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Results for “Extracellular Matrix”

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PubMed1992

The chicken neural extracellular matrix molecule restrictin: similarity with EGF-, fibronectin type III-, and fibrinogen-like motifs.

Restrictin is a chick neural extracellular matrix protein implicated in neural cell attachment and found to be associated with the cell surface recognition protein F11. Here we show by cDNA cloning that restrictin is a large multidomain protein composed of 4 structural motifs. At the N-terminus restrictin contains a cysteine-rich segment of about 140 aa that might link restrictin monomers into oligomers. This region is followed by 4.5 epidermal growth factor-like repeats and then by 9 consecutive motifs that are similar to fibronectin type III motifs. At the C-terminus restriction is related to the beta and gamma chains of fibrinogen, including similarity to a calcium-binding segment. Restrictin shows substantial sequence similarity with tenascin (cytotactin) throughout the polypeptide, and like tenascin, it forms oligomeric structures, as revealed by electron microscopy of immunoaffinity-purified restriction. The cell attachment site of restrictin is mapped to the C-terminal region by antibody perturbation experiments.

Amino Acid Sequence↗

PubMed1992

Influence of extracellular matrix in tumor necrosis factor-induced increase in endothelial permeability.

We examined the possibility that alterations of the extracellular matrix (ECM) contribute to the tumor necrosis factor-alpha (TNF-alpha)-induced increase in endothelial monolayer permeability. Endothelial permeability to 125I-labeled albumin was determined using bovine pulmonary microvessel endothelial cell (BPMVE) monolayers grown to confluence on microporous (0.8 microns diam) gelatin- and fibronectin-coated polycarbonate filters. Treatment of BPMVE with TNF-alpha (10(2) to 10(4) U/ml for 4-24 h) produced concentration- and time-dependent increases in endothelial permeability that paralleled the changes in morphology from cobblestone to elongated cells and the formation of prominent intercellular gaps and actin stress fibers. We examined the role of ECM in these changes using filters coated with ECM made by the BPMVE. Fresh BPMVE seeded onto filters coated with ECM produced by TNF-alpha-treated BPMVE had two- to threefold higher 125I-albumin permeability values than BPMVE monolayers seeded onto filters coated with ECM from control cells (P < 0.05). BPMVE seeded onto ECM from TNF-alpha-treated BPMVE also developed intercellular gaps and centralized actin filaments characteristic of the TNF-alpha-treated BPMVE. This effect was not attributable to TNF-alpha adsorbed to ECM. Polyacrylamide gel electrophoresis of ECM extracted from BPMVE treated with TNF-alpha showed decreased fibronectin. These findings suggest that the TNF-alpha-induced increase in endothelial permeability involves the loss of fibronectin and remodeling of the ECM. The increase in endothelial permeability may be secondary to decreased endothelial cell-ECM contacts resulting in elongation of cells and formation of intercellular gaps.

Animals↗

PubMed1992

The Walter Herbert Lecture. Control of cell motility and tumour invasion by extracellular matrix interactions.

Integrins are heterodimeric transmembrane proteins with large ectodomains and a short cytoplasmic tail inside the cell. They mediate cell adhesion to extracellular matrix proteins and to the surfaces of other cells. In many cases the sequence recognised by the integrins in the extracellular matrix proteins is the tripeptide Arg-Gly-Asp (RGD). Short synthetic peptides containing this sequence can inhibit invasion in vitro and tumour dissemination in vivo. Thus, the alpha 5 beta 1 fibronectin binding integrin appears to be the key integrin in the invasion of at least melanoma, osteosarcoma and glioblastoma cells. Modulation of the level and activities of this integrin can suppress invasion, whereas the alpha v beta 3 vitronectin binding integrin appears to be associated with increased invasiveness. There is increasing evidence that some of these effects are mediated through signals elicited by the binding of integrins to their target proteins. This possibility has generated a great deal of interest in the cytoplasmic molecules that might mediate the integrin-associated signalling.

Amino Acid Sequence↗

PubMed1992

Modulation of neuroblastoma cell differentiation by the extracellular matrix.

