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PubMedDate not supplied

The extracellular matrix and its modulation in the trabecular meshwork.

The extracellular matrix (ECM) in the trabecular meshwork is is believed to be essential for maintenance of the normal outflow system. Excessive, abnormal accumulations of ECM materials have been noted in the trabecular meshwork of eyes obtained from patients with primary open angle glaucoma. This review summarizes the current knowledge regarding the composition of this matrix and the receptors for ECM proteins in the trabecular meshwork. Modulations of the ECM elements by constituents in the aqueous humor after phagocytic challenges and by glucocorticoids are also described. The ECM is known to regulate cell differentiation and cell behavior in a number of systems. It will thus be of particular interest to establish the relationship between the modulated ECM and the functional status of trabecular meshwork cells and to examine the possible relevance of such modulation to outflow resistance.

Animals↗

PubMed1998

Mode of adsorption and orientation of an extracellular matrix protein affect its cell-adhesion-promoting activity.

Cell adhesion to extracellular matrix contributes to the organization of tissues and modulates cell behavior. In conventional cell adhesion assays, plastic wells are coated with matrix proteins and assayed for their adhesion-promoting activity. We show here that factors such as sample composition, coating buffers, and manufacturers' plastic treatment markedly affect cell adhesion to the extracellular matrix protein laminin-5 (Ln-5). These factors were shown to affect adsorption efficiency as determined by measuring total adsorbed protein with a polyclonal anti-Ln-5 antiserum. They also influence the availability of the epitope for an adhesion-blocking anti-Ln-5 monoclonal antibody, suggesting that coating conditions affect the orientation of Ln-5. Generally, cell adhesion correlates more strongly with the availability of the epitope for the adhesion-blocking antibody than with total adsorbed Ln-5. Our data further indicate that cell adhesion to other matrix proteins may be influenced by similar factors. Adding Ln-5 samples to plastic wells that had been precoated with non-adhesion-blocking anti-Ln-5 antibodies made cell adhesion independent of factors such as sample composition, coating buffers, and source of plastic. Thus, the control of adsorption efficiency and orientation of extracellular matrix proteins is essential for creation of reliable and reproducible conditions in cell adhesion assays.

Adsorption↗

PubMed2003

Modulation of cultured corneal keratocyte phenotype by growth factors/cytokines control in vitro contractility and extracellular matrix contraction.

The purpose of this study was to evaluate specific keratocyte phenotypes (keratocyte, fibroblast, myofibroblast) for cell contractility and ability to contract extracellular matrix. Rabbit keratocyte phenotype was modulated by exposure to optimal proliferative doses of IGF-I, IL-1alpha, FGF2, PDGF-AB, and TGFbeta(1). Cells were then evaluated by immunocytochemistry, western blot, collagen gel contraction and LPA stimulation to measure: (1) focal adhesion (FA), fibronectin (FN) and f-actin assembly; (2) expression of alpha-smooth muscle actin (alpha-SMA); (3) ability to contract extracellular matrix and (4) determine contractile ability, respectively. Untreated keratocytes showed no ability to contract collagen matrix. IGF-I and IL-1alpha increased cell proliferation (70.2 and 74.3%, respectively) but did not alter keratocyte phenotype or ability to contract matrix. FGF2 and PDGF induced fibroblast differentiation with FA and FN assembly and significant (p<0.05) extracellular matrix contraction. TGFbeta(1) induced myofibroblast differentiation with prominent FA and FN assembly, expression of alpha-SMA and significantly greater (p<0.05) matrix contraction. Addition of LPA induced actin filament assembly in growth factor starved fibroblasts and myofibroblasts but had no effect on the cultured keratocyte phenotype. We report for the first time that the keratocyte phenotype is non-contractile and that cell quiescence is not a defining characteristic. We further establish that changes in environmental conditions modulate the keratocyte phenotype resulting in physiologically functional differences regarding cell contractility and capacity to contract extracellular matrix.

Animals↗

PubMed2005

Papillote and Piopio: Drosophila ZP-domain proteins required for cell adhesion to the apical extracellular matrix and microtubule organization.

