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PubMedDate not supplied

Transport of nanoparticles across an in vitro model of the human intestinal follicle associated epithelium.

An in vitro model of the human follicle associated epithelium (FAE) was characterized and the influence of nanoparticle properties on the transcellular transport across the in vitro model was investigated. The model was established by co-culturing Caco-2 and Raji cells, with Caco-2 cells alone as control. The conversion of Caco-2 cells to follicle associated epithelium (FAE) like cells was monitored by following the surface expression of beta1-integrins (immunofluorescence) and nanoparticle transport (flow cytometry). The influence of the nanoparticle concentration at the apical side, temperature, size and surface properties of nanoparticles on transport was evaluated, as well as the influence of transport conditions. The conversion of Caco-2 cells into FAE-like cells occurred. The transport was concentration, temperature and size-dependent. Aminated nanoparticles were more efficiently transported than carboxylated nanoparticles, suggesting a role of nanoparticle surface functional groups and hydrophobicity, possibly leading to a different pattern of protein adsorption at their surface. In conclusion, this in vitro model is a promising tool to study the role of M cells in transintestinal nanoparticle transport, as well as to evaluate new drug delivery systems.

B-Lymphocytes↗
PubMed2006

Discoidin domain receptor 1 mediates collagen-induced nitric oxide production in J774A.1 murine macrophages.

Nitric oxide (NO) is an important regulator of immune responses. Effects of cytokines, such as tumor necrosis factor (TNF)-alpha or IFN-gamma, and bacterial products, such as lipopolysaccharide, on macrophage NO production have been well documented; however, the role of the extracellular matrix proteins, including collagen, in this process remains unclear. We previously reported that discoidin domain receptor 1 (DDR1), a nonintegrin collagen receptor, was expressed in human macrophages, and its activation facilitated their differentiation as well as cytokine/chemokine production. Here, we examined the role for DDR1 in collagen-induced NO production using the murine macrophage cell line J774 cells that endogenously express DDR1. Activation of J774 cells with collagen induced the expression of inducible NO synthase (iNOS) and NO production. Inhibition of DDR1, but not beta1-integrins, abolished collagen-induced iNOS and NO production. Activation of J774 cells with collagen-activated nuclear factor-kappaB, p38 mitogen-activated protein kinase (MAPK), and c-jun N-terminal kinase (JNK) and a pharmacological inhibitor of each signaling molecule significantly reduced collagen-induced NO production. Thus, we have demonstrated, for the first time, that the interaction of DDR1 with collagen induces iNOS expression and subsequent NO synthesis in J774 cells through activation of NF-kappaB, p38 MAPK, and JNK and suggest that intervention of DDR1 signaling in macrophages may be useful in controlling inflammatory diseases in which NO plays a critical role.

Animals↗
PubMed2006

Structure of the alpha-actinin-vinculin head domain complex determined by cryo-electron microscopy.

The vinculin binding site on alpha-actinin was determined by cryo-electron microscopy of 2D arrays formed on phospholipid monolayers doped with a nickel chelating lipid. Chicken smooth muscle alpha-actinin was cocrystallized with the beta1-integrin cytoplasmic domain and a vinculin fragment containing residues 1-258 (vinculin(D1)). Vinculin(D1) was located at a single site on alpha-actinin with 60-70% occupancy. In these arrays, alpha-actinin lacks molecular 2-fold symmetry and the two ends of the molecule, which contain the calmodulin-like and actin binding domains, are held in distinctly different environments. The vinculin(D1) difference density has a shape very suggestive of the atomic structure. The atomic model of the complex juxtaposes the alpha-actinin binding site on vinculin(D1) with the N-terminal lobe of the calmodulin-like domain on alpha-actinin. The results show that the interaction between two species with weak affinity can be visualized in a membrane-like environment.

Actinin↗
PubMed2006

Activation of bombesin receptor subtype-3 stimulates adhesion of lung cancer cells.