The effect of a complex in vitro synthesized extracellular matrix (ECM) and its components on growth and phenotypical differentiation of a human neuroblastoma (NB) cell line (HTLA230) was investigated. Rat smooth-muscle-cell (R22CIF)-derived ECM composed of collagen, glycoproteins, and glycosaminoglycans (GAGs) promoted spontaneous neurite outgrowth of HTLA230 cells but did not alter their growth kinetic or cloning efficiency as compared with cells seeded onto gelatin-coated dishes. The matrix significantly enhanced, quantitatively and qualitatively, the responsiveness of HTLA230 cells to retinoic acid (RA), and a substantially reduced growth rate was observed in the presence of RA with cells grown on the ECM. Biochemical modification of the composition of the R22CIF-matrix by trypsin digestion and/or high-salt extraction (4 M guanidinium) demonstrated that the ratio of chondroitin sulfate to hyaluronic acid (HA) present in the ECM determines the capacity of the matrix to promote NB differentiation. A human fibroblast (T-1)-derived ECM, which has a biochemical composition of the GAG component similar to that of the trypsinized R22CIF-matrix, but which has a high amount of glycoproteins, confirmed these results. Nerve-growth-factor (NGF)-induced differentiation in a variant HTLA 230 cell line was inhibited when cells were grown on an ECM with a low ratio of chondroitin sulfate/HA. The composition of the ECM thus modulates the responsiveness to various differentiation-inducing agents and alters the phenotype of NB cells.

Animals↗

PubMed1992

Switching from differentiation to growth in hepatocytes: control by extracellular matrix.

Studies were carried out to analyze how different extracellular matrix (ECM) molecules regulate hepatocyte growth and differentiation. Freshly isolated rat hepatocytes were cultured on non-adhesive plastic dishes that were pre-coated with defined densities of either laminin, fibronectin, type I collagen, or type IV collagen. Sparse cell plating densities were used to minimize cell-cell contact formation and all studies were carried out in chemically defined medium that contained a saturating amount of soluble growth factors. Dishes coated with a low ECM density (1 ng/cm2) supported hepatocyte attachment, but did not promote cell spreading or growth. Computerized image analysis confirmed that over 80% of cells remained free of contact with other cells under these conditions. Yet, these round cells maintained high levels of albumin gene expression as well as elevated secretion rates for multiple liver-specific proteins (albumin, transferrin, and fibrinogen), regardless of the type of ECM molecule used for cell attachment. When ECM coating densities were raised from 1 to 1,000 ng/cm2, cell spreading, expression of histone mRNA, DNA synthesis, and cell proliferation all increased in parallel. Activation of growth by high ECM densities was also accompanied by a concomitant down-regulation of differentiated functions and again, dishes coated with all four types of ECM molecules produced similar effects. Thus, the ability to switch hepatocytes from differentiation to growth (i.e., between different genetic programs) is not limited to a single ECM molecule, a distinct three dimensional ECM geometry, or due to alteration of cell-cell interactions. Rather, the regulatory signals conveyed by immobilized ECM molecules depend on the density at which they are presented and thus, on their ability to either prohibit or support cell spreading.

Animals↗

PubMed1992

Extracellular matrix synthesis and turnover by type II pulmonary epithelial cells.

Both type I and type II pulmonary epithelial cells contact the extracellular matrix (ECM). Type II cell-ECM interactions are bidirectional; they involve matrix-mediated modulation of type II cell differentiation, as well as cellular synthesis and deposition of ECM components. The present experiments examine the kinetics of accumulation of newly synthesized proteins in cell and matrix fractions from primary cultures of type II pneumocytes. Cycloheximide-sensitive incorporation of [3H]leucine into total protein of both the cell and ECM fractions was linear for 24-30 h, when steady-state labeling was reached and maintained to at least day 8. Over this interval, the cells enlarged but did not divide. Newly synthesized proteins recovered in the matrix fraction averaged 1-2% of those in the cells. Relative rates of radiolabeling of matrix proteins peaked at culture day 2 and increased in the absence of serum. In short-pulse studies, initial rates of protein synthesis were equal on culture days 1 and 3; this suggested that the steady-state labeling kinetics above reflected protein turnover. This was supported by rapid loss of radioactivity from the ECM after fresh type II cells were seeded on a prelabeled, cell-free matrix surface. Fresh or conditioned Dulbecco's modified Eagle's medium containing 10% fetal calf serum had little effect on matrix stability. These results demonstrate regulated deposition and turnover of a complex ECM by type II cells and provide a basis for further investigations of factors that control these processes.