Adhesion between epithelial cells and extracellular substrates is normally mediated through basal adhesion complexes. However, some cells also possess comparable junctions on their apical surface. Here, we describe two new Drosophila proteins, Piopio and Papillote, that are required for the link between the apical epithelial surface and the overlying apical extracellular matrix (aECM). The two proteins share a zona pellucida (ZP) domain with mammalian aECM components, including the tectorins found in the vertebrate inner ear. Tagged versions of both proteins localized to the apical epithelial surface. Mutations in piopio, papillote and dumpy (another gene encoding a ZP-domain protein) cause defects in the innermost layer of the aECM and its detachment from the epidermis. Loss of Piopio, but not Papillote or Dumpy, causes the absence of specialized microtubule bundles from pupal wings, suggesting that Piopio plays a role in microtubule organization. Thus, ZP domain-containing proteins may have shared functions within the aECM, while also exhibiting specific interactions with the cytoskeleton.

Amino Acid Sequence↗

PubMed2004

Gamma-irradiation modulates vascular smooth muscle cell and extracellular matrix function: Implications for neointimal development.

OBJECTIVE: Migration of vascular smooth muscle cells (SMCs) into the subintimal space, and their proliferation and resultant deposition of extracellular matrix are key processes in the development of intimal hyperplasia, leading to vascular recurrent stenosis. The purpose of this study was to investigate the effects of clinically administered doses of gamma-radiation on SMCs and extracellular matrix proteins in vitro, to better understand how it impinges on cellular and extracellular components of recurrent stenosis. METHODS: The effects of gamma-irradiation (10, 20 Gy) on SMC migration into three-dimensional collagen matrix gels was quantitated by calibrated light microscopy, and the release of metalloproteinases into conditioned media was investigated with an enzyme-linked immunosorbent assay and zymography. Collagen production was assayed with [(3)H]-proline incorporation, and SMC phenotype changes with confocal microscopy with a fluorescent alpha-actin antibody. The effect of gamma-irradiation on extracellular matrix was investigated by quantitating untreated SMC proliferation ((3)H-thymidine incorporation) on irradiated endothelial cell-derived matrix and by assessing structural collagen matrix changes with sodium dodecylsulfate polyacrylamide gel electrophoresis. All groups were compared with nonirradiated control groups. RESULTS: SMC vertical migration was significantly decreased by gamma-irradiation (48% and 55%, respectively; P <.0001). Irradiation did not generate measurable matrix protein crosslinks, nor did it alter the production of metalloproteinases or collagen synthesis. However, gamma-irradiation decreased the ability of extracellular matrix to induce nonirradiated SMC proliferation (15% reduction; P =.0028). Moreover, gamma-irradiation reversed the secretory phenotype of cultured SMCs to a contractile type. CONCLUSIONS: The gamma-irradiation-induced reduction of cellular migration, changes in SMC phenotype, and functional activity of matrix-bound factors, and no measurable effects on the production of extracellular matrix proteins, may in part explain the diverse effects of gamma-irradiation on the restenotic response.

Animals↗

PubMed2004

Reconstruction of rabbit urethra using urethral extracellular matrix.

BACKGROUND: Urethral reconstruction for both congenital and acquired etiologies remains a challenge for most urologic surgeons. Tissue engineering has been proposed as a strategy for urethral reconstruction. The purpose of this study was to determine whether a naturally derived extracellular matrix substitute developed for urethral reconstruction would be suitable for urethral repair in an animal model. METHODS: A urethral segmental defect was created in 20 male rabbits. The urethral extracellular matrix, obtained and processed from rabbit urethral tissue, was trimmed and transplanted to repair the urethral defect. Then, the regenerated segment was studied histologically by haematoxylin-eosin staining and Van Gieson staining at 10 days, 3 weeks, 6 weeks, and 24 weeks postoperation. Retrograde urethrography was used to evaluate the function of the regenerated urethras of 4 rabbits 10 and 24 weeks after the operation. The urodynamics of 4 rabbits from the experimental group and control group I were assessed and compared. In addition, 4 experimental group rabbits were examined by a urethroscope 24 weeks after the operation. RESULTS: At 10 days after operation, epithelial cells had migrated from each side, and small vessels were observed in the extracellular matrix. The matrix and adjacent areas of the host tissue were infiltrated with inflammatory cells. The epithelium covered the extracellular matrix fully at 3 weeks postoperation. Well-formed smooth-muscle cells were first confirmed after 6 weeks, at which point the inflammatory cells had disappeared. At 24 weeks postoperation, the regenerated tissue was equivalent to the normal urethra. Urethrography and urodynamic evaluations showed that there was no difference between normal tissue and regenerated tissue. CONCLUSIONS: Urethral extracellular matrix appears to be a useful material for urethral repair in rabbits. The matrix can be processed easily and has good characteristics for tissue handling and urethral function.

