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Plasma and cellular fibronectin: distinct and independent functions during tissue repair

Wing S To, Kim S Midwood

Fibrogenesis & Tissue Repair · 2011 · Review

Abstract

Fibronectin (FN) is a ubiquitous extracellular matrix (ECM) glycoprotein that plays vital roles during tissue repair. The plasma form of FN circulates in the blood, and upon tissue injury, is incorporated into fibrin clots to exert effects on platelet function and to mediate hemostasis. Cellular FN is then synthesized and assembled by cells as they migrate into the clot to reconstitute damaged tissue. The assembly of FN into a complex three-dimensional matrix during physiological repair plays a key role not only as a structural scaffold, but also as a regulator of cell function during this stage of tissue repair. FN fibrillogenesis is a complex, stepwise process that is strictly regulated by a multitude of factors. During fibrosis, there is excessive deposition of ECM, of which FN is one of the major components. Aberrant FN-matrix assembly is a major contributing factor to the switch from normal tissue repair to misregulated fibrosis. Understanding the mechanisms involved in FN assembly and how these interplay with cellular, fibrotic and immune responses may reveal targets for the future development of therapies to regulate aberrant tissue-repair processes.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 17, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

1Fibronectin (FN) is a ubiquitous and essential component of the extracellular matrix (ECM). It functions both as a regulator of cellular processes and an important scaffolding protein to maintain and direct tissue organization and ECM composition.

2During tissue repair, the body acts in a series of tightly regulated steps to rapidly reconstitute damaged tissue: the formation of a fibrin clot acts as the platform for granulation tissue assembly, with subsequent contraction and remodeling of the ECM to reform normal tissue. Different forms of FN play differential and temporally discrete roles during tissue repair. Plasma FN and cellular FN possess distinct structures and rates of assembly into three-dimensional matrices.

3In this paper, we discuss the differences in the structure of plasma and cellular FN, and their roles during the different stages of tissue repair. We summarize current theories of how FN is assembled into a three-dimensional matrix, and how this process is regulated. Understanding this complex matrix-assembly process may highlight potential targets for therapeutic advancement in the treatment of aberrant tissue-repair conditions.

Structure of fibronectin isoforms

4FN is a multi-domain glycoprotein composed of an array of multiple repeated modular structures: twelve FN type I repeats (FNI), two FN type II repeats (FNII), fifteen constitutively expressed and two alternatively spliced (in this paper, referred to as EIIIA and EIIIB) FN type III (FNIII) repeats, and a non-homologous variable (V) or type III connecting segment (IIICS) region. The multimodular structure and intermodular regions allow flexibility of the FN molecule, which is involved in regulating its function. These modules are organized into functional domains, including the N-terminal 70-kDa domain (FNI1-9), the 120-kDa central binding domain (CBD; FNIII1-12) and the heparin-binding domain HepII (FNIII12-14). The specific domains of FN can interact with multiple binding partners, including other ECM components and cell-surface receptors. FN is secreted as a dimer maintained by two disulfide S-S bonds at its C-terminus (Figure 1).

Plasma fibronectin

5Plasma FN is synthesized by hepatocytes and secreted into the blood plasma, where it circulates at 300-400 μg/ml in a soluble, compact, inactive form. In soluble plasma FN, only one subunit possesses a V domain, and the EIIIB and EIIIA modules are absent. Only very low levels (1.3-1.4 μg/ml) of FN possessing the EIIIA and/or EIIIB modules (cellular FN) have been reported to circulate in the blood plasma, but blood plasma levels have been shown to increase after major trauma resulting in vascular tissue damage, after inflammation, and in diseases such as atherosclerosis, ischaemic heart disease and stroke.

Cellular fibronectin

6Cellular FN is synthesized by many cell types, including fibroblasts, endothelial cells, chondrocytes, synovial cells and myocytes. Cellular FN is a mixture of FN isoforms. The alternative splicing of EIIIB and EIIIA and more complex splicing of the V or IIICS domain during transcription of cellular FN allows different isoforms of FN to be expressed in a tissue-dependent, temporally regulated, and cell-type-specific manner. In humans, 20 potential FN isoforms can be generated. Increased expression of the EIIIA+ and EIIIB+ isoforms of FN are associated with areas of physiological or pathological tissue remodeling, including wound healing and tissue repair. The observed isoforms of FN, and their association with physiological or pathological conditions, are outlined in Table 1. These isoforms modulate the properties of the ECM, and affect cellular processes.

