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PubMed1994

The extracellular matrix components, tenascin and fibronectin, in Hirschsprung's disease: an immunohistochemical study.

Previous in vitro studies have suggested that successful neural crest cell migration in the developing gut could be influenced by the composition of the extracellular matrix components, tenascin and fibronectin. The authors aimed to gain insight into the pathogenesis of Hirschsprung's disease (HD) by studying the distribution of tenascin and fibronectin in bowel specimens of patients with HD. Immunohistochemical examination was performed in specimens from 10 HD patients (8 aganglionic, 5 transitional, and 10 normoganglionic zones) and 18 age- and site-matched controls undergoing other types of gastrointestinal surgery. The distribution of tenascin was restricted to the basement membranes of the smooth muscle and vasculature, and in the basement membranes surrounding neuronal ganglia in all the controls and in 10 proximal normoganglionic HD specimens. More intense tenascin immunofluorescence was observed in the smooth muscle basement membranes of the muscularis externa of eight aganglionic and five transitional zones of HD. Wide-spread distribution of fibronectin was found in all the basement membranes as well as in the lamina propria and submucosa of all control and 10 normoganglionic HD sections. However, more intense immunofluorescence with fibronectin was observed in all the layers of eight aganglionic and five transitional zones of HD specimens. The present findings show that the mesenchymal and basement membrane extracellular matrix constitution is abnormal in the affected bowel of HD. Although a causal relationship has not been demonstrated, corroborative evidence from earlier animal experiments in other studies suggests that the extracellular matrix abnormalities may contribute to the pathogenesis of HD.

Basement Membrane↗

PubMed1989

Formation of extracellular matrix by cultured rat mesangial cells.

Formation of extracellular matrix (ECM) by mesangial cells (MCs) contributes to progressive glomerulosclerosis. The authors investigated the production and distribution of ECM constituents by cultured rat MCs, using immunocytochemistry and immunoelectron microscopy. Staining for all ECM constituents increased after serum feeding. Localization was strictly intracellular until confluency, when extracellular deposition of collagen IV and laminin appeared, followed by fibronectin and collagen III. In parallel, the intracellular staining for these proteins diminished markedly. Neither extracellular deposition nor intracellular loss was observed for collagen I and thrombospondin. On surfaces coated with collagen IV or laminin, extracellular deposition of ECM constituents clearly preceded confluency. These results indicate that synthesis of ECM constituents parallels MC growth, and that extracellular deposition of ECM occurs at cell-cell contact. Collagen IV or laminin secreted by MCs in the substratum accelerates production and facilitates secretion of other ECM constituents in an autocrine fashion.

Animals↗

PubMed2006

Extracellular matrix bioscaffolds for orthopaedic applications. A comparative histologic study.

BACKGROUND: Biologic scaffold materials prepared from extracellular matrix are currently available for the surgical repair of damaged or missing musculotendinous tissue. These scaffolds differ in their species and tissue of origin, methods of processing, and methods of terminal sterilization. The purpose of the present study was to evaluate the host-tissue morphologic response to five commercially available extracellular matrix-derived biologic scaffolds used for orthopaedic soft-tissue repair in a rodent model. METHODS: One hundred twenty-six Sprague-Dawley rats were divided into six groups of twenty-one animals each. A defect was created in the musculotendinous tissue of the abdominal wall of each animal and then was repaired with one of five different scaffold materials (GraftJacket, Restore, CuffPatch, TissueMend, Permacol) or with the excised autologous tissue. Three animals from each group were killed at one of seven time-points after surgery (two, four, seven, fourteen, twenty-eight, fifty-six, and 112 days), and the specimens were examined with histologic and morphologic methods. The degree of cellular infiltration, multinucleated giant cell presence, vascularity, and organization of the replacement connective tissue were evaluated with semiquantitative methods. RESULTS: Each device elicited a distinct morphologic response that differed with respect to cellularity (p<0.001), vascularity (p<0.01), the presence of multinucleated giant cells (p<0.01), and organization of the remodeled tissue (p<0.01) at or after the Day 7 time-point. More rapidly degraded devices such as Restore and autologous tissue showed the greatest amount of cellular infiltration, especially at the early time-points. Devices that degraded slowly, such as CuffPatch, TissueMend, and Permacol, were associated with the presence of foreign-body giant cells, chronic inflammation, and/or the accumulation of dense, poorly organized fibrous tissue. CONCLUSIONS: Biologic scaffold materials composed of extracellular matrix elicit distinct host-tissue histologic and morphologic responses, depending on species of origin, tissue of origin, processing methods, and/or method of terminal sterilization.

