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PubMed1996

[Extracellular matrix].

Extracellular matrix is composed of four families: collagens, proteoglycans, elastin and extracellular matrix structural glycoproteins. The extracellular matrix should not be viewed as merely providing strength and physical support for tissues and organisms. It is now quite clear that this matrix exerts profound influence on both the behaviour (e.g. adherence, spreading, and migration) and the pattern of gene expression of the cells. Extracellular matrix research is an active field in biology.

Animals↗
PubMed1998

Inter-alpha-trypsin inhibitor proteoglycan family--a group of proteins binding and stabilizing the extracellular matrix.

Extracellular matrix (ECM) is composed of several macromolecules associated in a complex network. This structure allows cells to adhere, migrate and interact. Hyaluronic acid (HA) is a glycosaminoglycan (GAG) and a major representative of ECM. HA-binding proteins such as CD44, aggrecan, and versican, have been implicated in structuring the ECM by stabilizing large macromolecular aggregates. They also play an important role in tumor metastasis and cell motility. Recently, further HA-binding proteins were identified: the inter-alpha-trypsin inhibitor(ITI)-related proteins. ITI is a glycoprotein composed of three polypeptides: two heavy chains (HC1 and HC2) and one light chain (bikunin). Bikunin confers the protease-inhibitor function. The heavy chains' function was unknown. Recent studies have shown that HC1 and HC2 are linked in vivo and in vitro to hyaluronic acid. This linkage greatly improves extracellular matrix stability. It also demonstrates that ITI-related proteins might be considered as HA-binding proteins (HABP). The ITI related proteins are composed of four polypeptides (HC1, HC2, HC3 and the bikunin) encoded by four genes H1, H2, H3 and L. Unlike the majority of plasma protein a non-disulfide covalent linkage exists between heavy chains and bikunin. This review presents the recent progress concerning the interactions between ITI and ECM showing that ITI-related proteins are HABP members. We will focus on the heavy chain linkage with HA, which represents the demonstration of covalent binding between proteins and HA.

Alpha-Globulins↗
PubMed1992

Beta 1 and beta 3 integrins have different roles in the adhesion and migration of vascular smooth muscle cells on extracellular matrix.

Extracellular matrix receptors on ductus arteriosus smooth muscle cells (SMC) must enable the cells to migrate through both interstitial and basement membrane matrices to form intimal mounds during postnatal ductus closure. We examined the role of beta 1 and beta 3 integrin receptors on SMC adhesion and migration. Using a new assay to measure cell migration, we found that lamb ductus arteriosus SMC attach to and migrate over surfaces coated with fibronectin (FN), laminin (LN), vitronectin (VN), and collagens I (I) and IV (IV). Blocking antibodies, specific to different integrin complexes, showed that SMC adhesion to FN, LN, I, and IV depended exclusively on functioning beta 1 integrins with little, if any, contribution by the alpha V beta 3 integrin; on the other hand, cell migration over these substrates depended to a large extent on the alpha V beta 3 receptor. Immunofluorescent staining demonstrated that during the early phase of SMC migration, the beta 1 integrins organized rapidly into focal plaques that, with time, gradually covered the cell's basal surface; on the other hand, the beta 3 receptor remained concentrated at all times at the cell's margins. Ligand affinity chromatography and immunoprecipitation techniques identified a unique series of beta 1 integrins binding to each matrix component: FN (alpha 5 beta 1, alpha 3 beta 1, alpha V beta 1), LN (alpha 1 beta 1, alpha 7 beta 1), VN (alpha V beta 1), I (alpha 1 beta 1, alpha 2 beta 1), and IV (alpha 1 beta 1). In contrast, the beta 3 integrin, alpha V beta 3, bound to all the substrates tested: FN, LN, VN, I, and IV. The results indicate that beta 1 and beta 3 integrins may play different roles in attachment and migration as SMC move through the vascular extracellular matrix to produce obliteration of the ductus arteriosus lumen.

Amino Acid Sequence↗
PubMed2001

Connexin expression by alveolar epithelial cells is regulated by extracellular matrix.

