap junctions and fascia adherens junctions. These changes in the distribution of intercellular electrical and adhering junctions may parallel the changing functional requirements of the ventricle, from a distribution that facilitates the remodeling necessitated by rapid growth and changing hemodynamics to that of the relatively stable and rapidly conducting adult myocardium. These age-related changes may also diminish the ability for appropriate myocardial remodeling in response to physiological, pathological, or surgical hemodynamic alterations.

Adolescent↗
PubMed2004

Comparison of differentiation markers between normal and two squamous cell carcinoma cell lines in culture.

This study examines differences between cultures of normal human oral epithelial cells and two squamous cell carcinoma cell lines (SCC15 and SCC25) in the expression of structural proteins, adhesion molecules, plasma membrane lipid composition, and intercellular junctions. Based on immunocytochemistry, most normal cell cultures appeared to express more E-cadherin, integrin beta-1, cytokeratin (CK) 14, CK19, and involucrin than SCC cultures. By Western blot analysis, normal cultures expressing high levels of E-cadherin also expressed high levels of involucrin and low levels of CK19. Both SCC cultures demonstrated lower expression of E-cadherin and involucrin, whereas only SCC15 cells showed high levels of CK19. Expression of beta-catenin, an E-cadherin associated protein with potential oncogene function, did not vary among normal and SCC cells. Proportions of saturated fatty acids quantified by thin layer chromatography were higher in the normal cell cultures, than in both SCC cell lines. No morphological differences were evident by transmission electron microscopy (TEM) between normal and SCC cell-cell intercellular junctions. Although no quantitation was attempted, observation suggested that normal cells form more intercellular junctions (TEM observation) and larger intercellular bridges (SEM observation) compared to both SCC cell lines. Of the factors examined, main variations between cultures of normal oral epithelium and the two SCC cell lines examined include the expression of structural and adhesion proteins, lipid composition, and intercellular junctions. The extent of the differences varies according to the stage of terminal differentiation demonstrated by the normal cell cultures.

Biomarkers, Tumor↗
PubMed1998

Bystander tumoricidal effect and gap junctional communication in lung cancer cell lines.

Tumor cells expressing the herpes simplex virus-thymidine kinase (HSV-tk) gene become sensitive to ganciclovir (GCV), and the phenomenon by which tumor cells surrounding the HSV-tk expressing cells also become sensitive to GCV is known as the "bystander effect." The purpose of this study was to investigate the bystander effect in human lung-cancer cell lines, and the role of gap-junctional intercellular communication as the mechanism responsible for it. Gap-junctional intercellular communication was measured both with a dye-transfer assay involving single-cell microinjection of Lucifer Yellow and with a PKH26/calcein-AM double-dye-transfer assay. Significant bystander tumoricidal effect was observed in lung-cancer cell lines when cultured cells contained only 10% HSV-tk expressing cells. This was also observed to occur with cell lines of different origin or from different species. Although gap-junctional intercellular communication characterized by rapid transfer of Lucifer Yellow was not observed, we did detect gap-junctional communication marked by the slow transfer of calcein-AM in lung-cancer cell lines. However, neither an inhibitor (1-octanol) nor an enhancer (all trans-retinoic acid [ATRA]) of gap-junctional communication affected the extent of the bystander effect. These findings suggest that low levels of gap-junctional communication may be efficient for producing the bystander effect in lung-cancer cells, or that other mechanisms may underlie this effect. Although gap-junctional communication may play an important role in generating the bystander effect in tumor cells expressing the HSV-tk gene, further knowledge of the mechanism of this effect may help improve the treatment of lung cancer with an HSV-tk system.

1-Octanol↗
PubMed1998

VE-Cadherin mediates endothelial cell capillary tube formation in fibrin and collagen gels.

Various cell adhesion molecules mediate the diverse functions of the vascular endothelium, such as cell adhesion, neutrophil migration, and angiogenesis. In order to identify cell adhesion molecules important for angiogenesis, we used an in vitro model (Chalupowicz, Chowdhury, Bach, Barsigian, and Martinez, J. Cell Biol. 130, 207-215, 1995) in which human umbilical vein endothelial cell monolayers are induced to form capillary-like tubes when a second gel, composed of either fibrin or collagen, is formed overlying the apical surface. In the present investigation, we observed that a monoclonal antibody directed against the first extracellular domain of human vascular endothelial cadherin (VE-cadherin, cadherin 5) inhibited the formation of capillary tubes formed between either fibrin or collagen gels. Moreover, when added to preformed capillary tubes, this antibody disrupted the capillary network. In contrast, monoclonal antibodies directed against the extracellular domain of N-cadherin, the alphavbeta3 integrin, and PECAM-1 failed to inhibit capillary tube formation. During capillary tube formation, Western blot and RT-PCR analysis revealed no marked change in VE-cadherin expression. Immunocytochemical studies demonstrated that VE-cadherin was concentrated at intercellular junctions in multicellular capillary tubes. Thus, VE-cadherin plays a specific role in fibrin-induced or collagen-induced capillary tube formation and is localized at areas of intercellular contact where it functions to maintain the tubular architecture. Moreover, its function at tubular intercellular junctions is distinct from that at intercellular junctions present in confluent monolayers, since only the former was inhibited by monoclonal antibodies.

Animals↗