Animals↗

PubMed1991

Role of the extracellular matrix in tissue-specific gene expression in the sea urchin embryo.

The role of extracellular matrix (ECM) in the differentiation of tissue types was examined in embryos of Strongylocentrotus purpuratus. We have examined the expression of various tissue-specific molecular markers after disrupting the ECM by culturing embryos in the presence of beta-aminoproprionitrile fumarate (BAPN), which disrupts collagen deposition, and beta-D-xyloside, which disrupts proteoglycan metabolism. The markers examined included accumulation of primary mesenchyme-specific mRNA (SM 50); an aboral ectoderm-specific mRNA (Spec 1); and a gut-specific enzyme, alkaline phosphatase. Treatment with BAPN or beta-D-xyloside results in developmental arrest at the mesenchyme blastula stage. Although spicule formation is inhibited, the accumulation of SM 50 transcripts and the synthesis of most of the prominent spicule matrix proteins is similar to that of control embryos. Spec 1 mRNA, in contrast, while accumulating to a significant extent when collagen and proteoglycan metabolism is disrupted, does accumulate to a level somewhat lower than that seen in control embryos. Additionally, the postgastrula rise in gut-specific alkaline phosphatase is reversibly inhibited by BAPN and xyloside treatment. These results demonstrate a differential effect of the ECM on expression of tissue-specific molecular markers.

Alkaline Phosphatase↗

PubMedDate not supplied

[Extracellular matrix, hepatic fibrosis and anti-fibrosis treatment].

Over recent years, the study of the extracellular matrix (ECM) in the liver has considerably progressed. The application of new biochemical and genetic techniques led to the discovery of 13 different collagen proteins and a growing number of collagen-associated proteins such as fibronectin, laminin and proteoglycans. Many of these proteins have been cloned and sequenced. Progress also includes a better knowledge of the biological roles of ECM components as well as its dynamic remodeling in various pathophysiological conditions. Even if the clinical goal of prophylaxis and therapy of fibrosis remains distant, progress can be anticipated in the near future as basic processes are being elucidated.

Collagen↗

PubMed1993

Cell spreading on extracellular matrix proteins induces tyrosine phosphorylation of tensin.

A small number of proteins becomes tyrosine-phosphorylated in response to integrin-mediated cell adhesion to extracellular matrix proteins. Previous work has identified two of these tyrosine-phosphorylated proteins as the focal adhesion kinase and paxillin. Here we identify a third focal adhesion protein, tensin, that becomes tyrosine-phosphorylated during cell adhesion to extracellular matrix proteins. The tyrosine phosphorylation of tensin does not occur when cells adhere to plastic or polylysine and is blocked when microfilament assembly and cell spreading are inhibited with cytochalasin D. In addition, we show that other focal adhesion proteins such as talin and vinculin do not become tyrosine-phosphorylated under the same conditions of cell spreading on extracellular matrix proteins.

Animals↗

PubMed1996

The human lumbar intervertebral disc: evidence for changes in the biosynthesis and denaturation of the extracellular matrix with growth, maturation, ageing, and degeneration.