Animals↗

PubMed1992

Human ovarian surface epithelial cells are capable of physically restructuring extracellular matrix.

OBJECTIVE: After ovulation the human ovarian surface epithelium proliferates at the wound edges, migrates over the ovulatory defect, and contributes to its repair primarily by the action of proteolytic enzymes and by the deposition of new matrix material. We examined the potential for human ovarian surface epithelial cells to physically remodel extracellular matrix in culture, similar to collagen gel lattice contraction by fibroblasts, a well-known culture model for wound repair, as an additional role of human ovarian surface epithelium in wound repair. STUDY DESIGN: Human ovarian surface epithelium cells from ovarian biopsies of 11 patients were grown in culture and plated onto a combination of collagen gel and rat ovarian surface epithelial-derived extracellular matrix. The degree of matrix contraction was measured as the percentage of the original culture diameter. RESULTS: Human ovarian surface epithelial cells surrounded and contracted the combination of matrices into a dense matrix organoid. The degree of organoid contraction was related to the number of human ovarian surface epithelial cells plated per organoid and to the inclusion of fibroblasts within the collagen gel but was not affected either by adding epidermal growth factor and hydrocortisone to the culture medium or by reducing the serum component of the medium. CONCLUSION: Human ovarian surface epithelial organoids may be useful for the study of normal and abnormal ovarian events such as ovulatory wound repair and cyst formation.

Adult↗

PubMedDate not supplied

Newer knowledge of skeletogenesis: macromolecular transitions in the extracellular matrix.

Morphogenesis of skeletal tissues is accompanied by dramatic changes in the types and amounts of extracellular macromolecules synthesized. These changes correlate with the morphological and structural characteristics of each tissue type involved in skeletogenesis, viz. mesenchyme, cartilage and bone. At the beginning of skeletogenesis, a hyaluronate-rich extracellular matrix may provide a beneficial milieu for mesenchymal cell migration and proliferation, and prevent precocious differentiation. This matrix also contains type I collagen and possibly a unique sulfated proteoglycan. Cartilage differentiation, during endochondral osteogenesis, involves the removal of hyaluronate and the production of large amounts of type II collagen and a characteristic chondroitin sulfate-proteoglycan. Further complex transitions in arrangement and concentration of proteoglycan occur in the epiphyseal growth plate followed by sudden depletion at the site of initiation of bone formation. In addition, at this site, the type of collagen synthesized reverts from type II back to type I. Bone formation at periosteal sites also involves removal of proteoglycan. The collagen component of both osteoid and bone matrix is type I but the level of hydroxylation of lysine moieties may be significantly higher in osteoid. It is proposed that changes in extracellular matrix composition are important factors in the control of morphogenesis as well as in providing suitable structural properties to the developing skeletal tissues.

Animals↗

PubMed1977

Failure of cultured chick embryo fibroblasts to incorporate collagen into their extracellular matrix when transformed by Rous sarcoma virus. An effect of transformation but not of virus production.

Whole chick embryo fibroblasts were infected with the Prague wild type Rous sarcoma virus and with a temperature sensitive mutant of this strain, RSVtsLA24. Normal fibroblasts and fibroblasts infected with the temperature-sensitive mutant and cultured at the nonpermissive temperature-sensitive mutant and cultured at the nonpermissive temperature, secreted procollagen into the medium and incorporated collagen into their extracellular matrix. On the other hand, transformed fibroblasts and fibroblasts infected with the temperature-sensitive mutant and cultured at the permissive temperature, were able to secrete procollagen into the medium, but there was no evidence that they were able to convert procollagen to collagen and incorporate collagen into an extracellular matrix. The inability of the infected cells to incorporate collagen into an extracellular matrix was found to be a result of transformation rather than of virus production in these cells.

Animals↗

PubMed1992

The role of extracellular matrix in peripheral nerve regeneration: a wound chamber study.

