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At least 73 records · Page 4Linked to original sources
PubMed1996

Regulation of human (Caco-2) intestinal epithelial cell differentiation by extracellular matrix proteins.

Extracellular matrix regulation of intestinal epithelial differentiation may affect development, differentiation during migration to villus tips, healing, inflammatory bowel disease, and malignant transformation. Cell culture studies of intestinal epithelial biology may also depend on the matrix substrate used. We evaluated matrix effects on differentiation and proliferation in human intestinal Caco-2 epithelial cells, a model for intestinal epithelial differentiation. Proliferation, brush border enzyme specific activity, and spreading were compared in cells cultured on tissue culture plastic with interstitial collagen I and the basement membrane constituents collagen IV and laminin. Each matrix significantly increased alkaline phosphatase, dipeptidyl peptidase, lactase, sucrase-isomaltase, and cell spreading in comparison to plastic. However, the basement membrane proteins collagen IV and laminin further promoted all four brush border enzymes but inhibited spreading compared to collagen I. Proliferation was most rapid on type I collagen and slowest on laminin and tissue culture plastic. Basement membrane matrix proteins may promote intestinal epithelial differentiation and inhibit proliferation compared with interstitial collagen I.

Alkaline Phosphatase↗
PubMed1992

Cultures of human retinal pigment epithelium. Modulation of extracellular matrix.

The extracellular matrix of retinal pigment epithelial (RPE) cells is an important component of the fibroelastic membranes formed in proliferative vitreoretinopathy (PVR). These membranes consist of cells intermingled with fibrillar proteins, such as elastin and collagen. Because RPE cells may be exposed to vitreous and serum-derived factors in conditions that lead to PVR, the effects of vitreous and serum on the deposition of fibrillar proteins by RPE cells were studied using radioactive labeling and indirect immunofluorescence techniques. The RPE cells, modulated by combined vitreous and serum into a fibrocytic-like appearance, deposited less fibroelastic proteins per cell. However, as a result of simultaneous cell proliferation, the total deposition of fibroelastic proteins per culture was increased. Indirect immunofluorescence studies suggest that it is type I collagen that is altered in the matrix of these modulated cell cultures. This information is important in pathologic conditions characterized by intraocular cell proliferation and fibroelastic membrane formation; these phenomena are seen in many vitreoproliferative disorders.

Cell Count↗
PubMed2000

Regulation of tissue injury responses by the exposure of matricryptic sites within extracellular matrix molecules.

Extracellular matrix (ECM) is known to provide signals controlling cell shape, migration, proliferation, differentiation, morphogenesis, and survival. Recent data shows that some of these signals are derived from biologically active cryptic sites within matrix molecules (matricryptic sites) that are revealed after structural or conformational alteration of these molecules. We propose the name, matricryptins, for enzymatic fragments of ECM containing exposed matricryptic sites. Mechanisms regulating the exposure of matricryptic sites within ECM molecules include the major mechanism of enzymatic breakdown as well as others including ECM protein multimerization, adsorption to other molecules, cell-mediated mechanical forces, and ECM denaturation. Such matrix alterations occur during or as a result of tissue injury, and thus, the appearance of matricryptic sites within an injury site may provide important new signals to regulate the repair process. Here, we review the data supporting this concept and provide insight into why the increased exposure of matricryptic sites may be an important regulatory step in tissue responses to injury.

Binding Sites↗
PubMed2005

Scleroderma, fibroblasts, signaling, and excessive extracellular matrix.

Excessive extracellular matrix (ECM) deposition in the skin, lung, and other organs is a hallmark of systemic sclerosis (SSc). The pathogenesis of SSc is still poorly understood, but increasing evidence suggests that various cytokines such as transforming growth factor (TGF)-beta and their signaling pathways are key mediators of tissue fibrosis as a consequence of ECM accumulation in the pathogenesis of fibrosis such as SSc. TGF-beta regulates diverse biologic activities including cell growth, cell death or apoptosis, cell differentiation, and ECM synthesis. TGF-beta is known to induce the expression of ECM proteins in mesenchymal cells, and to stimulate the production of protease inhibitors that prevent enzymatic breakdown of the ECM. This paper focuses on the possible role of ECM, various cytokines, especially TGF-beta signal transduction pathways in the pathogenesis of fibrosis in SSc.

Extracellular Matrix↗
PubMed2002

Domain structure and organisation in extracellular matrix proteins.