Animals↗

PubMed1990

Neutrophil bactericidal activity against Staphylococcus aureus adherent on biological surfaces. Surface-bound extracellular matrix proteins activate intracellular killing by oxygen-dependent and -independent mechanisms.

The activation patterns of surface adherent neutrophils are modulated via interaction of extracellular matrix proteins with neutrophil integrins. To evaluate neutrophil bactericidal activity, Staphylococcus aureus adherent to biological surfaces were incubated with neutrophils and serum, and the survival of surface bacteria was determined. When compared to albumin-coated surfaces, the bactericidal activity of neutrophils adherent to purified human extracellular matrix was markedly enhanced (mean survival: 34.2% +/- 9.0% of albumin, P less than 0.0001) despite similar efficient ingestion of extracellular bacteria. Enhancement of killing was observed when surfaces were coated with purified constituents of extracellular matrix, i.e., fibronectin, fibrinogen, laminin, vitronectin, or type IV collagen. In addition to matrix proteins, the tetrapeptide RGDS (the sequence recognized by integrins) crosslinked to surface bound albumin was also active (survival: 74.5% +/- 5.5% of albumin, P less than 0.02), and fibronectin-increased killing was inhibited by soluble RGDS. Chemiluminescence measurements and experiments with CGD neutrophils revealed that both oxygen-dependent and -independent bactericidal mechanisms are involved. In conclusion, matrix proteins enhance intracellular bactericidal activity of adherent neutrophils, presumably by integrin recognition of RGDS-containing ligands. These results indicate a role for extracellular matrix proteins in the enhancement of the host defense against pyogenic infections.

Amino Acid Sequence↗

PubMed1991

The role of extracellular matrix components in dentin mineralization.

The extracellular matrix of dentin consists of mineral (hydroxyapatite), collagen, and several noncollagenous matrix proteins. These noncollagenous matrix proteins may be mediators of cell-matrix interactions, matrix maturation, and mineralization. This review describes the current knowledge of the chemistry of mineral crystal formation in dentin with special emphasis on the roles of the dentin matrix proteins. The functions of some of these matrix proteins in the mineralization process have been deduced based on in vitro studies. Functions for others have been postulated based on analogy with some of the bone matrix proteins. Evidence suggests that several of these matrix proteins may have multiple effects on nucleation, crystal growth, and orientation of dentin hydroxyapatite.

Crystallization↗

PubMedDate not supplied

Synovial extracellular matrix: partial characterization of matrix components and identification of type VI collagen molecular forms.

Alterations in the synovial extracellular matrix (ECM) in chronic inflammatory arthritis may affect synoviocyte adhesion and may be important in the regulation of pannus growth and invasion. Immunohistochemical examination of synovium has revealed enhanced deposition of fibronectin and collagen in interstitial areas consistent with expansion of the ECM in inflammatory arthritis. In order to functionally characterize the ECM of synovium, synovial extracellular matrix was purified from pannus removed at joint replacement surgery. A prominent 140 Kd 6M guanidine extractable component was found to mediate synoviocyte adhesion in a cell-blotting assay. This 140 Kd component was identified as a form of type VI collagen. Type VI collagen appears to be a significant component of synovial ECM.

Cell Adhesion Molecules↗

PubMed2002

Extracellular matrix glycoproteins inhibit neurite production by cultured neurons.