Extracellular matrix (ECM) proteins promote attachment, spreading, and differentiation of cultured alveolar type II epithelial cells. The present studies address the hypothesis that the ECM also regulates expression and function of gap junction proteins, connexins, in this cell population. Expression of cellular fibronectin and connexin (Cx) 43 increase in parallel during early type II cell culture as Cx26 expression declines. Gap junction intercellular communication is established over the same interval. Cells plated on a preformed, type II cell-derived, fibronectin-rich ECM demonstrate accelerated formation of gap junction plaques and elevated gap junction intercellular communication. These effects are blocked by antibodies against fibronectin, which cause redistribution of Cx43 protein from the plasma membrane to the cytoplasm. Conversely, cells cultured on a laminin-rich ECM, Matrigel, express low levels of Cx43 but high levels of Cx26, reflecting both transcriptional and translational regulation. Cx26 and Cx43 thus demonstrate reciprocal regulation by ECM constituents.

Animals↗
PubMed1994

Balance of expression of genes coding for extracellular matrix proteins and extracellular matrix degrading proteases in chronic pancreatitis.

Chronic pancreatitis is characterized by proliferation of the extracellular matrix and by increased deposition of interstitial extracellular matrix proteins (collagens type I and III, fibronectin). In this study we analyzed the balance of expression of mRNAs encoding extracellular matrix components (collagens I, III and IV, laminin, fibronectin), extracellular matrix degrading metalloproteinases (MMP-1, -2 and -3) and tissue inhibitors of metalloproteinases (TIMP-1 and -2) in chronic pancreatitis (n = 8) and control pancreas (n = 7) by northern blot analysis. Transcripts for MMP-1 (interstitial collagenase), MMP-3 (stromelysin) and TIMP-1 were not detectable in chronic pancreatitis and control tissues. Steady-state levels of transcripts encoding extracellular matrix proteins, MMP-2 (72 kDa collagenase IV) and TIMP-2 were enhanced in 7 out of 8 chronic pancreatitis tissue samples and showed a large degree of variation between individual patients. Transcript levels could not be correlated to the histologically detectable degree of inflammation and fibrosis or to the total amount of deposited collagen protein, which was high in all chronic pancreatitis tissue samples as determined by a standard colorimetric procedure. Increased steady state levels of transcripts encoding extracellular matrix proteins or extracellular matrix degrading proteases may thus reflect the activity of processes involved in the remodeling of the gland during chronic inflammation. The precise role of overexpression of MMP-2 and its inhibitor TIMP-2 will have to be elucidated in further studies.

Chronic Disease↗
PubMed1995

Extracellular matrix interactions. 2: Extracellular matrix structure is important for growth factor localization and function.

The influence of extracellular matrix components and of extracellular matrix structure on in vitro cell growth was investigated in the UWOV2 (Pf), protein-free cell culture model. This cell line constitutively produces an ordered extracellular matrix in the absence of any exogenous protein or growth factor. Extracellular matrix from UWOV2 (Pf) cells was found to contain both transforming growth factor beta (TGF beta) and platelet-derived growth factor (PDGF), which were shown to have an autostimulatory role for UWOV2 (Pf) cell growth. Matrix structure was shown to be important for allowing expression of the functional activity of these two growth factors. In addition, a nonuniform distribution of PDGF, embedded within the matrix structure, was demonstrated by immunoelectronmicroscopy. Apart from these two well-defined growth factors, additional but as yet unidentified growth stimulatory factor(s) were extractable from UWOV2 (Pf) extracellular matrix. These investigations indicate the potential role of extracellular matrix both as a mechanism for concentrating as well as modulating the function of cellular growth factors.

3T3 Cells↗
PubMed1997

Oxidized LDL binding to a macrophage-secreted extracellular matrix.

Extracellular matrix (ECM), which was shown to be secreted by arterial wall cells, is a major part of the atherosclerotic lesion. ECM can contribute to low density lipoprotein (LDL) retention which can then lead to macrophage foam cell formation, the hallmark of early atherogenesis. The present study demonstrated that in addition to the known ability of endothelial cells and smooth muscle cells to produce ECM, macrophages can also secrete an ECM layer. The macrophage derived ECM was shown to contain the proteoglycans chondroitin sulfate, heparan sulfate and dermatan sulfate. Macrophage derived ECM can bind native LDL, as well as oxidized LDL (3 fold more than native LDL), and this binding is significantly increased in the presence of lipoprotein lipase. Glycosaminoglycans from the ECM (mainly chondroitin sulfate and heparan sulfate) participate in the binding of Ox-LDL to the macrophage derived ECM. These observations suggest that ECM is produced also by macrophages, and it can contribute to a specific and local delivery of atherogenic LDL to macrophages, leading to cellular cholesterol accumulation and foam cell formation.

