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PubMed1999

Cell adhesion to textured silicone surfaces: the influence of time of adhesion and texture on focal contact and fibronectin fibril formation.

Cell adhesion and spreading on biomaterials is a key issue in the study of cell-biomaterial interactions. With the development of new disciplines within biomaterials research such as tissue engineering and cellular therapy, information at molecular and structural levels is needed in order to conceive and design biomaterials that elicit specific, functional cell responses. In this study we determined the formation of focal adhesions and fibronectin fibrillar structures by human fibroblasts and human umbilical vein endothelial cells adhered to fibronectin-precoated, smooth, and textured silicones as a function of time. Textures consisted of parallel ridges and 0.5 mm deep grooves with a width of 2, 5, and 10 mm. In addition, pillar and well constructs were used. Cells assembled focal adhesions within the first 24 h of adhesion. Fibronectin production and assembly resulted in a dense fibrillar network at day 6. Initial focal adhesion density and size were dictated by the presence of the texture. Topography also influenced initial fibronectin deposition, although the differences did not result in apparent differences in fibronectin networks after 6 days of incubation. Without fibronectin preadsorption, cells did not proliferate on the silicone surfaces. Cells adhered to glass removed all the preabsorbed fibronectin, whereas on silicone they did not. The present study shows that different textures initially give rise to differences in focal contact and fibronectin fibril assembly. The effects of the small, initial in vitro differences on in vivo tissue biocompatibility remains to be studied.

Adult↗
PubMed1989

Fibronectin turnover in the premature neonate measured with [15N]glycine.

Fibronectin is a large-molecular-weight glycoprotein present on most cell surfaces and in plasma. Plasma fibronectin concentrations in neonates are lower than those in adults and a direct relationship exists between plasma concentration and gestational age. We determined the half-life and fractional synthetic rate (FSR) of plasma fibronectin in the premature infant. Infants and adults received a loading dose of [15N]glycine followed by a constant infusion [15N]glycine incorporation into plasma fibronectin and urine hippurate was determined by gas chromatography-mass spectrometry. The plasma fibronectin FSR in the preterm neonates was 15.5 +/- 9.9%/d(means +/- SD) and the half-life was 5.55 +/- 2.25 d. Birth weight correlated inversely with plasma fibronectin half-life. In the adults the plasma fibronectin FSR ranged from 20 to 87%/d and half-life ranged between 0.79 and 3.47 d. These data suggest that decreased plasma fibronectin levels in preterm infants are due to reduced FSRs rather than to greater turnover of a relatively small plasma pool.

Adult↗
PubMedDate not supplied

Role of fibronectin in diseases of newborn infants and children.

Fibronectin is a large-molecular-weight glycoprotein present on most cell surfaces, in extracellular fluids, and in plasma. Both cell-associated and soluble fibronectin are thought to have important roles in the inflammatory response and host defense and may contribute to the maintenance of microvascular integrity during septic episodes. Newborn infants have levels of fibronectin in plasma that are one-third to one-half those found in the healthy adult. In addition, neonates with respiratory distress syndrome, perinatal asphyxia, bacterial sepsis, intrauterine growth retardation, or postnatal malnutrition have a further depression in their plasma levels of fibronectin. The low plasma concentration of fibronectin in newborn infants may contribute to the hypofunction of the neonatal reticuloendothelial system and predispose to the development of sepsis. Rates of synthesis of plasma fibronectin are diminished in the neonate, and an inverse correlation between fibronectin half-life and gestational age exists. The role of fibronectin in treatment or prophylaxis of neonatal sepsis remains to be determined.

Fibronectins↗
PubMedDate not supplied

Fibronectin: an enhancer of phagocyte function.

Although fibronectin does not act as a direct opsonin as originally described, it does mediate important interactions with phagocytes throughout the inflammatory process. Fragments of fibronectin released by neutrophil proteases are chemoattractants for monocytes. Moreover, subendothelial matrix fibronectin and "inflammatory" fibronectin released from phagocytes enhance phagocyte adherence to host tissues at an inflammatory site. Fibronectin also increases chemokinesis. Once the phagocyte enters tissues, fibronectin promotes C3- and Fc-receptor activation, allowing complement-coated bacteria to be ingested. Finally, fibronectin enhances the bactericidal activity of monocytes. Thus, fibronectin plays an important, but indirect role, in the activities of phagocytes.