Extracellular matrix (ECM) proteins are large modular molecules built up from a limited set of modules, or domains. The basic folds of many domains have now been determined by crystallography or NMR spectroscopy. Recent structures of domain pairs and larger tandem arrays, as well as of oligomerisation domains, have begun to reveal the principles underlying the higher order architecture of ECM proteins. Structural information, coupled with site-directed mutagenesis, has been instrumental in showing how adjacent domains can co-operate in ligand binding. Very recently, the first heterotypic ECM protein complexes have become available. Here, we review the advances of the last 5 years in understanding ECM protein structure, with special emphasis on those structures that have given insight into the biological functions of ECM proteins.

Activins↗
PubMed1996

Ca2+ channel blockers modulate metabolism of collagens within the extracellular matrix.

The extracellular matrix (ECM) is an intricate network composed of an array of macromolecules capable of regulating the functional responsiveness of cells. Its composition greatly varies among different types of tissue, and dysregulation of its metabolism may contribute to vascular remodeling during the pathogenesis of various diseases, including atherosclerosis. In view of their antiatherosclerotic effects, the role of Ca2+ channel blockers in the metabolism of ECM was examined. Nanomolar concentrations of the five Ca2+ channel blockers amlodipine, felodipine, manidipine, verapamil, or diltiazem significantly decreased both the constitutive and platelet-derived growth factor BB-dependent collagen deposition in the ECM formed by human vascular smooth muscle cells and fibroblasts. The drugs inhibited the expression of fibrillar collagens type I and III and of basement membrane type IV collagen. Furthermore, Ca2+ channel blockers specifically increased the proteolytic activity of the 72-kDa type IV collagenase as shown by gelatin zymography and inhibited the transcription of tissue inhibitor of metalloproteinases-2.

Amlodipine↗
PubMed1996

Organization of F-actin filaments in human glioma cell lines cultured on extracellular matrix proteins.

Extracellular matrix (ECM) constituents likely play an important role in cell proliferation and the invasion of malignant human gliomas. We examined the formation of stress fibers and the growth of the human glioblastoma cell lines A172 and T98G cultured on collagen types I, IV, and V, laminin (LN), and fibronectin (FN). A172 cells cultured on LN and FN formed complete F-actin filaments after 24 h of culture and grew logarithmically after 48 h. In contrast, T98G cells on LN and FN reorganized only short F-actin filaments after 24 h of culture and grew rapidly after 72 h. However, on the collagen preparations, neither cell line formed definite stress fibers and both showed lower rates of cellular proliferation. Significantly positive correlation was observed between the relative intensity of F-actin filaments and the cell proliferation. The results indicate that the ability of ECM components to modulate the growth and differentiation of malignant glioma cells may be mediated, in part, by the assembly and disassembly of F-actin filaments.

Actins↗
PubMed2005

The expression and role of protein kinase C in neonatal cardiac myocyte attachment, cell volume, and myofibril formation is dependent on the composition of the extracellular matrix.

The extracellular matrix (ECM) is a dynamic component of tissues that influences cellular phenotype and behavior. We sought to determine the role of specific ECM substrates in the regulation of protein kinase C (PKC) isozyme expression and function in cardiac myocyte attachment, cell volume, and myofibril formation. PKC isozyme expression was ECM substrate specific. Increasing concentrations of the PKC delta inhibitor rottlerin attenuated myocyte attachment to randomly organized collagen (1, 5, and 10 microM), laminin (5 and 10 microM), aligned collagen (5 and 10 microM), and fibronectin (10 microM). Rottlerin significantly decreased cell volume on laminin and randomly organized collagen, and inhibited myofibril formation on laminin. The PKC alpha inhibitor Gö 6976 inhibited attachment to randomly organized collagen at 6 nM but did not affect cell volume. The general PKC inhibitor Bisindolylmalemide I (10 and 30 microM) did not affect myocyte attachment; however, it significantly decreased cell volume on randomly organized collagen. Our data indicate that PKC isozymes are expressed and utilized by neonatal cardiac myocytes during attachment, cell growth, and myofibril formation. Specifically, it appears that PKC delta and/or its downstream effectors play an important role in the interaction between cardiac myocytes and laminin, providing further evidence that the ECM influences cardiac myocyte behavior.

Animals↗
PubMed2006

The basement membrane component of biologic scaffolds derived from extracellular matrix.