7The orientation and rotational interdomain flexibilities of FNIII modules are known to be affected by neighboring domains, so the inclusion or exclusion of alternatively spliced domains may change the global conformation of FN, affecting the presentation of FNIII loop structures and binding sequences to modulate FN-cell signaling and FN-FN interactions during matrix assembly. The structural composition of the different FN isoforms are important, as they play distinct roles in early and late wound-healing events.

Fibronectin in early wound-healing responses

8Plasma FN is a major component of the fibrin clot. Multiple mechanisms allow FN to be incorporated into the fibrin matrix. FN can interact via non-covalent interactions with fibrin via its FNI1-5 and FNI10-12 domains. FN is also covalently crosslinked to fibrin by activation of the blood coagulation cascade involving activated Factor XIIIa (plasma transglutaminase or coagulation factor XIII). This crosslinks FN via glutamine residues within its N-terminus to the fibrin α chains via ε-(γ-glutamyl) lysine cross links. Furthermore, plasma FN can also be bound and then assembled into a high-molecular-weight multimeric matrix on the platelet surface. Platelet activation by thrombin induces increased cell-surface expression of the major platelet integrin αIIbβ3, which binds and assembles FN via a fibrin-independent mechanism. Platelets also express a lower number of α5β1 and αvβ3 receptors on their surface, which mediate platelet adhesion. Aggregated platelets can also assemble FN via a fibrin-dependent pathway. The polymerization of fibrin into a three-dimensional network has been shown to be essential for FN assembly, as the γ chain of unprocessed fibrinogen signals via αIIbβ3 to inhibit this process.

9Platelet-producing megakaryocytes endocytose and pinocytose FN from the plasma, which becomes packaged into the α granules of platelets. This has been shown to involve the αIIbβ3 integrin; mice with a mutation in the gene encoding the fibrinogen γ chain (which prevents fibrinogen interactions with αIIbβ3), von Willebrand factor null mice, and fibrinogen null mice show increased FN levels in their α granules. Upon platelet activation, FN is released from α granules in a process called degranulation. The FN released from platelets can also assemble on the surface of platelets. FN incorporation into the fibrin matrix is important for various platelet functions, including adhesion, migration and aggregation (Figure 2). However, in vitro fibrin assembly was shown to be unaffected by a complete absence of plasma FN. Furthermore, plasma FN conditional knockout mice, or mutant mice with reduced plasma FN levels of 50% or 70-80%, were shown to have normal clotting and bleeding times. Minimal effects on wound healing in these mice were seen in vivo. Cellular FN isoforms possessing the alternatively spliced EIIIA and EIIIB domains, derived from platelets, are thought to compensate for the loss of plasma FN in these conditions. Although it has been shown that cellular FN isoforms are not efficiently incorporated into the fibrin clots in vitro, it is thought that they may be sufficient to allow normal wound-healing events in vivo.

10The fibrin-FN provisional matrix allows FN to adopt extended conformations within the fibrin-FN matrix, which leads to the exposure of cryptic cell binding domains to facilitate cellular processes (Figure 2). For example, fibroblast activation by various growth factors such as platelet-derived growth factor requires specific sequences within the heparin domain and IIICS region.