Bombesin receptor subtype-3 (BRS-3) is an orphan G protein-coupled receptor having sequence homologies to gastrin-releasing peptide and neuromedin B receptors. [d-Phe6, beta-Ala11, Phe13, Nle14]bombesin(6-14) is known to act as a synthetic receptor agonist for BRS-3. To characterize BRS-3-mediated biological responses, we examined the effect of BRS-3 activation by [d-Phe6, beta-Ala11, Phe13, Nle14]Bn(6-14) on the adhesion of the small cell lung cancer NCI-N417 cells that express native BRS-3. We found that the BRS-3 agonist stimulated adhesion of NCI-N417 cells in laminin-coated culture wells. The adhesion of the cells to laminin induced by BRS-3 activation was accompanied by an increase in vinculin-like immunoreactivity and diminished in the presence of an anti-beta1 integrin antibody, suggesting that the receptor activation stimulates focal adhesion formation. We suggest that BRS-3 may be involved in invasion and metastasis of certain cancer cells, like small cell lung cancer cells, upon attachment to laminin.

Bombesin↗
PubMed2005

Odontoblast expression of semaphorin 7A during innervation of human dentin.

Semaphorin 7A (SEMA 7A) is a membrane-anchored member of the semaphorin family of guidance proteins, previously identified in the immune system. Expressed in central and peripheral nervous system during embryonic and post-natal stages, it can mediate neuronal functions by promoting axonal growth. We show here that SEMA 7A is expressed in human odontoblasts in vivo and in vitro and that its expression is correlated with the establishment of dentin-pulp complex terminal innervation . Co-cultures of trigeminal ganglion (TG) with COS cells overexpressing SEMA 7A demonstrate that SEMA 7A can promote the growth of trigeminal nerve fibers. Finally, by RT-PCR and immunochemistry, we show that beta1-integrin, a SEMA 7A putative receptor, is expressed in pulpal nerve fibers but we failed to detect a co-localization between nerves and odontoblasts through these molecules. On the basis of these data, we suggest that SEMA 7A might be a molecule involved in the terminal innervation of the dentin-pulp complex.

Adolescent↗
PubMed2005

Ischemia depletes dystrophin and inhibits protein synthesis in the canine heart: mechanisms of myocardial ischemic injury.

In this study we tested our previous hypothesis that ischemia is a multifactorial injurious event involving all components of the myocyte simultaneously. This hypothesis was based on ultrastructural findings and was now tested again by protein analysis of sarcolemmal structural proteins and of markers of transcriptional and translational activities. This knowledge may help to clarify the cellular mechanisms involved in progression of acute ischemic myocardial injury and reperfusion. Therefore, we investigated all three intracellular/extracellular linkage systems of the sarcolemma using antibodies against dystrophin, beta-dystroglycan, gamma-sarcoglycan, vinculin, beta1-integrin, laminin, and spectrin. In addition, antibodies were used to evaluate membrane permeability (albumin), transcriptional efficacy (non-snRNP splicing factor SC-35), and translational capacity (phosphorylated p70 ribosomal protein S6 kinase). Tissue samples were obtained from a canine model of regional myocardial ischemia (90 min or 4.5 h) with or without reperfusion. Immunoconfocal microscopy and Western blotting revealed that the rank order of sensitivity was the following: dystrophin, beta-dystroglycan, gamma-sarcoglycan, vinculin, spectrin, integrin and laminin. Different levels of dystrophin loss indicate reversible/irreversible injury as established by albumin uptake and electron microscopy. Dystrophin depletion closely coincided with generally depressed transcription and translation. These changes occurred simultaneously in a time-dependent manner and persisted during reperfusion. In conclusion, damage of the different structural proteins results in membrane destabilization and disruption of the contractile apparatus from the sarcolemma. These changes, concomitantly associated with disturbances in transcription and translation, are major mechanisms determining the transition to irreversibility of myocardial ischemic injury and confirm our hypothesis that ischemia is a multifactorial injurious event involving all components of the cardiac myocyte.