The extracellular matrix (ECM) has been successfully used as a scaffold for constructive remodeling of multiple tissues in both preclinical studies and in human clinical applications. The basement membrane is a specialized form of the ECM that supports and facilitates the growth of epithelial cell populations. The morphology and the molecular composition of the ECM, including the basement membrane, vary depending upon the organ from which the ECM is harvested and the methods by which it is processed for use as a medical device. Processing steps, such as decellularization, lyophilization, disinfection, and terminal sterilization, may affect the morphology and composition of an ECM scaffold, including, but not limited to, the integrity of a basement membrane complex. The present study evaluated the presence and integrity of a basement membrane complex in processed ECM derived from three different tissues: the urinary bladder, small intestine, and liver. Immunohistochemical determination of the presence and localization of three basement membrane molecules, collagen IV, laminin, and collagen VII, was conducted for each ECM scaffold. Scanning electron microscopy (SEM) was used to further explore the surface ultrastructure of selected ECM scaffolds. The effect of a surface basement membrane presence upon the pattern of in vitro growth of two separate cell types, NIH 3T3 fibroblasts and human microvascular endothelial cells (HMEC), was also evaluated for each ECM scaffold. Results showed that the only intact basement membrane complex was found on the luminal surface of the ECM derived from the urinary bladder and that the basement membrane was an effective barrier to penetration of the scaffold by the seeded cells. We conclude that the urinary bladder ECM but not the small intestine- or liver-derived ECM contains a surface with composition and morphology consistent with that of an intact basement membrane complex, that the basement membrane complex can survive processing, and that the basement membrane structure can modulate in vitro cell growth patterns.

Animals↗
PubMed1996

Cellular response to transforming growth factor-beta1 and basic fibroblast growth factor depends on release kinetics and extracellular matrix interactions.

The extracellular matrix plays an important role in growth factor biology, serving as a potential platform for rapid growth factor mobilization or a sink for concentrated sequestration. We now demonstrate that when a growth factor binds reversibly to the matrix, its effects are augmented by this interaction, and when the factor is absorbed irreversibly to the extracellular matrix, it becomes sequestered. These findings call into question the notion that all growth factors are best presented to cells and tissues in a sustained and controlled fashion. In our studies, we examined basic fibroblast growth factor (bFGF) and transforming growth factor-beta1 (TGF-beta1) release kinetics from synthetically fabricated microsphere devices and naturally synthesized extracellular matrix. While the sustained release of bFGF was up to 3.0-fold more potent at increasing vascular endothelial and smooth muscle cell proliferation than bolus administration, the reverse was true for TGF-beta1. A bolus of TGF-beta1 inhibited vascular cells up to 3.8-fold more efficiently than the same amount of TGF-beta1 if control-released. Both growth factors bound to the extracellular matrix, but only bFGF was released in a controlled fashion (2.8%/day). Contact with the extracellular matrix and subsequent release enhanced bFGF activity such that it was 86% more effective at increasing smooth muscle cell numbers than equal amounts of growth factor diluted from frozen stock. TGF-beta1 remained tightly adherent. The small amount of TGF-beta1 released from the extracellular matrix was approximately 30% less effective than bolus administration at inhibiting vascular endothelial and smooth muscle cell growth. Sustained growth factor release may be the preferable mode of administration, but only when a similar mode of metabolism is utilized endogenously.

Animals↗
PubMed1992

Interactions between HIV-infected monocytes and the extracellular matrix: increased capacity of HIV-infected monocytes to adhere to and spread on extracellular matrix associated with changes in extent of virus replication and cytopathic effects in infected cells.

Monocytes express cell surface receptors for extracellular matrix (ECM) proteins of basement membranes. These receptors are engaged during extravasation of cells through capillary endothelium into tissue. The number of human immunodeficiency virus (HIV)-infected monocytes that adhered to ECM over 2 h was threefold higher than that of uninfected control cells. This difference was ECM specific and was not observed with a bovine serum albumin substrate. Enhanced adhesion to ECM was evident in monocytes by 4 days after HIV infection and increased through 10 days. Monocytes exposed to a T cell-tropic HIV strain that binds to but does not replicate in monocytes showed no changes in adherence to ECM. Thus, productive infection of monocytes by HIV induces a significant increase in the capacity of these cells to interact with ECM. Enhanced adhesion of HIV-infected monocytes to ECM was associated with increased spreading: at 12 h, sixfold more HIV-infected monocytes were spread on ECM than were uninfected control cells. Cell processes of HIV-infected monocytes formed a complex network on ECM: many of these cells expressed HIV proteins as detected by indirect immunofluorescence. HIV-associated cytopathic effects and levels of virion-associated reverse transcriptase activity depended on the substrate to which monocytes were attached. Virus replication and cytopathic effects in monocytes adhered to ECM, fibronectin, or plastic alone were comparable. In contrast, HIV-infected monocytes attached to laminin showed a significant increase in virus replication and in extent of cytopathic effects through 2 weeks after infection. The lowest levels of HIV replication and cytopathic effects were in monocytes attached to collagen IV. Interactions between monocytes and ECM profoundly affect the manner in which these cells control HIV infection: HIV infection changes the capacity of infected monocytes to attach and spread on ECM; attachment to ECM alters the extent of virus replication in infected cells.