We have analyzed the role of extracellular matrix glycoproteins in the formation of a bipolar outgrowth pattern of identified leech neurons in culture. Adult anterior pagoda (AP) neurons cultured on the inner surface of the ganglion capsules that surround central nervous system, generate two processes oriented in opposite directions. This pattern differs from those produced by these neurons cultured on other substrates, and is similar to the pattern of developing AP neurons at embryonic day 10. We used different lectins to identify subsets of glycoproteins in the extracellular matrix (ECM) of the capsules and to study their contribution to the formation of the bipolar outgrowth pattern. ECM glycoproteins binding to peanut agglutinin (PNA) or Galanthus nivalis aglutinin (GNA) lectins were detected in ganglion capsules and in ganglion extracts that had been separated by electrophoresis and blotted to nitrocellulose membranes. Four protein bands bound to PNA lectin and six other bands, including laminin subunits, bound to GNA lectin. Other lectins failed to recognize any of the proteins. For AP neurons cultured on capsules, addition of PNA lectin to the culture medium produced a dose-dependent increase in the number of primary neurites without affecting their shape, length or number of branch points. However, PNA lectin used as substrate did not affect sprouting of AP neurons. Our results suggest that PNA-binding extracellular matrix glycoproteins regulate the formation of the bipolar pattern of AP neurons by inhibiting the formation of neurites.

Animals↗

PubMed2003

Transient forebrain ischemia modulates signal transduction from extracellular matrix in gerbil hippocampus.

Cell adhesion to the extracellular matrix (ECM) functions as a survival factor and disruption of cell-ECM interaction can lead to cell death. Our previous study has demonstrated ischemia-induced enhancement of activity of extracellular metalloproteinases, which might result in the alteration of adhesive contact with ECM and affect the intracellular signaling pathway. The enzyme thought to play a major role in conveying survival signals from ECM to the cell interior is focal adhesion kinase (pp125(FAK)). In the present study, the temporal relation between activation of extracellular metalloproteinases (MMP-2 and MMP-9), degradation of extracellular matrix protein laminin and the expression of pp125(FAK) after 5 min of global ischemia in gerbil hippocampus were investigated. While significant activation of both investigated metalloproteinases occurred in the course of reperfusion, only changes in MMP-9 activity were correlated with degradation of laminin. These ischemia-induced extracellular events coincide temporarily with proteolytic modification of FAK protein and diminished level of its phosphorylated form, to about 50% of the initial value. These results are indicative of an involvement of ECM-pp125(FAK) signaling pathway in ischemia-induced neuronal degeneration.

Animals↗

PubMedDate not supplied

An immunofluorescence study of extracellular matrix associated with cytotrophoblast of the chorion laeve.

Using immunofluorescence we have studied the distribution within and beneath the cytotrophoblast of chorion laeve of five extracellular matrix components: types I, III and IV collagen, fibronectin and laminin. Fibronectin, laminin and types I and IV collagen are located in a network of extracellular matrix which encapsulates cells of the cytotrophoblast multilayer. The results suggest that cytotrophoblast in all layers is active in matrix biosynthesis. The pseudo-basement membrane, which links this intercellular matrix to the underlying reticular layer, contains rich deposits of fibronectin and type III collagen along with more restricted foci of laminin and type IV collagen. The reticular layer contains fibronectin, type III collagen and small amounts of type I collagen, but no laminin or type IV collagen. Type III collagen is also found in the maternal decidua. Extracellular matrix markers may be useful in defining trophoblast differentiation pathways. Possible reasons are discussed for the unusual architecture of extracellular matrix of cytotrophoblast of the chorion laeve. Cytoplasmic actin occurs in cells throughout the chorion laeve, while cytokeratin appears only in cytotrophoblast. Plasminogen also occurs throughout cytotrophoblast in pericellular locations.

Actins↗

PubMed1993

Perinatal food restriction in rats reduces the content but not concentration of liver extracellular matrix proteins.

Fibrosis of the liver has been reported to be associated with malnutrition, based on qualitative histological and histochemical approaches. The aim of this study was to quantitatively examine the effect of perinatal food-restriction on the expression of extracellular matrix components of the liver, using rats fed 50% of ad libitum intake, determined by the food consumption of the control group on the previous day. Levels of extracellular matrix proteins were measured by dot blot analysis using monospecific antibodies against collagen types I, III and IV, laminin and fibronectin. The body weights of 4, 8 and 13-wk-old malnourished groups were 25, 35 and 48% of the control group body weights, respectively, and the liver weights were 22, 32 and 60% of the controls. The total contents of the extracellular matrix components were significantly reduced to 30, 34 and 58% of the controls, but when expressed per tissue or per milligram protein there were no significant differences. Indirect immunofluorescence revealed no major changes in extracellular matrix localization. The major histological change in the food-restricted rats was fatty infiltration. Our observations suggest that the effect of perinatal food restriction is mainly liver steatosis, and that the liver of food-restricted animals during the perinatal period has the capacity to preserve its main extracellular matrix components.