Very little is known about the turnover of extracellular matrix in the human intervertebral disc. We measured concentrations of specific molecules reflecting matrix synthesis and degradation in predetermined regions of 121 human lumbar intervertebral discs and correlated them with ageing and Thompson grade of degeneration. Synthesis in intervertebral discs, measured by immunoassay of the content of a putative aggrecan biosynthesis marker (846) and the content of types I and II procollagen markers, is highest in the neonatal and 2-5-yr age groups. The contents of these epitopes/molecules progressively diminished with increasing age. However, in the oldest age group (60-80 yr) and in highly degenerated discs, the type I procollagen epitope level increased significantly. The percentage of denatured type II collagen, assessed by the presence of an epitope that is exposed with cleavage of type II collagen, increased twofold from the neonatal discs to the young 2-5-yr age group. Thereafter, the percentage progressively decreased with increasing age; however, it increased significantly in the oldest group and in highly degenerate discs. We identified three matrix turnover phases. Phase I (growth) is characterized by active synthesis of matrix molecules and active denaturation of type II collagen. Phase II (maturation and ageing) is distinguished by a progressive drop in synthetic activity and a progressive reduction in denaturation of type 11 collagen. Phase III (degeneration and fibrotic) is illustrated by evidence for a lack of increased synthesis of aggrecan and type II procollagen, but also by an increase in collagen type II denaturation and type I procollagen synthesis, both dependent on age and grade of tissue degeneration.

Adult↗

PubMed2002

Integrins in development: moving on, responding to, and sticking to the extracellular matrix.

Integrins are cell surface receptors of the extracellular matrix present in all animals. Genetic analysis in worms, flies, and vertebrates has revealed integrin involvement in key developmental processes, and we focus here on examples of integrin functions that are comparable across these model organisms. Integrins contribute to cell movement by providing traction to migrating cells, through assembly of extracellular matrices that can serve as tracks for migration, and by transmitting guidance signals that direct cells or cell processes to their targets. Integrins also participate in signaling events that govern tissue differentiation and organogenesis. Finally, adhesion by integrin-mediated junctions allows tissues to withstand mechanical load and is essential for tissue integrity.

Animals↗

PubMed2005

The subendothelial extracellular matrix modulates NF-kappaB activation by flow: a potential role in atherosclerosis.

Atherosclerotic plaque forms in regions of the vasculature exposed to disturbed flow. NF-kappaB activation by fluid flow, leading to expression of target genes such as E-selectin, ICAM-1, and VCAM-1, may regulate early monocyte recruitment and fatty streak formation. Flow-induced NF-kappaB activation is downstream of conformational activation of integrins, resulting in new integrin binding to the subendothelial extracellular matrix and signaling. Therefore, we examined the involvement of the extracellular matrix in this process. Whereas endothelial cells plated on fibronectin or fibrinogen activate NF-kappaB in response to flow, cells on collagen or laminin do not. In vivo, fibronectin and fibrinogen are deposited at atherosclerosis-prone sites before other signs of atherosclerosis. Ligation of integrin alpha2beta1 on collagen prevents flow-induced NF-kappaB activation through a p38-dependent pathway that is activated locally at adhesion sites. Furthermore, altering the extracellular matrix to promote p38 activation in cells on fibronectin suppresses NF-kappaB activation, suggesting a novel therapeutic strategy for treating atherosclerosis.

Animals↗

PubMed2003

Maspin functions as tumor suppressor by increasing cell adhesion to extracellular matrix in prostate tumor cells.