Extracellular Matrix↗
PubMed1990

Evidence that the B2 chain of laminin is responsible for the neurite outgrowth-promoting activity of astrocyte extracellular matrix.

Extracellular matrix (ECM) derived from cerebral cortical astrocytes stimulates neurite outgrowth from pheochromocytoma (PC12) cells in the absence of the classical nerve growth factor (NGF). We have shown here that astrocyte ECM can also stimulate neurite outgrowth from primary cultures of central nervous system (CNS) neurons. Using PC12 cells for a quantitative assay, we also demonstrated that the neurite growth-promoting activity increased as the astrocytes matured in vitro: ECM from older astrocytes (3-12 weeks in vitro) exhibited two-fold more neurite growth-promoting activity than ECM for younger astrocytes (5 days to 2 weeks in vitro). We applied various antibodies to identify the neurite growth-promoting factor of astrocyte ECM and found that anti-laminin inhibited neurite outgrowth by 50%, whereas anti-fibronectin and anti-NGF had no effect. Immunoblots, using laminin chain-specific antibodies, and cDNA hybridization of laminin mRNA demonstrated that cultured astrocytes synthesize only the B2 chain of laminin. This suggests that the B2 chain of laminin suffices to stimulate neurite outgrowth.

Animals↗
PubMed2006

Quantitative characterization of binding of small molecules to extracellular matrix.

Extracellular matrix (ECM) is a major tissue component that, besides its cell support function, is implicated in cell-cell signaling, wound repair, cell adhesion, and other cell and tissue functions. For small molecules acting in tissues, including chemicals, signaling peptides, effectors, inhibitors, and other man-made and physiological compounds, non-specific binding to ECM is a critical phenomenon affecting their disposition. We describe here a method for a quantitative characterization of the ECM binding, using a solidified ECM layer incubated with medium containing studied small molecules. Working conditions of Matrigel, a commercial basement membrane preparation, were optimized in terms of the protein concentration, surface area, gel layer thickness, solidification time, and mixing speed. The release of proteins from the solidified layer into the buffer was monitored and taken into account. Two major proteins, laminin and collagen IV, dissolve at different rates. The Matrigel stability data, obtained under varying incubation conditions and gentle mixing, can also be useful in other ECM-related research. The experimental binding data, averaged over all binding sites, were analyzed assuming a fast linear binding. The binding constants were determined for 10 small organic molecules for both dissolved proteins and the solidified layer. The binding constants tend to increase with lipophilicity of the compounds, as characterized by the 1-octanol/water partition coefficients.

Animals↗
PubMed1993

Multi-faceted regulation of cell differentiation by extracellular matrix.

Extracellular matrix (ECM) is an intricate network composed of an array of macromolecules, the importance of which is becoming increasingly apparent. The ECM is an integral part of the machinery that regulates cell function; its role in cell differentiation and tissue-specific gene expression, although essential, is not yet understood. It can act as a positive as well as a negative regulator of functional differentiation depending on the cell type and the genes studied. It also acts in a hierarchical fashion, exacting higher and higher degrees of stringency to achieve full functional differentiation. Regulation by ECM is closely interrelated with the action of other regulators of cellular function, such as growth factors and hormones. But ECM may exert its regulation of gene expression by mechanisms distinct from those known for soluble transcription factors. In this short review, we describe three systems in which ECM has been shown to play a crucial role in functional differentiation, but we emphasize mainly the work from our own laboratory to provide a more in-depth analysis of one system. The three systems are: mouse mammary epithelial cells, rat hepatocytes, and human keratinocytes. The crucial role of ECM in normal cell differentiation implies that its alteration may have serious consequences in malignancies and other diseases. The current functional cell culture models could provide powerful tools not only for understanding regulation of normal cell function but also for the studies of tumorigenesis and possibly cancer therapy.

Animals↗
PubMed1995

Expression and in-situ localization of genes coding for extracellular matrix proteins and extracellular matrix degrading proteases in pancreatic cancer.