A wound chamber model was used for the study of the interaction between axon, Schwann cell and extracellular matrix during peripheral nerve regeneration. Impermeable silicone tubes, 8 mm long and 1.4 mm in internal diameter were sutured to transected rat sciatic nerve and the contents of the tubes were removed at intervals for chemical, histological, immunocytochemical and electron microscopic studies. There was an initial phase of fluid accumulation and the formation of a fibrin/fibronectin clot or cable which connected the cut ends of the nerve. The chamber fluid was shown to have a protein profile similar to that of rat serum. Schwann cells, endothelial cells and fibroblasts migrated first into the cable, apparently mediated by cell-fibrin interaction. Axons buried within the Schwann cell cytoplasm were led into the cable but an axon-fibrin interaction was not observed. After 1 week, the fibrin matrix underwent dissolution, with replacement by collagen. This marked the onset of myelination and the organization of nerve fibers into fascicles. The findings from the present study suggest that the interactions between axon and Schwann cell and between Schwann cell and a changing extracellular matrix are the essential driving force in nerve growth and differentiation during peripheral nerve regeneration.

Animals↗

PubMed1992

Glucocorticoid ameliorates altered gene expression of extracellular matrix components in kidneys of New Zealand black/white F1 mice.

1. We examined the effects of methylprednisolone on the levels of messenger RNA encoding for extracellular matrix components, including alpha 1(IV) collagen chain, laminin B1 and B2 chains, heparan sulphate proteoglycan and alpha 1(I) and alpha 1(III) collagen chains, and on the accumulation of these proteins in the renal cortex of New Zealand Black/White F1 mice. 2. At the onset of nephritis, at about 5 months of age, New Zealand Black/White F1 mice were divided in two groups that received either methylprednisolone or saline injections for 5 months. 3. The development of histological lesions and the glomerular deposition of IgG, IgM and C3 were suppressed by methylprednisolone treatment from 5 to 10 months of age. 4. The distribution and intensity of type IV collagen, laminin, heparan sulphate proteoglycan, type I collagen and type III collagen in renal cortex were decreased by the administration of methylprednisolone. 5. Levels of messenger RNA encoding for alpha 1(IV) collagen chain, laminin B1 and B2 chains, heparan sulphate proteoglycan and alpha 1(I) and alpha 1(III) collagen chains in the renal cortex of New Zealand Black/White F1 mice were significantly ameliorated at 8-10 months of age by methylprednisolone administration. 6. These results indicate that methylprednisolone treatment can serve as an effective therapeutic approach to abnormal extracellular matrix regulation in murine lupus nephritis.

Animals↗

PubMed1992

Sodium vanadate, a tyrosine phosphatase inhibitor, affects expression of hematopoietic growth factors and extracellular matrix RNAs in SV40-transformed human marrow stromal cells.

Protein tyrosine kinases represent a subset of proteins that mediate signal transduction between the extracellular environment and the nucleus. We have previously described a coordinated upregulation between RNA transcripts of a tyrosine kinase, c-abl, and those of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin 6 (IL-6) in human marrow stromal cells (SVMSC). Moreover, an inverse relationship exists between expression of c-abl transcripts and those of extracellular matrix proteins such as type collagen I transcripts. In the present study, these inverse relationships were again seen in SVMSC when tyrosine kinase effects were enhanced by treatment of the cells with the tyrosine phosphatase inhibitor sodium orthovanadate. This suggests that tyrosine kinases are involved in the coordinate regulation of these genes.

Bone Marrow Cells↗

PubMed1992

Monoclonal antibody MT2 identifies an extracellular matrix glycoprotein that is co-localized with tenascin during adult newt limb regeneration.