PURPOSE: Maspin, a unique member of the serine protease inhibitor family, shows tumor suppressing activity for breast cancer progression and metastasis. Few studies have directly linked maspin function to prostate cancer. We used prostate tumor cells derived from the TRAMP (transgenic adenocarcinoma of mouse prostate) prostate tumor model to study the tumor suppressive function of maspin in prostate cancer. MATERIALS AND METHODS: Maspin cDNA was introduced via a retroviral plasmid into TRAMP C2N prostate tumor cells, which are aggressive and invasive in nature. We investigated the tumorigenesis of these stable cell lines in vitro by assessing the growth rate, anchorage independence and adhesion to extracellular matrix proteins such as fibronectin and laminin. RESULTS: Stable cell lines expressing maspin had decreased tumorigenic potential, as assessed by anchorage independent growth in soft agar assay compared with controls. Maspin stable transfectants showed decreased metastatic potential, as evaluated by modified Boyden chamber assay and increased adhesion to fibronectin and laminin. CONCLUSIONS: Our study confirms that maspin has a tumor suppressive role not only in breast cancer, but also in prostate cancer. The data in this study suggest that maspin can decrease the tumorigenic and metastatic potential of prostate tumors, most probably by remodeling cell-extracellular matrix interactions or triggering extracellular matrix mediated signaling pathways that negatively regulate tumor migration and invasion.

Adenocarcinoma↗

PubMed2003

The extracellular matrix and its role in cell migration and development of the enteric nervous system.

The extracellular matrix (ECM), a network consisting of many different macromolecules, fulfils many important functions in every multicellular organism, especially during their development. Among other factors, ECM molecules are necessary for cell migration and also regulate cell differentiation, as could be shown in a wide range of animals. The enteric nervous system (ENS) is built up by neural crest cells (NCC) migrating along predetermined pathways into the developing gut. Studies done for example in mice and chickens did not only enable scientists to reconstruct these routes but also to demonstrate their dependence on ECM molecules such as laminin. Currently we are investigating the influence of different ECM constituents, growth factors and noxious factors on NCC migration and differentiation in the developing chicken gut. The easy handling of the chicken embryo and the use of different methods will give us valuable insights for further investigations.

Animals↗

PubMed2006

The effect of natural extracellular matrix deposited on synthetic polymers on cultured primary hepatocytes.

It is well known that natural extracellular matrix (ECM) molecules are deposited on the surface of biomaterials during culture of cells and affect cellular behaviors. However, it has not been fully understood what kinds of ECM molecules are deposited on the surface of biomaterials although the cellular behaviors were affected by deposited ECM. In this study, to investigate the effect of deposited natural ECM on behaviors of hepatocytes cultured on biomaterials such as poly (N-p-vinylbenzyl-4-O-beta-D-galactopyranosyl-D-gluconamide) (PVLA) as a hepatocyte-specific matrix and poly (L-lysine) (PLL) as a non-specific one during the culture of hepatocytes in vitro, we investigated expression pattern of ECM genes and adsorption of ECM molecules onto PVLA- and PLL-coated surfaces. It was found that the expression levels of type I collagen and fibronectin genes in the hepatocytes cultured on PVLA-coated surface were different from them in the hepatocytes cultured on PLL-coated one. Also, the results showed that laminin was dominantly deposited on PVLA-coated surface whereas fibronectin was dominantly deposited on PLL-coated one. Hepatocytes maintained liver-specific functions on PVLA- and laminin-coated surfaces. It is thought that deposited laminin during the culture of hepatocytes affects the liver-specific functions of hepatocytes cultured on PVLA-coated surface.

Actins↗

PubMed2006

Effects of osmotic pressure in the extracellular matrix on tissue deformation.

In soft tissues, large molecules such as proteoglycans trapped in the extracellular matrix (ECM) generate high levels of osmotic pressure to counter-balance external pressures. The semi-permeable matrix and fixed negative charges on these molecules serve to promote the swelling of tissues when there is an imbalance of molecular concentrations. Structural molecules, such as collagen fibres, form a network of stretch-resistant matrix, which prevents tissue from over-swelling and keeps tissue integrity. However, collagen makes little contribution to load bearing; the osmotic pressure in the ECM is the main contributor balancing external pressures. Although there have been a number of studies on tissue deformation, there is no rigorous analysis focusing on the contribution of the osmotic pressure in the ECM on the viscoelastic behaviour of soft tissues. Furthermore, most previous works were carried out based on the assumption of infinitesimal deformation, whereas tissue deformation is finite under physiological conditions. In the current study, a simplified mathematical model is proposed. Analytic solutions for solute distribution in the ECM and the free-moving boundary were derived by solving integro-differential equations under constant and dynamic loading conditions. Osmotic pressure in the ECM is found to contribute significantly to the viscoelastic characteristics of soft tissues during their deformation.