Pancreatic cancer shows a strong desmoplastic reaction characterized by a remarkable proliferation of interstitial connective tissue (collagens type I and III, fibronectin). In this study we have analyzed the balance of expression of mRNAs encoding extracellular matrix components (collagens I, III and IV, laminin, fibronectin), extracellular matrix-degrading metalloproteinases (MMP-1, -2, -3 and -9) and tissue inhibitors of metalloproteinases (TIMP-1 and -2) in pancreatic cancer and control pancreatic tissue by Northern-blot analysis and mRNA in situ hybridization. Transcripts for MMP-1 (interstitial collagenase) and MMP-3 (stromelysin-1) were not detectable in pancreatic cancer and control tissues. Steady-state levels of transcripts encoding extracellular matrix proteins, MMP-2 (72-kDa collagenase IV), MMP-9 (92-kDa collagenase type IV), TIMP-1 and TIMP-2 were elevated in the majority of pancreatic-cancer tissue samples as compared to control pancreatic tissue. A good correlation was seen between overexpression of these MMPs and TIMPs and the steady-state levels of transcripts coding for extracellular matrix proteins, the amount of collagen protein and the severity of the desmoplastic reaction. In situ hybridization studies localized transcripts coding for collagens type I and III to spindle-shaped stromal cells, whereas transcripts for MMP-2, MMP-9, TIMP-1 and TIMP-2 were found in both stromal and tumor cells. However, MMP-2 transcripts appeared to be more abundant in stromal cells, TIMP-1 and TIMP-2 transcripts were evenly distributed over tumor and stromal cells and relatively more MMP-9 transcripts were found in tumor cells. We conclude that, in human pancreatic cancer, MMP-2, MMP-9, TIMP-1 and TIMP-2 may be involved in processes leading to the strong desmoplastic reaction observed in these tumors. Both stromal and tumor cells appear to be the source of MMPs and TIMPs in human pancreatic cancer.

Blotting, Northern↗
PubMed2001

Three-dimensional imaging of extracellular matrix and extracellular matrix-cell interactions.

In summary, noninvasive and nondestructive imaging modalities such as reflection and autofluorescence can readily be used in conjunction with the 3-D optical sectioning capabilities of confocal and multiphoton microscopy to investigate biological processes within living systems. The elimination of specimen fixation and extensive processing reduces the possibility of structural artifacts and facilitates repeat observations within a single sample. Therefore, information representing up to four dimensions (x, y, z, and time) can be readily collected and reconstructed for purposes of visualization and/or quantitative analysis. An advantage of using the techniques described in this chapter is the possibility of performing quantitative measurement of cell size, surface area, volume, depth (in matrix), orientation, receptor density, as well as fluorescence-based indicators of phenotype and function. At present, we are effectively utilizing these techniques to study collagen fibrillogenesis and ECM assembly, structural aspects of ECM-based biomaterials, as well as cell interactions within 3-D matrices (e.g., migration). New insights provided by these techniques regarding ECM and ECM-cell signaling will further the understanding of tissue structure and function and contribute to the development of new and improved strategies for tissue repair, replacement, and maintenance.

Animals↗
PubMed2006

The matrix reorganized: extracellular matrix remodeling and integrin signaling.

Via integrins, cells can sense dimensionality and other physical and biochemical properties of the extracellular matrix (ECM). Cells respond differently to two-dimensional substrates and three-dimensional environments, activating distinct signaling pathways for each. Direct integrin signaling and indirect integrin modulation of growth factor and other intracellular signaling pathways regulate ECM remodeling and control subsequent cell behavior and tissue organization. ECM remodeling is critical for many developmental processes, and remodeled ECM contributes to tumorigenesis. These recent advances in the field provide new insights and raise new questions about the mechanisms of ECM synthesis and proteolytic degradation, as well as the roles of integrins and tension in ECM remodeling.

Animals↗
PubMed1987

Growth and differentiation of human keratinocytes on extracellular matrix.