Bacteria↗
PubMed1985

Modulation of fibronectin gene activity in chick embryo fibroblasts transformed by a temperature-sensitive strain (ts68) of Rous sarcoma virus.

Transcriptional regulation of the fibronectin gene is a major mechanism for lowering steady-state levels of fibronectin mRNA in chick embryo fibroblasts (CEF) transformed by Rous sarcoma virus (RSV) (1). In the present study, we have measured the change of transcriptional activity of the fibronectin gene in CEF transformed by a temperature-sensitive strain of RSV (ts68). Ts68-CEF maintained at either 35 degrees C or 41 degrees C were shifted to 41 degrees C or 35 degrees C, respectively, at 5-hour intervals, and isolated nuclei were used in runoff transcription assays. Nuclear RNA labeled with [alpha-32P]UTP was hybridized to DNA fragments encoding the src gene, the beta-actin gene and the fibronectin gene. In shift-up (35 degrees C----41 degrees C) and shift-down (41 degrees C----35 degrees C) experiments, src gene and beta-actin gene activities in ts68-CEF nuclei remained relatively unchanged. In ts68-CEF shifted to the nonpermissive temperature (41 degrees C), a lag time of at least 5 hours was followed by a 4- to 5-fold increase in fibronectin specific RNA 15 hours after the shift. When cells were shifted to the permissive temperature (35 degrees C), a 4- to 5-fold decrease in fibronectin RNA was apparent within 5 hours of the temperature shift and a 17- to 18-fold decrease was observed 15 hours after the shift. The relatively slow rates of changes of fibronectin gene activity in shift-up experiments suggest that the effect of p60src on fibronectin gene activity is indirect.

Animals↗
PubMed1996

Conformational change precedes the formation of multimeric fibronectin.

Plasma fibronectin incubated with a low concentration of SH reagent under physiological conditions without cells formed a multimer which retained the ability of heparin-binding and cell-binding but lost gelatin affinity [Sakai, K., Fujii, T., and Hayashi, T. (1994) J. Biochem. 115, 415-421]. The conformation of the multimeric fibronectin, as observed by ultraviolet circular dichroism and fluorescence spectroscopy was different from that of dimeric plasma fibronectin. Monitoring the change in ellipticity indicated that conformational change was mostly accomplished within the first 3 h of incubation with 0.5 mM dithiothreitol at 37 degrees C. In contrast, multimers became detectable after 4 h of incubation. The results indicate that the overall reaction of multimerization of plasma fibronectin consists of two steps: the initial step of conformational change of dimeric fibronectin, and the later polymerization step of the polypeptide in an altered conformation. The initial step, involving the conformational change of fibronectin, depended on temperature: it proceeded at 37 degrees C but not at 25 degrees C. In contrast the second step took place at 25 degrees C at a low, yet significant rate. Proteolytic susceptibility of the fibronectin to thermolysin or m-calpain changed within 3 h of incubation with dithiothreitol at 37 degrees C in accordance with the conformational change detected by circular dichroism. Namely, the fibronectin in an altered conformation appeared to be less susceptible to thermolysin, but more susceptible to m-calpain. The changes in enzymatic susceptibilities tended to be localized in the amino- and carboxyl-terminal regions, which are consistent with the implications from the spectroscopic analysis.

Animals↗
PubMed2004

Fibronectin upregulation in human temporomandibular joint disks with internal derangement.