Animals↗

PubMed1992

Motility of IL-2-stimulated lymphocytes in neutral and acidified extracellular matrix.

The migration of lymphocytes through extracellular matrix (ECM) is an essential feature of the infiltration process. In the course of their extravasation into poorly perfused neoplastic lesions, lymphocytes often encounter regions of acidified ECM. This study was designed to determine whether lymphocyte adherence and motility in ECM are influenced by ambient pH. Murine splenic lymphocytes, activated by culture with high-titer IL-2, were allowed to migrate into three-dimensional gels of Type I collagen, a major component of interstitial stroma, or into Matrigel, a basement membrane model. After 18 hr at pH 7.1, the leading cell front traveled a mean distance of approx 475 microM into Type I collagen gel. Approx 50% of the cells remained nonadherent, 25% adhered to the gel surface, and 25% were motile (penetrated beneath the surface). At pH 6.7, the leading-front distance increased significantly, by a factor of 1.4X, but there was little change in the proportion of cells exhibiting nonadherence, surface adherence, or motility. The relative motilities of CD3+ and AsGM1+ subsets were also unaltered. It therefore appears that acidification of collagen matrix increases the locomotory activity of motile lymphocytes, but causes little recruitment of nonmotile lymphocytes into the motile pool. Similar results were obtained in experiments with Matrigel. The increased motility observed at pH 6.7 did not reflect breakdown or relaxation of matrix lattices, as measured by the passive diffusion of latex beads of defined diameter. Preincubation of lymphocytes at pH 6.7 did not alter their subsequent motility in pH 7.1 gels. The findings establish ambient pH as a microenvironmental variable which can influence lymphocyte migration through ECM. The weak acidity characteristic of certain tumor microenvironments may be a factor which encourages lymphocyte infiltration through tissue matrix. Treatments which alter intratumor pH could potentially be used to manipulate the infiltration process for immunotherapeutic benefit.

Animals↗

PubMed1994

The extracellular matrix molecule janusin regulates neuronal morphology in a substrate- and culture time-dependent manner.

Janusin is an extracellular matrix glycoprotein with structural homology to tenascin. In search of extracellular matrix components which govern the differentiation of neurons in the central nervous system, we have investigated the influence of janusin on the differentiation of hippocampal neurons in vitro. Janusin coated onto nitrocellulose was a good substrate for attachment of cell bodies and neurite outgrowth after 21 h of culture. Most cells exhibited a polarized morphology with one long major neurite and one or two short minor neurites. When janusin was coated onto a polyornithine-conditioned plastic surface, it increased the polarity of neurons in that the length of major neurites was increased and the length and number of minor neurites were decreased when compared with the control polyornithine-conditioned plastic without janusin. As we have shown before for tenascin, laminin and fibronectin, polarization was preceded by an increase in the number and length of all neurites during the first hours after cell plating. This study therefore adds janusin to the increasing number of extracellular matrix glycoproteins which promote axonal but not dendritic growth.

Animals↗

PubMed2002

Extracellular matrix ligands promote RPE attachment to inner Bruch's membrane.