Cell Adhesion↗
PubMed2005

Pathogen elicitor-induced changes in the maize extracellular matrix proteome.

The extracellular matrix is a vital compartment in plants with a prominent role in defence against pathogen attack. Using a maize cell suspension culture system and pathogen elicitors, responses to pathogen attack that are localised to the extracellular matrix were examined by a proteomic approach. Elicitor treatment of cell cultures induced a rapid change in the phosphorylation status of extracellular peroxidases, the apparent disappearance of a putative extracellular beta-N-acetylglucosamonidase, and accumulation of a secreted putative xylanase inhibitor protein. Onset of the defence response was attended by an accumulation of glyceraldehyde-3-phosphate dehydrogenase and a fragment of a putative heat shock protein. Several distinct spots of both proteins, which preferentially accumulated in cell wall protein fractions, were identified. These three novel observations, viz. (i) secretion of a new class of putative enzyme inhibitor, (ii) the apparent recruitment of classical cytosolic proteins into the cell wall and (ii) the change in phosphorylation status of extracellular matrix proteins, suggest that the extracellular matrix plays a complex role in defence. We discuss the role of the extracellular matrix in signal modulation during pathogen-induced defence responses.

Cell Wall↗
PubMed1996

Extracellular matrix components of the mouse thymus microenvironment. V. Interferon-gamma modulates thymic epithelial cell/thymocyte interactions via extracellular matrix ligands and receptors.

Extracellular matrix (ECM) proteins influence cell migration and differentiation in a variety of cell systems. Within the thymus, the ECM distribution pattern is conserved among various mammalian species, but its physiological role is not completely understood. Interferon-gamma (IFN-gamma), a cytokine produced by thymocytes, is able to in vitro modulate ECM production by thymic epithelial cells (TEC) in a dose-dependent biphasic pattern. In the same model, we determined herein that the expression of VLA-5 and VLA-6 (fibronectin and laminin receptors, respectively) were upregulated by low doses of IFN-gamma, whereas high doses of the cytokine induced an opposite effect. In a second in vitro system, we evidenced that thymocyte adhesion to a TEC line was also modulated by IFN-gamma. Importantly, such effects were due to the biphasic modulation of ECM ligands and receptors since they could be specifically prevented by preincubating the TEC cultures with anti-ECM or anti-ECM receptor antibodies. Additionally, spontaneous thymocyte release from thymic nurse cells was similarly biphasically modulated by IFN-gamma. Our data provide support for the notion that thymocyte-derived products can play a role in the dialogue that exists in the thymus, involving differentiating thymocytes and microenvironmental cells. Moreover, we bring arguments indicating that one of the implicated mechanisms involved is the modulation of ECM ligands and receptors by the thymic epithelium.

Animals↗
PubMed1995

[Normal synoviocytes and synoviocytes from osteoarthritis and rheumatoid arthritis bind extracellular matrix proteins differently].

Extracellular matrix proteins are increased in inflammatory synovitis. We showed previously that the in situ expression of the corresponding extracellular matrix receptors (beta 1-integrins) is enhanced in synoviocytes (SC) of synovitis of different etiology (16). To investigate the adhesion of SC to extracellular matrix proteins, we examined the attachment of SC from normal and inflamed synovia to fibronectin, tenascin, laminin and collagen type IV. Compared to normal SC and SC of osteoarthritis, SC of rheumatoid arthritis showed an increased binding to tenascin, laminin, fibronectin and collagen type IV, suggesting a distinctive interaction of SC and extracellular matrix proteins in rheumatoid arthritis. Furthermore, the increased binding of SC of rheumatoid arthritis to extracellular matrix proteins may play a role in tissue remodelling associated with rheumatoid arthritis.