Extracellular matrices (ECM) have been reported to enhance epithelial cell attachment and proliferation as well as to induce differentiation in vitro. Since ECM components are physiological constituents of the dermoepidermal basement membrane, we studied the growth and differentiation of human keratinocytes on ECM in order to determine the benefits of culturing epidermal epithelial cells (keratinocytes) on reconstituted basement membranes. Disaggregated epidermal cells were grown in primary and subcultures in liquid medium; the attachment of the cells was greatly enhanced by ECM and noted within the first few hours after seeding; cells formed small islets that reached confluence within 2-12 days depending upon the plating density and the type of culture (primary or passages). Histological and ultrastructural cross-sections of the cultures clearly indicated that a multilayered epithelium can be obtained including a basal cell layer, several intermediate cell layers with cytoplasmic organelles, intermediate size filaments, desmosomes, and keratohyaline granules, and an upper layer of anucleated cells. Using immunofluorescence, both pemphigus and pemphigoid (basal membrane zone) antigens were expressed. The keratin pattern noted indicated that these epithelia differentiate and keratinize but do not express a complete program of keratinization, a finding usually noted when cells are grown submersed. These data show that ECM favor epidermal cell proliferation and differentiation and suggest that they may be used to obtain large amounts of epidermal equivalent suitable for grafting and/or in vitro studies.

Adult↗
PubMed1993

Extracellular matrix. 2: Role of extracellular matrix molecules and their receptors in the nervous system.

Extracellular matrix molecules help regulate many aspects of neural development, including survival, migration, axon growth, and synapse formation by neurons. These same molecules have been shown to modulate regeneration of neurons after injuries. They also regulate the development and differentiation of other neural cells, such as astroglia and Schwann cells. Significant progress has been made recently in characterizing both ECM constituents and their receptors in the nervous system. Extracellular matrix molecules promote cell adhesion, activate intracellular signaling pathways, and modulate the activities of several growth factors and proteins. Our current understanding of the extracellular matrix, its receptors, and its functions in the nervous system are discussed.

Animals↗
PubMed2002

Fibronectin peptides mediate HMEC adhesion to porcine-derived extracellular matrix.

Extracellular matrices (ECM) derived from porcine tissues have been shown to support the successful repair and remodeling of injured tissues when evaluated in animal models. Cell-matrix interactions, including ligand-integrin associations that facilitate endothelial cell adhesion, are clearly important in the tissue remodeling process. The goal of the present study was to identify the peptide sequences within the ubiquitous protein fibronectin (FN) that may be important in the initial interactions between the host endothelial cells and the ECM scaffold. Human microvascular endothelial cells (HMEC) were seeded upon porcine ECM after having been subjected to pretreatment with peptide ligands derived from tissue FN and were allowed to attach for 20 min. Non-adherent cells were removed and the remaining, tritium-labeled cells attached to the ECM were counted. Results showed that cyclo-RGD and REDV, but not LDV or PHSRN, play a role in mediating the attachment of HMEC to porcine ECM.

Animals↗
PubMed1990

Regulation of extracellular matrix degradation by cell-extracellular matrix interactions.

An appropriate balance of extracellular matrix synthesis and degradation is required for normal morphogenesis and maintenance of tissue architecture. Extracellular matrix molecules and their receptors, as well as proteinases and their inhibitors, are all involved in matrix remodeling. In this report we show that signal transduction through extracellular matrix receptors regulates matrix remodeling.

Animals↗
PubMed2004

The use of extracellular matrix probes and extracellular matrix-related probes for assessing diagnosis and prognosis in renal diseases.

PURPOSE OF REVIEW: Scarring in the kidney results from excessive local synthesis and exogenous accumulation of extracellular matrix components. Once chronic damage is present in the biopsy, therapeutic intervention for the renal patient encounters severe limitations. It is therefore essential to determine clinical outcome preferably at a time point before the development of overt scarring. Clinical parameters and morphologic alterations in the biopsy are currently used as tools for the diagnosis of the renal disease entity and for assessment of the patient's prognosis. Expression levels of extracellular matrix and matrix-related components may serve as additive and even superior prognostic indicators to conventional parameters. We will elaborate on studies supporting this concept. RECENT FINDINGS: Several investigators have shown in experimental models for renal disease that extracellular matrix probes and related probes reflect disease progression and predict outcome. In this review, we will provide an update on the most recent studies of human renal biopsies showing that expression of extracellular matrix components, regulators of matrix degradation, and cytokines affecting matrix deposition may be employed for discrimination of diagnostic groups and predicting prognosis. SUMMARY: Molecular techniques are expected to be used more and more for diagnostic and prognostic purposes in nephrological practice to supplement the histopathological analysis of the renal biopsy. Assessment of expression of matrix molecules, matrix-regulating cytokines, and metalloproteinases in renal kidney biopsies is helpful to distinguish patients who are at risk of developing progressive renal failure from patients who are likely to recover from renal tissue injury by natural remodeling mechanisms.

Biomarkers↗