Albumins↗
PubMed2003

Regulation of CD43-induced U937 homotypic aggregation.

CD43 (leukosialin, sialophorin), a prominent component of the hemopoietic cell surface, has an enigmatic role in cell-cell interaction. The observation that CD43 ligation triggers homotypic aggregation of monoblastoid U937 cells has permitted analysis of this: CD43-induced aggregation was distinguishable from CD29- (also known as beta1 integrin) or CD98- (also known as 4F2, or fusion-related protein 1) induced aggregation, with different energy requirements and with partial dependence on beta2 integrins. Previous studies have focused on the role of CD43 ligation in tyrosine phosphorylation. However, in the homotypic adhesion assay, although there is initial tyrosine phosphorylation, protein tyrosine kinase inhibitors did not block aggregation. Therefore, other signaling pathways were examined. CD43 ligation induced protein tyrosine dephosphorylation, and protein tyrosine phosphatase inhibitors blocked aggregation. Activation of MAP kinases was not necessary. Cytoskeletal inhibitors amplified aggregation. Protein kinase C (PKC) inhibitors amplified aggregation, implicating PKC as a negative regulator. CD43 ligation up-regulated surface adhesion molecules and enhanced CD29- and CD98-induced aggregation. Thus, CD43 participation in cell-cell adhesion is under stringent control, involving both surface events and several different intracellular signaling pathways, acting together to regulate the process. These mechanisms add a further dimension to the potential role of CD43 in tissue immune responses.

Antigens, CD↗
PubMed2001

Dedifferentiation of epidermal cells to stem cells in vivo.

The effects of growth factors on wound healing have been studied extensively; however epidermal regeneration is not fully understood. We treated eight patients with leg ulcers with recombinant human epidermal growth factor (rhEGF) and compared biopsies of regenerating epidermis with those of controls who did not receive rhEGF. We used immunohistochemistry to identify cells expressing keratin 19 and beta1 integrin in regenerated epidermis from patients and controls. Patients treated with rhEGF had stem cells in the spinous and granular layers of regenerated epidermis. Histological analysis showed that these stem cells had reverted from differentiated to undifferentiated stem cells. Our findings provide evidence for epidermal cell reversion.

Adult↗
PubMed2001

Structural alterations of adhesion mediating components in cells cultured on poly-beta-hydroxy butyric acid.

Polymers may serve as a biodegradable material in tissue engineering. To assess the biocompatibility of poly-beta-hydroxy butyric acid (PHB), we studied the structural organization of cellular molecules involved in adhesion using osteoblastic and epithelial cell lines. On PHB, both cell lines revealed a rounded cell shape due to reduced spreading. The filamentous organization of the actin cytoskeleton was impaired. In double immunofluorescence analyses we demostrated that the colocalization of the fibronectin fibrils with the actin filaments was lost in cultures on PHB. Similarly, collagen II distribution was altered, whereas the organization of collagen I was not obviously affected. Further evidence for impaired structural organization was obtained for the beta1-integrin receptor and vinculin which mediate the interaction of the cytoskeleton with the extracellular matrix. In confluent epithelial cells, the tight junction protein ZO-1 showed a larger lateral extension in the cell-cell contacts when cells were grown on PHB. Because structural organization of components which mediate cell-matrix and cell-cell adhesion controls cell physiology these parameters could be a sensitive indicator for the biocompatibility of implant materials.

Actins↗
PubMed2002

Expression of transmembrane 4 superfamily (TM4SF) proteins and their role in hepatic stellate cell motility and wound healing migration.