Animals↗

PubMed1991

Thromboxane stimulates synthesis of extracellular matrix proteins in vitro.

The vasoconstrictor eicosanoid thromboxane plays an important role in the pathogenesis of several renal diseases. As an autacoid, its local release alters blood flow and induces platelet aggregation. We report a direct stimulatory effect of thromboxane on extracellular matrix protein production and gene expression in vitro. Treatment of two cell types, differentiated mouse teratocarcinoma cells (F9+) and human glomerular mesangial cells, with two different thromboxane analogues resulted in increased production of components of the extracellular matrix including fibronectin and the basement membrane proteins laminin and type IV collagen. These responses to thromboxane were not the result of a mitogenic effect of thromboxane nor the result of an increase in total cellular protein. The increased production of extracellular matrix proteins was, at least in part, due to an increase in the steady-state level of mRNA for these genes. Furthermore, the effect of thromboxane was markedly inhibited by cotreatment with a thromboxane-receptor antagonist. These results suggest a new potential role for thromboxane as a mediator of the sclerotic and fibrotic responses to injury.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1991

Concomitant changes in endothelial cell junctions and extracellular matrix components in the chick embryo aorta.

According to previous studies, a process of endothelial activation seems to be occurring in the chick embryo between days 7 and 18. Also, endothelial cells respond to collagen as a substratum between 12 and 18 days, and this response diminishes until it almost disappears after birth. In the present study, aortas from chick embryos (days 7 to 21), and from chicks (14 days posthatching) were used. The results obtained by the freeze-fracturing technique, showed that between days 12 and 14 the intramembranous particles were aggregated into linear or clustered arrays in the fracture P-face of endothelial cells. This could signify that some kind of gap junction-like coupling may occur between adjacent endothelial cells. Our results also indicate that in advanced stages (21-day-old chick embryos and 14-day-old chicks) the growth of small aggregates into larger aggregates or plaques could occur. In addition to gap junctions, the presence of macular and linear tight junctions, reported as focal tight junctions (day 14 of development) macular and linear tight junctions with free-ending strands oriented parallel to one another (21 days) and smooth contoured ridges (14 days post-hatching) were observed. This sequence of changes may represent a development from linear to macular, to a more occluding arrangement, and may also reflect an endothelial cell polarization. Histochemical study of proteoglycans was done by using cuprolinic blue according to the critical electrolyte concentration method. Cuprolinic blue-positive granular, elongated and microfibrillar materials were found in the subendothelial region, forming a meshwork that occupies the extracellular space. Qualitative and quantitative changes were observed both in proteoglycans and in other extracellular matrix components throughout development, suggesting an increase in extracellular matrix complexity. These results lead us to suggest that the assembly of a more complex extracellular matrix, concomitantly with the formation of intercellular junctions during development, might influence the polarization of endothelium in the aorta of the chick embryo.

Animals↗

PubMed1995

High affinity immunoreactive FGF receptors in the extracellular matrix of vascular endothelial cells--implications for the modulation of FGF-2.