Using immunohistochemical techniques and mAb MT2, we describe here a novel extracellular matrix (ECM) molecule that is developmentally regulated during limb regeneration in adult newts. The MT2 antigen appears during preblastema stages, is most abundant during blastema stages, and persists, near undifferentiated cells, until digit stages. The MT2 antigen is located in an acellular layer under the wound epithelium and throughout the ECM of the undifferentiated mesenchyme as a thick, cord-like component. In unamputated limbs mAb MT2 reactivity is restricted to tendons, myotendinous junctions, periosteum and to a layer of material beneath the epidermis. In both unamputated limbs and regenerating limbs, the reactivity to mAb MT2 colocalizes closely with urodele tenascin. Immunoblot analysis of blastema extracts showed that the unreduced form of the MT2 antigen is a large, polydispersed protein of approximately the same size as tenascin. However, based upon (a) molecular weights of reduced subunits, (b) competition experiments on tissue sections, and (c) analysis of molecules immunoprecipitated by mAb MT2, we conclude that the MT2 substance is unrelated biochemically to tenascin. The results from immunoblots, enzyme digestions and DEAE-Sephacell binding studies suggest that the unreduced MT2 antigen is a large protein composed of subunits which are connected by disulfide bonds. Reduction of the MT2 antigen results in three components recognized by mAb MT2. The largest of these reduced components is a chondroitin sulfate-like glycoprotein with a molecular weight (Mr) of 310-325 x 10(3). A second component (Mr, 285-300 x 10(3)) is the core protein of the 310-325 x 10(3) glycoprotein.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

Enhanced expression of the developmentally regulated extracellular matrix molecule tenascin following adult brain injury.

Tenascin is an extracellular matrix molecule synthesized and released by young astrocytes during embryonic and early postnatal development of the nervous system, and it is concentrated in boundaries around emerging functional neuronal units. In the adult nervous system, tenascin can be detected only in very low levels. Distinct spatial and temporal distributions of tenascin during developmental events suggest a role in the guidance and/or segregation of neurons and their processes within incipient functional patterns. We show here, using in situ hybridization and immunocytochemistry, that stab wounds of the adult mouse cerebellar and cerebral cortices result in an enhanced expression of tenascin in a discrete region around the lesion site that is associated with a subset of glial fibrillary acidic protein-positive astrocytes. Tenascin up-regulation in the lesioned adult brain may be directly involved in failed regeneration or indirectly involved through its interactions with other glycoconjugates that either inhibit or facilitate neurite growth.

Age Factors↗

PubMed1992

Lipoprotein lipase enhances binding of lipoproteins to heparan sulfate on cell surfaces and extracellular matrix.

Lipoprotein lipase enhances binding at 4 degrees C of human plasma lipoproteins (chylomicrons, VLDL, intermediate density lipoprotein, LDL, and HDL3) to cultured fibroblasts and hepG-2 cells and to extracellular matrix. Heparinase treatment of cells and matrix reduces the lipoprotein lipase enhanced binding by 90-95%. Lipoprotein lipase causes only a minimal effect on the binding of lipoproteins to heparan sulfate deficient mutant Chinese hamster ovary cells while it promotes binding to wild type cells that is abolished after heparinase treatment. With 125I-LDL, lipoprotein lipase also enhances uptake and proteolytic degradation at 37 degrees C by normal human skin fibroblasts but has no effect in heparinase-treated normal cells or in LDL receptor-negative fibroblasts. These observations prove that lipoprotein lipase causes, predominantly, binding of lipoproteins to heparan sulfate at cell surfaces and in extracellular matrix rather than to receptors. This interaction brings the lipoproteins into close proximity with cell surfaces and may promote metabolic events that occur at the cell surface, including facilitated transfer to cellular receptors.

Animals↗

PubMed1992

Hepatic fibrogenesis: the puzzle of interacting cells, fibrogenic cytokines, regulatory loops, and extracellular matrix molecules.