BACKGROUND/AIMS: Migration of activated hepatic stellate cells (HSC) is a key event in the progression of liver fibrosis. Little is known about transmembrane proteins involved in HSC motility. Tetraspanins (TM4SF) have been implicated in cell development, differentiation, motility and tumor cell invasion. We evaluated the expression and function of four TM4SF, namely CD9, CD81, CD63 and CD151, and their involvement in HSC migration, adhesion, and proliferation. METHODS/RESULTS: All TM4SF investigated were highly expressed at the human HSC surface with different patterns of intracellular distribution. Monoclonal antibodies directed against the four TM4SF inhibited HSC migration induced by extracellular matrix proteins in both wound healing and haptotaxis assays. This inhibition was independent of the ECM substrates employed (collagen type I or IV, laminin), and was comparable to that obtained by incubating the cells with an anti-beta1 blocking mAb. Importantly, cell adhesion was unaffected by the incubation with the same antibodies. Co-immunoprecipitation studies revealed different patterns of association between the four TM4SF studied and beta1 integrin. Finally, anti-TM4SF antibodies did not affect HSC growth. CONCLUSIONS: These findings provide the first characterization of tetraspanins expression and of their role in HSC migration, a key event in liver tissue wound healing and fibrogenesis.

Antibodies, Monoclonal↗
PubMed1999

A novel model to study the dorsolateral migration of melanoblasts.

Melanocytes derived from pluripotent neural crest cells migrate initially in the dorsolateral pathway between the ectoderm and dermomyotome. To understand the role of specific proteins involved in this cell migration, we looked for a cellular model that mimics the in vivo behavior of melanoblasts, and that allows functional studies of their migration. We report here that wild-type embryonic stem (ES) cells are able to follow the ventral and dorsolateral neural crest pathways after being grafted into chicken embryos. By contrast, a mutant ES cell line deficient for beta1 integrin subunits, proteins involved in cell-extracellular interactions, had a severely impaired migratory behavior. Interestingly, ES cells deficient for Kit, the tyrosine kinase receptor for the stem cell factor (SCF), behaved similarly to wild-type ES cells. Thus, grafting mouse ES cells into chicken embryos provides a new cellular system that allows both in vitro and in vivo studies of the molecular mechanisms controlling dorsolateral migration.

Animals↗
PubMed2002

Human fibronectin and MMP-2 collagen binding domains compete for collagen binding sites and modify cellular activation of MMP-2.

The region of fibronectin (FN) surrounding the two type II modules of FN binds type I collagen. However, little is known about interactions of this collagen binding domain with other collagen types or extracellular matrix molecules. Among several expressed recombinant (r) human FN fragments from the collagen binding region of FN, only rI6-I7, which included the two type II modules and both flanking type I modules, bound any of several tested collagens. The rI6-I7 interacted specifically with both native and denatured forms of types I and III collagen as well as denatured types II, IV, V and X collagen with apparent K(d) values of 0.2-3.7 x 10(-7) M. Reduction with DTT disrupted the binding to gelatin verifying the functional requirement for intact disulfide bonds. The FN fragments showed a weak, but not physiologically important, binding to heparin, and did not bind elastin or laminin. The broad, but selective range of ligand interactions by rI6-I7 mirrored our prior observations for the collagen binding domain (rCBD) from matrix metalloproteinase-2 (MMP-2) [J. Biol. Chem. 270 (1995) 11555]. Subsequent experiments showed competition between rI6-I7 and rCBD for binding to gelatin indicating that their binding sites on this extracellular matrix molecule are identical or closely positioned. Two collagen binding domain fragments supported cell attachment by a beta1-integrin-dependent mechanism although neither protein contains an Arg-Gly-Asp recognition sequence. Furthermore, activation of MMP-2 and MMP-9 was greatly reduced for HT1080 fibrosarcoma cells cultured on either of the fibronectin fragments compared to full-length FN. These observations imply that the biological activities of FN in the extracellular matrix may involve interactions with a broad range of collagen types, and that exposure to pathologically-generated FN fragments may substantially alter cell behavior and regulation.

Binding Sites↗
PubMed2002

Ovariectomy hinders the early stage of bone-implant integration: histomorphometric, biomechanical, and molecular analyses.