Fibronectin in the late wound-healing responses

11Endothelial cells and fibroblasts repopulate the wound and deposit cellular FN, an important and abundant component of granulation tissue. FN organizes into fibrillar structures within the stroma of granulation tissue, and forms a dense network around fibroblasts, which polarize along the FN fibrils, parallel to the epidermis. FN assembly into a three-dimensional fibrillar network on the cell surface is vital for establishing and maintaining tissue architecture and for regulating cellular processes including adhesion, spreading, proliferation, migration and apoptosis (Figure 2). The three-dimensional FN structural matrix plays an important role in regulating both ECM composition and the deposition of other ECM molecules, including collagen types I and III, fibrinogen, fibrillins 1 and 2, fibulin, laminin and tenascin (TN)-C. Reticulin has also been shown to colocalize with FN fibrils within the granulation tissue. The FN matrix can also sequester growth factors and associated proteins, including bone morphogenetic protein-1, vascular endothelial growth factor (VEGF) and latent transforming growth factor (TGF)-β binding proteins (LTBP) 1, 3 and 4 to regulate cell signaling events. While the FN matrix is continuously assembled, remodeled and turned over by cells, a more mature and stable ECM network assembles on this FN-matrix scaffold (Figure 2).

12FN in the wound site is also vital for regulating the neovascularisation of granulation tissue during the resolution of tissue injury. Exposure of different ECM protein conformations in the vascular basement during wounding acts as an important cue to regulate angiogenesis. FN expression, especially of isoforms possessing the alternatively spliced EIIIA+ and EIIIB+ modules are highly upregulated around neovessels and capillary sprouts within the highly vascularized granulation tissue. An FN fibrillar network has been shown to be required for proliferation and migration of human umbilical-vein endothelial cells in a three-dimensional environment, and functions to promote endothelial-cell survival (Figure 2).

13Myofibroblast differentiation is dependent on the presence of both TGF-β and EIIIA+FN and on the dramatic changes in the mechanical properties of the wound microenvironment. Myofibroblasts form specialized actin-associated fibronexus adhesion complexes, which function in mechano-transduction to allow transmission of intracellular actin-generated contractile forces and the sampling of extracellular tension. These specialized adhesion complexes may also function in myofibroblast-dependent contracture of the wound, which acts to 'shorten' and remodel the collagen-rich matrix, resulting in closure of the wound and recapitulation of normal tissue architecture and function.

14The data highlighted here indicate distinct and discrete roles for the two different forms of FN during tissue injury and repair. Plasma FN and cellular FN are differentially expressed both temporally and spatially during wound healing: plasma FN circulates in the blood and functions during early wound-healing responses, whereas cellular FN is expressed and assembled locally and functions during later wound-healing responses. However, despite this non-overlapping expression and localization of the FN isoforms during wound healing, exogenous plasma FN can be assembled into pre-existing or newly assembling cellular FN matrices even if the plasma FN is isolated from a different species. Although plasma FN shows slower initial kinetics of assembly than cellular FN, these data imply that plasma and cellular FN could potentially perform the same functions. Supporting this hypothesis, conditional plasma FN knockout mice were found to have normal wound healing and hemostasis, suggesting possible compensation by cellular isoforms of FN. However, in other physiological and pathological processes, these isoforms have been shown to be distinct and unique in their functions; plasma FN was found to be essential for protecting neuronal and non-neuronal cells from apoptosis after transient focal cerebral tissue ischaemia and after traumatic brain injury, as cellular FN is not expressed in these damaged brain tissues. Furthermore, EIIIA-FN null mice were shown to have impaired abnormal skin wound-healing responses with reduced cell compaction and edematous-like areas within the granulation tissue and delayed re-epithelialization. These results would suggest that EIIIA+FN plays an important role in the resolution of late wound-healing processes. Tan et al. reported that EIIIA-FN null mice on a different background strain showed no effect on wound healing, but did show reduced atherosclerosis, suggesting that cellular isoforms of FN contribute to pathological conditions. These studies suggest independent roles for the different isoforms of FN, which cannot always be compensated for in their absence.

Fibronectin-matrix assembly

15There is still much that we do not know about how FN is assembled or how the rate of deposition is controlled. Understanding the mechanisms that regulate FN-matrix assembly will allow us to control this process when it becomes misregulated.

16Plasma FN in solution alone will not polymerize and will not form a three-dimensional matrix in the absence of cells. Both plasma and cellular FN are expressed and secreted in a soluble, compact form, which is maintained by intramolecular electrostatic interactions between the FNI1-5, FNIII1-2, FNIII2-3 and FNIII12-14 domains (Figure 3A). In low-salt conditions, this compact quaternary structure can be seen by electron microscopy, and Förster resonance energy transfer studies have shown that the arms of soluble FN overlap each other. FN mutants lacking FNIII12-14 or having this region replaced by the alternatively spliced FN type III domains A1-A3 from tenascin-C (TN-C), had lower sedimentation coefficient values, reflecting adoption of a more open conformation and highlighting the importance of FNIII12-14 in maintaining these intramolecular interactions.