Fibronectin is a large fibril-forming extracellular glycoprotein that seems to be involved in joint diseases. The objective of this study was to investigate the expression of fibronectin in human temporomandibular joint disks obtained from patients with internal derangement and varying extents of disk tissue degeneration/regeneration with that of temporomandibular joint disks free of significant morphological alterations by means of immunohistochemical methods. Twelve adult human temporomandibular joint disks (10 diseased disks and 2 normal disks) were used in this study. Temporomandibular joint disks were fixed in 10% buffered formalin. Sections were then immunohistochemically processed using a monoclonal antibody specific to human fibronectin and streptavidin-biotin detection methods. Positive reactions to fibronectin were found in normal and diseased disk tissues but to a different extent. Normal disk tissues revealed weak fibronectin expression, which was mainly located along the collagen bundles. Temporomandibular joint disks with internal derangement exhibited a higher immunoreactivity. Distinct reticular fibronectin structures were found inside the diseased disk, particularly nearby the newly formed blood vessels, tears, and clefts. In the covering layer of the disk surface, fibronectin was expressed in a fascicular pattern running parallel to the disk surface. The findings suggest that temporomandibular joint disk tissue can express fibronectin and that the expression is more pronounced in disk specimens of patients with internal derangement of the temporomandibular joint, supporting a role of this glycoprotein in the degeneration/regeneration processes of human temporomandibular joint disk tissue.

Adult↗
PubMed1997

Assessment of plasma fibronectin in malnourished Nigerian children.

BACKGROUND: Severe malnutrition is associated with septic infections. The concentrations of fibronectin, albumin, and transferrin in plasma were measured in three groups of children with protein-energy malnutrition, aged 1-3 years, each group comprising 20 children. The aim of which was to test whether plasma fibronectin, being an opsonic protein, was reduced in such children, and if it was a useful index for assessing the severity of malnutrition. METHODS: The concentrations of fibronectin, albumin, and transferrin in plasma were studied by enzyme immunoassay/ immunoblotting, spectrophotometry and immunoturbidimetry respectively. RESULTS: All values were significantly lower in the patients with malnutrition than in the age- and sex-matched well-nourished Nigerian reference children. Within the malnourished group, the fibronectin value was evenly reduced in all subgroups. Albumin and transferrin values were lowest in the patients with kwashiorkor, highest in the marasmic patients, and intermediate in the patients with marasmic kwashiorkor; the values correlated mutually in individual cases as well, but not with the fibronectin levels. Neither plasma fibronectin fragmentation nor tissue fibronectin was detected in any patient with malnutrition or in the reference subjects. CONCLUSIONS: The reduced plasma fibronectin values in these patients may be due to reduced synthesis by the liver, as evidenced by the equally reduced albumin and transferrin concentrations and/or to the multiple infections characteristic of the patients.

Biomarkers↗
PubMed1983

Effect of circulating fibronectin on stimulation of leukocyte oxygen consumption and serum opsonizing function in burned patients.

In a study of 27 thermally burned patients (mean TBSA, 58%; range, 32-96%) serum fibronectin levels were decreased with parallel decreased oxygen consumption of stimulated peripheral blood phagocytes and decreased EGTA-blocked burn serum opsonizing activity which correlated with serum fibronectin changes postburn. Normal and burn sera fibronectin content also correlated with the opsonizing times for zymosan and Staphylococcus aureus but not for Enterobacteriaceae. Although in vivo 14 cases showed circulating fibronectin 140 micrograms/ml or lower and a marked decrease in Staphylococcus aureus opsonization, only two patients from this group revealed positive Staphylococcus aureus blood cultures and serum fibronectin levels were higher in patients with Staphylococcus aureus sepsis than in patients with Enterobacteriaceae sepsis. Supplementary experiments on leukocyte oxidative response after zymosan stimulation in normal, fibronectin-depleted, and fibronectin-reconstituted serum demonstrated that the lag period of oxygen burst is a fibronectin-dependent reaction.

Adolescent↗
PubMed2002

Hepatocellular carcinomas show abnormal expression of fibronectin protein.