Postmenopausal osteoporosis is a contributing factor to alveolar bone atrophy associated with tooth loss in the elderly. The use of dental titanium implants has been increasingly adapted to treat these edentulous patients. This study examines whether female gonadal hormone deficiency interferes with the critical integration process between bone and implants. Two types of experimental titanium implants with acid-treated surfaces were placed in the femurs of ovariectomized (ovx) and sham-operated control rats: T-cell implants with a hollow chamber for histomorphometric and steady-state mRNA expression assays, and unthreaded cylindrical implants for biomechanical push-in tests. At week 2, less bone area was found in the ovx-implant group (p = 0.0495) than in the sham-implant group. The implant push-in test showed that the ovx-implant group had approximately half of the withstanding value of the sham-implant group (p = 0.009). However, these differences between the ovx and sham groups became diminished at week 4. Total RNA samples were examined by a reverse transcriptase-polymerase chain reaction assay for col1a1, col3a1, bone sialoprotein (bSP) II, osteonectin, osteopontin, osteocalcin, integrin beta1 and integrin beta3. In untreated bones and in created bone defects without implant placement, ovx did not affect the steady-state levels of the mRNAs tested. When implants were placed, significant upregulation of these genes was observed in the sham-implant group; however, only osteocalcin and integrins were upregulated in the ovx-implant group. The results suggest a biphasic effect of female gonadal hormone deficiency that may temporarily interfere with the early implant-tissue integration process, and which may be associated with a failure to upregulate a selected set of bone extracellular matrix genes. Once established, however, functional bone-implant integration can be achieved even in ovx rats.

Animals↗
PubMed2003

Establishment of an in vitro assay to measure the invasion of ovarian carcinoma cells through mesothelial cell monolayers.

Ovarian carcinoma is the leading cause of gynecological cancer deaths in the United States. Secondary tumor growths form by tumor cell invasion through the mesothelial lining of the peritoneal cavity and peritoneal organs. To study this interaction, we developed a dye-based in vitro model system in which mesothelial cells were grown as confluent monolayers, permeabilized, and then co-cultured with ovarian carcinoma cells for up to seven days. The mesothelial cells were then stained with trypan blue dye, which enabled the visualization of ovarian carcinoma cell invasion through the monolayers of mesothelial cells. Ovarian carcinoma cell invasion was inhibited for up to 7 days by the addition of GRGDSP peptides, a blocking monoclonal antibody against the beta1 integrin subunit, or blocking monoclonal antibodies against matrix metalloproteinases 2 and 9. Cell invasion was also inhibited by hyaluronan and GM6001, a chemical inhibitor of matrix metalloproteinases. Differential gene expression of matrix metalloproteinases, tissue inhibitors of matrix metalloproteinases, and disintegrins were observed in primary ovarian carcinoma tumors and secondary metastases, compared to normal ovaries. Taken together, these results suggest that complex interactions between integrins, disintegrins, matrix metalloproteinases, and tissue inhibitors of matrix metalloproteinases may mediate ovarian carcinoma cell invasion, and that the dye-based assay described herein is a suitable model system for its study.

Adenocarcinoma↗
PubMed2003

Gly511 to Ser substitution in the COL1A1 gene in osteogenesis imperfecta type III patient with increased turnover of collagen.

Osteogenesis imperfecta (OI) is a result of heterozygous mutations in the COL1A1 or COL1A2 genes, encoding type I procollagen chains. Here we described the molecular and biochemical defects detected in a case of severe type III OI. Cultured skin fibroblasts from the proband produced both normal and mutant type I collagen which was secreted into the medium. The mutation site was localized in alpha 1(I)-CB3 by CNBr cleavage of collagen chains. Subsequent reverse transcription-PCR amplification and direct sequencing of single-stranded PCR product led to identification of G to A transition in the COL1A1 gene, resulting in Gly511Ser substitution in the a1 chain of type I collagen. The new mutation conforms to the chain-specific non-lethal microdomain of Gly to Ser substitutions in the genotype-phenotype map. We have found that biosynthesis of collagen was increased in OI cells to about 160% of the control value. However, the amount of collagen deposed to the insoluble matrix was decreased as compared to the control. This suggests increased degradation of collagen, since the collagenolytic activity of OI cells was increased. Furthermore, the activity of prolidase, which is a marker of collagen turnover, was increased in OI cells. In regulation of activity of the enzyme are involved beta1 integrin and insulin-like growth factor (IGF) receptors. Western immunoblot analysis showed that the expressions of both receptors were markedly increased in OI cells. These results suggest that increase in activity of prolidase can be associated with increase in intensity of collagen metabolism in type III OI patient with identified new G511S mutation.