Fibrotic lesions affect a wide variety of organs but liver fibrosis is probably the most abundant form of organ fibrosis. Disturbances of the equilibrium between parenchyma and extracellular matrix (ECM) leading to a disproportionate increase and irregular deposition of newly formed connective tissue components (fibrosis) is a common and clinically most important sequelae of chronic active liver diseases. Significant progress has been made during the last years in the analysis of the structural composition of ECM in normal and fibrotic liver and in the dissection of the molecular and cellular mechanisms of exaggerated ECM-deposition in necroinflammatory areas using experimental models of hepatic fibrosis, isolated cells in mono- and coculture systems and the growing repertoire of molecular biological tools. Perisinusoidal, retinoid-storing cells (Ito cells, parasinusoidal lipocytes) transform under inflammatory stimuli to myofibroblast-like cells being qualitatively and quantitatively the most important connective tissue producing cell type in human and animal liver. Its activation and transformation is mediated by paracrine and autocrine loops involving transforming growth factor (TGF) beta as the main fibrogenic mediator secreted by activated liver macrophages, possibly also by endothelial cells and liberated by disintegrated thrombocytes. In advanced stages of retinoid-storing cell transformation additional growth factors like platelet derived growth factor (PDGF) become important indicating a sequential action of cytokines and fibrogenic mediators during the fibrogenic process. The molecular and cellular interactions in the course of liver fibrogenesis have gained model character for a number of other organ fibrotic processes, wound repair, and atherogenesis included.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

Human polymorphonuclear leucocytes stimulated by tumour necrosis factor-alpha show increased adherence to extracellular matrix proteins which is mediated via the CD11b/18 complex.

The present study demonstrates that tumour necrosis factor (TNF) and FMLP, but not IL-1 or IL-8, enhanced the adherence of polymorphonuclear neutrophil (PMN) to fibronectin, an extracellular matrix protein. The adherence induced by FMLP was very rapid, within 5 min while the induction of adherence by TNF was much slower, reaching maximum at 60 min. TNF also enhanced an adhesion of PMN to other extracellular matrix proteins, such as laminin, collagen IV and gelatin II, but not to human serum albumin. Anti-CD18 MoAb completely inhibited the binding of TNF-stimulated PMN to fibronectin and partially inhibited the binding to laminin. Further investigation showed that adhesion of TNF-stimulated PMN to fibronectin and laminin was inhibited by anti-CD11b MoAb and to a lesser extent by CD11a MoAb. In contrast to TNF-stimulated PMN the binding of unstimulated PMN to fibronectin and laminin was only inhibited by anti-CD11a MoAb. Anti-CD11c had no effect on PMN adherence. These results suggest that unstimulated PMN adhere to extracellular proteins through the CD11a/18, while TNF-stimulated PMN adhere through the CD11b/18. These results suggest that TNF secreted at the site of inflammation may enhance the interaction of PMN with the extravascular environment through the CD11b/18 complex.

Antigens, CD↗

PubMed1992

Altered glomerular extracellular matrix synthesis in experimental membranous nephropathy.

Chronic progressive membranous nephropathy (MN) in humans is characterized by thickening of the glomerular basement membrane (GBM) with formation of spikes which contain laminin and other extracellular matrix (ECM) proteins. We have utilized two models of MN in the rat (active and passive Heymann nephritis, AICN, PHN) to define the sequential changes in composition of GBM as they relate to changes in glomerular gene expression for ECM components, altered permeability and morphological changes. Renal biopsies obtained during the course of AICN and PHN were immunostained for various ECM proteins and total glomerular RNA was hybridized with cDNA probes specific for laminin B2-chain, s-laminin, and types I and IV collagen. In addition, the ability of anti-glomerular epithelial cell (GEC) antibody and complement on rat GEC in culture to induce laminin release or laminin and s-laminin mRNA expression was determined. The results demonstrate that at weeks 12, 16, and 20 of AICN, immunostaining for laminin, s-laminin, fibronectin, entactin, and heparan sulfate proteoglycan increased in the GBM in a spike-like pattern. Concomitantly, glomerular mRNA levels of laminin B2-chain and of s-laminin increased. Type IV collagen protein and gene expression remained unchanged or decreased. No glomerular immunostaining for type I collagen occurred during AICN despite increased expression of mRNA for this collagen type. In contrast to AICN, in PHN no pronounced changes of the glomerular ECM occurred, except for transient expression of type I collagen mRNA in whole glomerular RNA and type I collagen protein the GEC cytoplasm. Stimulation of GEC in culture with anti-GEC antibody and complement also failed to induce transcription of laminin or s-laminin mRNA or the release of laminin protein. These findings suggest that the polyantigenic expansion of GBM which occurs in chronic experimental MN may be stimulated by factors different from the C5b-9 mediated processes that cause the initial proteinuria.

Animals↗