Fibronectin plays an important role in cell-to-cell adhesion, cell migration, and cell signaling. In the liver, fibronectin expression has been studied primarily as a component of the extracellular matrix, but little information is available on the expression of fibronectin protein in the neoplastic cells of hepatocellular carcinomas (HCCs). Twenty-four surgically resected HCCs were immunostained with fibronectin. Tumor and normal liver tissues were concurrently analyzed in all cases, and expression in the tumor was evaluated in comparison to the nonneoplastic liver. The average age at resection was 54 +/- 18 years for the 18 men and 6 women. Twenty-one of the cases were classic HCCs including 6 cases that were well differentiated, 12 cases moderately differentiated, and 3 cases poorly differentiated. The remaining 3 cases were moderately differentiated fibrolamellar carcinomas. In the normal liver, fibronectin labeled the sinusoids and weakly to moderately stained the cytoplasm of hepatocytes. In HCCs, 15/24 showed overexpression of fibronectin in the cytoplasm, 8/24 showed no change from the nonneoplastic liver, and one case showed decreased cytoplasmic staining. In addition, an abnormal membranous staining pattern was noted in 16/24 HCCs. In contrast to the HCCs, none of the three fibrolamellar carcinomas showed increased cytoplasmic or membranous staining. Excluding fibrolamellar carcinoma, increased cytoplasmic staining and/or an abnormal membranous staining was noted in 19/21 (90%) of HCCs. Fibronectin shows abnormal cytoplasmic and/or membranous staining in the majority of HCCs. The implications of fibronectin overexpression are uncertain but may reflect a critical step in tumor genesis.

Adult↗
PubMed2002

Expression of fibronectin-binding protein FbpA modulates adhesion in Streptococcus gordonii.

Fibronectin binding is considered to be an important virulence factor in streptococcal infections. Adhesion of the oral bacterium Streptococcus gordonii to immobilized forms of fibronectin is mediated, in part, by a high molecular mass wall-anchored protein designated CshA. In this study, a second fibronectin-binding protein of S. gordonii is described that has been designated as FbpA (62.7 kDa). This protein, which is encoded by a gene located immediately downstream of the cshA gene, shows 85 and 81% identity to the fibronectin-binding proteins PavA, of Streptococcus pneumoniae, and FBP54, of Streptococcus pyogenes, respectively. Purified recombinant FbpA bound to immobilized human fibronectin in a dose-dependant manner, and isogenic mutants in which the fbpA gene was inactivated were impaired in their binding to fibronectin. This effect was apparent only for cells in the exponential phase of growth, and was associated with reduced surface hydrophobicity and the surface expression of CshA. Cells in the stationary phase of growth were unaffected in their ability to bind to fibronectin. By utilizing gene promoter fusions with cat (encoding chloramphenicol O-acetyltransferase), it was demonstrated that cshA expression was down-regulated during the exponential phase of growth in the fbpA mutant. Expression of fbpA, but not cshA, was sensitive to atmospheric O2 levels, and was found to be up-regulated in the presence of elevated O2 levels. The results suggest that FbpA plays a regulatory role in the modulation of CshA expression and, thus, affects the adhesion of S. gordonii to fibronectin.

Bacterial Adhesion↗
PubMed1985

Spreading and enhanced motility of human keratinocytes on fibronectin.

Soluble human plasma fibronectin or collagen types I or IV, when preincubated with tissue culture plastic dishes, were effective spreading agents for cultured human keratinocytes and increased spreading in a time-and concentration-dependent manner. Spreading on fibronectin, but not on type IV collagen, was inhibited by antifibronectin; therefore, the contribution of fibronectin to the spreading activity of the natural matrix produced by keratinocytes could not be determined using antifibronectin. Fibronectin mediated spreading at both high (1.1 mM) and low (0.1 mM) Ca++ concentrations, and spreading was not altered by cycloheximide. Insoluble fibronectin deposited by keratinocytes correlated with phagokinetic tracks on particulate gold salts, and added fibronectin, as well as type I collagen and type IV collagen, enhanced motility of keratinocytes. These studies show that production of fibronectin and responsiveness to it are similar in fibroblasts and keratinocytes and demonstrate that fibronectin can act as a matrix factor for keratinocytes.

Cell Movement↗
PubMed1985

Expression of fibronectin, laminin, and factor VIII-related antigen during development of the human cutaneous microvasculature.