Blotting, Western↗
PubMed2003

New and active role of the interstitium in control of interstitial fluid pressure: potential therapeutic consequences.

Here we present recent data indicating that the present view of the interstitium as a passive fluid reservoir has to be revised. The connective tissue cells and extracellular matrix have a role in the control of P(if) and a fundamental role in the rapid development of edema in burns and in the initial swelling in inflammation by generating a lowering of interstitial fluid pressure. In this process, the beta1-integrin system seems to provide a common pathway by which the cells can lower as well as raise P(if). Inflammatory swelling can be reversed by endo- and exogenous substances, thereby suggesting that the connective tissue can serve as a novel target for pharmacological intervention. Furthermore, the new knowledge in interstitial physiology on means to reduce interstitial fluid pressure may be of importance for drug delivery into solid tumors, where a high P(if) limits the uptake of therapeutic agents.

Animals↗
PubMed2001

Expression of adhesion and activation molecules in human buccal epithelial cell lines and normal human buccal epithelium in situ.

An in vitro culture system may be used to analyse interactions between T cells and epithelium. We have analysed two human buccal squamous epithelial cell lines: SqCC/Y1, derived from a buccal carcinoma, and SVpgC2a, an SV-transformed healthy buccal squamous epithelium. Under serum-free culture conditions, the cell lines resemble normal buccal squamous epithelium in situ in their expression of MHC class I, CD29 (beta1 integrin), CD40, CD44, CD54 (ICAM-1), CD58 (LFA-3), CD95 (Fas), and E-cadherin. Furthermore, when the SVpgC2a cell line was treated with T-cell derived cytokines, upregulation of CD40 expression was observed when the cells were treated with IL-4, whereas IFN-gamma caused upregulation in expression of CD40, CD54 and MHC class II. These buccal squamous epithelial cell lines, therefore, provide a good tool for analysing interactions between epithelium and T cells in vitro.

CD40 Antigens↗
PubMed2003

Xanthophore migration from the dermis to the epidermis and dermal remodeling during Salamandra salamandra salamandra (L.) larval development.

During larval development of Salamandra salamandra salamandra chromatophores organize to form the definitive pigment pattern constituted by a black background with yellow patches that are characterized by epidermal xanthophores and dermal iridophores. Simultaneously the dermis undergoes remodeling from the larval stage to that typical of the adult. In the present study we ultrastucturally and immunocytochemically examined skin fragments of S. s. salamandra larvae and juveniles in order to investigate the modalities of xanthophore migration and differentiation in the context of dermal remodeling from the larval to adult stage. Semithin and thin sections showed that the dermis in newly born larvae consists of a compact connective tissue (basement lamella), to which fibroblasts and xanthophores adhere, and of a loose deep collagen layer. As larval development proceeds, fibroblasts and xanthophores invade the basement lamella, skin glands develop and the adult dermis forms. At metamorphosis, xanthophores reach the epidermis crossing through the basal lamina. We examined immunocytochemically the expression of signal molecules, such as fibronectin, vitronectin, beta1-integrin, chondroitin sulfate, E-cadherin, N-cadherin and plasminogen activator, which are known to be involved in regulating morphogenetic events. Their role in dermal remodeling and in pigment pattern formation is discussed.

Animals↗