We recently characterized three FGF-binding proteins (FGF-BPs) which are soluble forms of the extracellular domains of the high affinity FGF receptors (Hanneken, A. M., W. Ying, N. Ling, and A. Baird. Proc. Natl. Acad. Sci. USA. 1994. 91:9170-9174). These proteins circulate in blood and have been proposed to modulate the biological activity of the FGF family of proteins. Immunohistochemical studies now demonstrate that these soluble, truncated FGF receptors are also present in the basement membranes of retinal vascular endothelial cells. These immunoreactive proteins can be detected with antibodies raised to the extracellular domain of FGFR-1 but not with antibodies raised to either the juxtamembrane domain or the cytoplasmic domain of FGFR-1. Western blotting of human retinal extracts with the antibody raised to the extracellular domain of FGFR-1 detects specific, low molecular mass proteins at 85 kD and 55 kD, corresponding in size to the FGF-BPs, which are not detected with antibodies against the cytoplasmic domain of the receptor. The interaction of this receptor with the extracellular matrix is not dependent on the presence of FGF-2. Immunoreactive receptors are still detected in vascular basement membranes after the removal of FGF-2 with heparitinase. In addition, the recombinant extracellular domain of FGFR-1 continues to bind to corneal endothelial cell matrix after endogenous FGF-2 has been removed with 2 M NaCl. Acid treatment, which has been shown to disrupt protein interactions with the extracellular matrix, leads to a significant reduction in the presence of the matrix form of the FGF receptor. This loss can be restored with exogenous incubations of the recombinant extracellular domain of FGFR-1. This report is the first demonstration that a truncated form of a high affinity growth factor receptor can be localized to the extracellular matrix. These findings add to the list of binding proteins associated with the extracellular matrix (IGFBP-5) and suggest a potentially new regulatory mechanism for controlling the biological availability of FGF, and other peptide growth factors, in the extracellular matrix.

Amino Acid Sequence↗

PubMed2006

Extracellular matrix dermatopontin modulates prostate cell growth in vivo.

Dermatopontin is a tyrosine-rich acidic extracellular matrix protein of 22 kDa with possible functions in cell-matrix interactions and matrix assembly. We have previously isolated mRNAs expressed in hormone-refractory, but not in hormone-sensitive, mouse mammary cancer by comparing the mRNAs expressed in either tumor. A partial mRNA sequence isolated was later proven to be a part of mouse dermatopontin mRNA sequence. Transfectants of mouse dermatopontin cDNA into PC-3 human prostate cancer cells enhanced tumor growth when those were implanted subcutaneously in nude mice compared with the controls. Those transfectants showed a prominent stroma compared with the controls. Localization of the targets of a fusion protein of mouse dermatopontin and alkaline phosphatase was in the stroma of the PC-3 tumor tissues, but not in the tumor cells themselves. Additionally, we have established mouse dermatopontin transgenic mice under the control of the rat probasin promoter. The prostatic dorsal lobes of dermatopontin transgenic mouse showed prostate intra-epithelial neoplasia at the age of 11 months, but the control littermates did not. Epithelium of other prostatic lobes was not markedly different from that of the controls. In conclusion, dermatopontin may be involved in the pathogenesis and growth of the prostate cancer.

Animals↗

PubMed1999

Proteoglycan changes in the extracellular matrix of lung tissue from patients with pulmonary emphysema.

To characterize the changes in the extracellular matrix in smoking-related pulmonary emphysema, we undertook immunohistochemical studies in lung tissues from controls (n = 7), from patients with mild (n = 11) and severe (n = 8) emphysema, and from patients with lung fibrosis (n = 6). We studied collagens, laminin, fibronectin, proteoglycans (PGs), and beta1-integrins. The majority of the patients with severe emphysema showed diminished staining for the interstitial PGs, decorin and biglycan, in the peribronchiolar area, compared with patients in the control and fibrosis groups. Only a minority of patients with mild emphysema showed this diminished staining. In contrast, decorin and biglycan were well preserved in the perivascular area of all of the specimens from the emphysema group. Heparan sulfate PG staining was diminished in the respiratory airspace walls of patients with emphysema and fibrosis. Staining for Types I, III, and IV collagen, as well as for laminin, fibronectin, and the integrins, showed no differences between the four groups. The specific loss of interstitial PGs may be crucial for elastic recoil loss and subsequent bronchiolar obstruction, as seen in patients with smoking-related emphysema.

Adolescent↗