The regulation of angiogenesis during human skin development is poorly understood. Since fibronectin is involved in cell movement and organization during embryogenesis and morphogenesis in a variety of species, we investigated the expression of fibronectin and factor VIII-related antigen, a marker for endothelial cells, at various stages in the development of the human cutaneous microvasculature. Skin specimens were obtained from 4 human fetuses during the second trimester (14-18 weeks), from newborn foreskins, and from consenting normal adults. Cryostat sections were stained with both fluorescein-conjugated rabbit antihuman fibronectin and rhodamine-conjugated goat antihuman factor VIII-related antigen. Expression of fibronectin in the microvasculature was striking in fetal skin but became progressively less prominent with maturation. Fibronectin appeared in fetal blood vessels as a bright continuous linear array, in neonatal blood vessels as a bright interrupted linear and speckled array, and in adult blood vessels as a sparse interrupted linear and speckled array. In contrast, expression of factor VIII-related antigen by the endothelium became more prominent with the degree of maturation of the microvasculature. Granular factor VIII-related antigen staining was scant in the newly forming blood vessels of fetal skin, bright but focal in the microvasculature of newborn skin, and intense and almost confluent in the blood vessels of adult skin. Although expression of fibronectin and factor VIII-related antigen changed, expression of laminin was consistent throughout development. Staining of the same skin specimens with fluorescein-conjugated sheep antihuman laminin produced a bright continuous linear pattern in all blood vessels. The reciprocal relationship manifested by intense fibronectin staining during human blood vessel development and prominent factor VIII-related antigen staining in mature blood vessels supports the hypotheses that fibronectin plays a role in human blood vessel modulation and morphogenesis, and that factor VIII-related antigen is a marker for endothelial cell differentiation.

Adult↗
PubMed1987

Production of fibronectin by epithelium in a skin equivalent.

Although human keratinocytes in vitro have been shown to produce fibronectin, whether keratinocytes can contribute fibronectin to the dermal-epidermal junction or wound matrix is unknown. In order to approach this problem experimentally, we used the "skin equivalent" model composed of a native collagen gel populated with cultured fibroblasts and covered by cultured keratinocytes. By using bovine fibroblasts to populate the gel, fetal bovine serum in the culture medium, and human keratinocytes to form the epithelium, we were able to be certain that any human fibronectin produced in the culture was synthesized by the keratinocytes. A monoclonal antibody to fibronectin was found to recognize human but not bovine fibronectin. When the skin equivalent was stained by indirect immunofluorescence with antifibronectin, fibronectin was visible as an intensely staining band at the dermal-epidermal junction. In sections in which the dermis and epidermis had separated, the staining was usually limited to the dermal aspect of the skin equivalent. The results indicate that epithelium can contribute fibronectin to the dermal-epidermal junction and suggest that dermal staining in skin sections may originate from the epidermis. Since the developing skin equivalent has a rapidly growing epithelium and simulates a healing wound, contribution of fibronectin by the epithelium, in addition to that possibly contributed by serum and fibroblasts, may be of importance in wound healing.

Animals↗
PubMed1982

Molecular and biological interactions of fibronectin.

Fibronectin is a high molecular weight glycoprotein present at cell surfaces and in various body fluids. It is involved in cellular adhesion. The frequent absence of fibronectin from the surface of malignant cells may contribute to the invasive growth of tumors. To develop a better understanding of the functions of fibronectin, we have studied its structure by making use of proteolytic fragmentation and monoclonal antibodies. Fragments of plasma fibronectin which retain one or several of the affinities of intact fibronectin have been purified using affinity chromatography on collagen and heparin, and on monoclonal antibodies. These studies reveal a structure in which the different functions are located in separate protease-resistant molecular domains. The NH2-terminal domain contains the binding sites for fibrin, actin, and Staphylococci; this is followed by a collagen-binding domain, the cell attachment domain, and at the COOH-terminal end, the heparin-binding domain. These binding sites allow fibronectin to participate in multiple interactions with collagens and proteoglycans. The insoluble complexes formed by these 3 components that can be generated in vitro may represent a model for the basic structure of extracellular matrices. The role of fibronectin in such a matrix may be to contribute to the stability of the complex and to provide adhesion sites for cells. Disturbances in the interactions involving fibronectin could be potentially important to understanding diseases of connective tissues and in malignancy.

Animals↗
PubMed1990

Fibronectin-cell interactions.