Arthritis, Rheumatoid↗
PubMed2003

Secretory proprotein convertases PACE4 and PC6A are heparin-binding proteins which are localized in the extracellular matrix. Potential role of PACE4 in the activation of proproteins in the extracellular matrix.

PACE4, PC6 and furin are potent subtilisin-like proprotein convertases (SPCs) which are responsible for the activation of transforming growth factor-beta (TGFbeta)-related factors such as bone morphogenetic proteins. Heparan sulfate proteoglycan within the extracellular matrix (ECM) is known to regulate the biological activity of various differentiation factors including TGFbeta-related molecules. PACE4 binds tightly to heparin and its heparin-binding region was found to be a cationic stretch of amino acids between residues 743 and 760. Furthermore, PACE4 was detected in the extracellular material fraction of the HEK293 cells, defined as the material remaining on the culture plate following the removal of the cells from the plate. PACE4 bound to the extracellular fraction was selectively dislodged by heparin into the culture medium. Heparin has no inhibitory activity against PACE4. Similarly, PC6A is also able to bind to heparin, whereas soluble furin does not. In human placenta, PACE4 is mainly present in syncytiotrophoblasts and can be released by heparin. These results suggest that PACE4 and PC6 are unique SPC family proteases that anchor heparan sulfate proteoglycans at the ECM. The interaction between PACE4 and heparan sulfate proteoglycans might play an important role in the delicate spatiotemporal regulation of TGFbeta-related factors' biological activity.

Amino Acid Sequence↗
PubMed2000

Control of cyclins, cyclin-dependent kinase inhibitors, p21 and p27, and cell cycle progression in rat hepatocytes by extracellular matrix.

BACKGROUND/AIMS: The extracellular matrix plays an essential role in the regulation of cell proliferation in different cell types. However, the regulation of cell cycle control in hepatocytes in response to growth factors and extracellular matrix signals is not well understood. The aims of this study were to investigate the expression of key cell cycle control elements, including cyclins, A and D1, and cyclin-dependent kinase inhibitors, p21 and p27, in rat hepatocytes in primary culture on dried collagen or Engelbreth-Holm-Swarm in the presence of epidermal growth factor. METHODS: Hepatocytes prepared from Wistar rats were cultured on various extracellular matrix in Williams medium E in the presence or absence of 20 ng/ ml epidermal growth factor. DNA synthesis was measured by [3H]thymidine uptake and mRNA expression of cell cycle-related genes was determined by reverse transcription polymerase chain reaction. RESULTS: Cyclins D1 and A mRNA levels were high at the G1/S boundary in epidermal growth factor-stimulated hepatocytes cultured on dried collagen. In contrast to spread cells, hepatocytes cultured on an Engelbreth-Holm-Swarm gel that were prevented from spreading failed to progress through the G1 phase and enter the S phase. This shape-dependent blockage of cell cycle progression correlated with the up-regulation of the cell cycle inhibitors p21 and p27. CONCLUSIONS: Changes in hepatocyte-extracellular matrix interactions may control hepatocyte growth within the local microenvironment by modulating cell shape and regulating cyclins and the cyclin-dependent kinase inhibitors p21 and p27.

Animals↗
PubMed2004

Extracellular matrix gene regulation.

Extracellular matrix metabolism plays a central role in development of skeletal tissues and in most orthopaedic diseases and trauma such as fracture or osteotomy repair, arthritis, cartilage repair, and congenital skeletal deformity. During development or disease, specific genes must be expressed in order to make or repair appropriate extracellular matrix. For example, specific gene expression patterns are characteristic of bone and cartilage. The precise expression pattern depends on a balance of positive and negative transcription factors, proteins that control the synthesis of mRNA from the specific gene. In cartilage, a number of studies indicate that Sox transcription factors are critical positive regulators in genes such as COL2A1, COL9A2, COL11A2, aggrecan, and CD-RAP. In addition, negative regulators are also essential to fine tune gene regulation in chondrocytes and to turn off gene expression in noncartilaginous tissues. Negative transcription factors in cartilage include partial differentialEF-1, snail/slug, CYRBP1, NT2, and C/EBP. Runx2 and osterix are critical transcription factors for osteogenesis but also have some influence on chondrogenesis. The availability of cis-regulatory sites in specific genes combined with the availability of transcription factors in the nucleus determines the level of gene expression.

Animals↗