PURPOSE: To determine if resurfacing layers of human Bruch's membrane with extracellular matrix ligands increases adult human retinal pigment epithelium (RPE) attachment. METHODS: We removed successive layers of Bruch's membrane sequentially by mechanical or enzymatic means to expose the RPE basal lamina, inner collagen layer, and elastin layer. Each layer was coated with extracellular matrix proteins (4 microg/cm(2) laminin, 4 microg/cm(2) vitronectin, 20 microg/cm(2) fibronectin, 20 microg/cm(2) collagen IV) for 2 hrs at 37 degrees C. First passage adult human RPE (15000 cells/6 mm explant) were plated onto coated or uncoated Bruch's membrane layers and RPE attachment was measured 18 hrs later. RESULTS: The reattachment rate to basal lamina derived from younger (age < 50) donors was higher than older (age >/= 70) donors (56.2 +/- 4.8% versus 46.7 +/- 0.7% respectively; p < 0.05). Coating with laminin or collagen IV increased RPE attachment to older but not younger basal lamina. The reattachment rate to inner collagen derived from younger donors was higher than older donors (51.3 +/- 2.7% versus 37.4 +/- 1.7% respectively, p < 0.05). Coating with laminin, fibronectin or collagen IV increased RPE attachment to older but not younger inner collagen layer. Adding extracellular matrix ligands did not increase RPE attachment to elastin. CONCLUSIONS: RPE attachment is increased by adding ligands to the basal lamina or inner collagen layer but not to the elastin layer. This may be important if the elastin layer is exposed in AMD patients after submacular surgery.

Adult↗

PubMed1993

The hepatic extracellular matrix. I. Components and distribution in normal liver.

The unique nature of the hepatic extracellular matrix (ECM) is predicated by the special configuration of the space of Disse. Whereas other epithelial organs have two basement membranes (BM) and a substantial ECM interposed between endothelial and epithelial cells, the liver lobule has no BM and only an attenuated ECM, consisting mostly of fibronectin, some collagen type I, and minor quantities of types III, IV, V, and VI. This configuration, together with the abundant fenestrations and gaps of the sinusoidal endothelial cells, seems ideally suited to facilitate the rapid bidirectional exchange of macromolecules normally taking place between plasma and hepatocytes. During organogenesis, the liver anlage is vascularized by continuous capillaries with BM, but by day 13.5 of development (in the rat) the vessels in the immediate proximity of hepatocytes become fenestrated, lacking specialized junctions and BM, suggesting that the hepatocytes produce signals capable of modulating the endothelial phenotype. In regeneration, hepatocyte proliferation precedes vascular proliferation resulting in the formation of hepatocyte clusters that, temporarily, lack sinusoids. Eventually, vascular proliferation follows and the normal hepatocyte-vascular relationships are restored. During this period laminin synthesis by Ito cells is prominent. As soon as hepatocytes become stable, secretion of the sinusoid phenotype-maintaining factors resumes and laminin synthesis and secretion terminates. The interplay between extracellular matrix and liver cells is essential for normal homeostasis and its modification results in deranged hepatic function.

Adult↗

PubMed2001

Glucocorticoids down-regulate the extracellular matrix proteins fibronectin, fibulin-1 and fibulin-2 in bone marrow stroma.

Glucocorticoids regulate hematopoietic cell interactions with the bone marrow microenvironment, but the molecules involved in the regulation are still largely unknown. We have studied the effect of glucocorticoids on mRNA expression and protein synthesis of the major extracellular matrix adhesion protein fibronectin and three other extracellular proteins, fibulin-1, fibulin-2 and nidogen-1, in mouse bone marrow cultures and in a hematopoiesis supporting the stromal MC3T3-G2/PA6 cell line. Glucocorticoids suppressed mRNA expression and protein synthesis of fibronectin, fibulin-1 and fibulin-2, but not nidogen-1, in adherent cells of bone marrow cultures, as shown by Northern blot analysis and immunoprecipitation. mRNA levels of all four proteins were down-regulated by dexamethasone in MC3T3-G2/PA6 cells, indicating a direct glucocorticoid effect on cells synthesizing extracellular matrix proteins. Dexamethasone down-regulated fibronectin mRNA rapidly, within 2 h of treatment, in the stromal cells. This effect did not require mRNA or protein synthesis, as shown by Northern blot analysis after treatment by actinomycin D and cycloheximide. Interferon-alpha, which also has been reported to modulate haematopoietic cell-matrix interactions, did not affect mRNA expression of the proteins in MC3T3-G2/PA6 cells. Our results indicate that glucocorticoids down-regulate expression of several mesenchymal-type extracellular matrix molecules in bone marrow, but with a variable effect on different proteins. Thus one mechanism by which glucocorticoids regulate haematopoiesis may be by altering the relative proportions of extracellular matrix proteins.

Animals↗