Fibronectins are widespread extracellular matrix and body fluid glycoproteins, capable of multiple interactions with cell surfaces and other matrix components. Their structure at a molecular level has been resolved, yet there are still many unanswered questions regarding their biologic activity in vivo. Much data suggests that fibronectins may promote extracellular matrix assembly, and cell adhesion to those matrices. However, one outstanding enigma is that fibronectins may, under different circumstances, promote both cell migration and anchorage. An analysis of the interaction of fibroblasts with proteolytically derived and purified domains of plasma fibronectin revealed that the type of adhesion and the correlated cytoskeletal organization depended on multiple interactions of fibronectin domains with the cell surface. Human dermal fibroblasts were capable of interacting with the integrin-binding domain and both heparin-binding domains of the plasma fibronectin molecule and their interactions determined the type of adhesion. The same principle was seen in a study of the ability of plasma fibronectin to promote basement membrane assembly in an endodermal cell line, PF-HR9. There also, interactions of both heparin- and integrin-binding domains combined to promote the deposition of a proteoglycan, laminin, and type IV collagen-containing basement membrane matrix. The underlying conclusion from our studies is, therefore, that fibronectins may, through their different isotypes, multiple receptors, and varying interaction of one or more domains with those receptors, result in a spectrum of responses in different cell types. The molecular details of this array of biologic activities is not resolved but is the target of much current research.

Animals↗
PubMed2004

The ShdA adhesin binds to the cationic cradle of the fibronectin 13FnIII repeat module: evidence for molecular mimicry of heparin binding.

Introduction of Salmonella enterica serotype Typhimurium into food products results from its ability to persist in the intestine of healthy livestock by mechanisms that are poorly understood. The non-fimbrial adhesin ShdA is a fibronectin binding protein required for persistent intestinal carriage of S. Typhimurium. We further investigated the molecular mechanism of ShdA-mediated intestinal persistence by determining the binding-site of this receptor in fibronectin. Analysis of ShdA binding to fibronectin proteolytic fragments and to recombinant fibronectin fusion proteins identified the (13)FnIII repeat module of the Hep-2 domain as the primary binding site for this adhesin. The (13)FnIII repeat module of fibronectin contains a cationic cradle formed by six basic residues (R6, R7, R9, R23, K25 and R54) that is a high affinity heparin-binding site conserved among fibronectin sequences from frogs to man. Binding of ShdA to the (13)FnIII repeat module of fibronectin and to a second extracellular matrix protein, Collagen I, could be inhibited by heparin. Furthermore, binding of ShdA to the Hep-2 domain was sensitive to the ionic buffer strength, suggesting that binding involved ionic interactions. We therefore determined whether amino acid substitutions of basic residues in the cationic cradle of the Hep-2 domain that inhibit heparin binding also abrogate binding of ShdA. Combined substitution of R6S and R7S strongly reduced ShdA binding to (13)FnIII. These data suggest that ShdA binds the Hep-2 domain of fibronectin by a mechanism that may mimic binding of the host polysaccharide heparin.

Animals↗
PubMed1984

Epithelio-mesenchymal interface and fibronectin in the differentiation of the rat mesonephric and paramesonephric ducts.

The distribution of fibronectin and the morphological differentiation of the genital ducts was studied in rat fetuses at ages from 15 to 21 days. Fibronectin was localized with the peroxidase-antiperoxidase and avidin-biotin method at the electron- and light-microscope level. In 15-day-old male and female fetuses, fibronectin was localized as a continuous lamella around the mesonephric duct and as a discontinuous lamella around the paramesonephric duct. During the differentiation of the female paramesonephric duct, the fibronectin layer became continuous and remained so after the age of 16 days. The fibronectin layer of the male mesonephric duct remained continuous at all ages. The accumulation of mesenchymal cells on the outer surface of the female mesonephric duct and the concomitant detachment of the fibronectin layer around the duct suggests that mesenchymal regulation plays a role in the regression of the mesonephric duct. In the regressing male paramesonephric duct fibronectin was simultaneously lost in the condensed periductal mesenchyme, the places of epithelio-mesenchymal contact, and the epithelial cytoplasmic protrusions towards the mesenchyme. Ultrastructurally, fibronectin was localized in the basal laminae, on the cell membrane in contact with the extracellular material, and on the surface of the fibrillar and flocculent extracellular material. In addition to auto- and heterophagy, epithelio-mesenchymal interactions seem to play an important role in the regression of the genital ducts, although in different ways in males and females. The present results give additional support to the theory of the possible migration of epithelial cells into the surrounding mesenchyme during the regression of the paramesonephric duct.

Animals↗