17FN-matrix assembly is a stepwise, cell-mediated process. The process seems to be rapid, as initial FN deposits appear at the cell surface within 10 minutes of plating, and in the conditioned medium within 30 minutes. FN dimerisation is required for FN assembly, as mutation of C-terminal cysteines results in the loss of fibrillogenesis. This process is briefly discussed below, but is discussed in more depth elsewhere.

Initiation of fibronectin-matrix assembly

18Initiation of assembly involves FN binding to cell-surface receptors (Figure 3A(i, ii). Integrins that bind FN are summarized in Table 2, although some (for example, αvβ1) do not support FN fibrillogenesis. Mice engineered to be deficient in FN, α5, β1 or αv, or to express FN-RGE (FNRGE/RGE; the RGD integrin-binding sequence of FNIII10 is mutated to RGE) all exhibit embryonic lethality, highlighting the importance of FN fibrillogenesis and the FN fibrillar matrix during development.

19FN is thought to bind first to the cell surface via FNI1-5 within the 70-kDa N-terminal domain of FN (hereafter referred to as '70-kDa'; Figure 3Ai). Initiation of FN-matrix assembly occurs at focal contacts, which are initial sites of ECM contact on the cell periphery, which are rich in paxillin, vinculin, phosphotyrosines, and β1 and β3 integrins. The receptor(s) for 70-kDa have not yet been clearly elucidated. Interactions with αvβ3 integrins have been shown to interact with the novel Gly-Asn-Gly-Arg-Gly (GNGRG) motif in FNI1-5. However, recent work has shown that mutation of the two GNGRG sequences within 70-kDa has no effect on the binding of 70-kDa or FN to adherent cells or on the ability of 70-kDa to compete for FN binding. However, this study did show that interactions of cells with 70-kDa did require activated αvβ3 integrins, and it has also been shown that in vivo, the presence of pre-existing three-dimensional FN matrices also stimulates αvβ3 activation to induce FN-matrix assembly. Another possible integrin-binding site is the Ile-Gly-Asp (IGD) sequence in FNI9. It has been suggested that initiation of FN-matrix assembly may be a process that is not dependent on a single integrin or region within FN, but may involve many different molecules.

20Other integrins may also be involved in the initiating the assembly of specific FN isoforms. In an interesting study, which demonstrated the essential role of FNIIIA+FN in lymphatic-valve development,α9β1 integrin was shown to be required for the assembly of EIIIA+FN by lymphatic endothelial cells; however, this assembly mechanism may be isoform-specific, as a separate study found that overall FN-matrix assembly by EIIIA-FN null fibroblasts was unaffected.

21It is well established that an essential step in the progression of FN-matrix assembly involves α5β1 integrin binding of the RGD loop on FNIII10 and the neighboring PHSRN sequence in FNIII9 in the CBD of FN (Figure 3Aii). α5β1 integrin binding to CBD is a high-affinity interaction (Kd = 0.2 μmol/l by solid-phase binding). FN mutants with loss of the RGD site or a mutation within the RGD site were found to be unable to assemble a complex fibrillar network, forming only linear fibrillar arrays at the periphery of cells. Antibodies against the RGD domain or small RGD peptides can also inhibit FN-matrix assembly. Furthermore, FNRGE/RGE-expressing mouse embryos had normal FN distribution, and isolated embryonic fibroblasts could assemble short, thick, FN fibrils, confirming that FNIII10 interactions with α5β1 are not essential for assembly initiation.

22The interaction of integrins with FN provides 'outside-in' signals, and induces integrin clustering in focal adhesions. Ligation of integrins can also induce intracellular signaling and the activation of integrins to a higher-affinity binding state by 'inside-out' signaling. Phosphorylation of integrin cytoplasmic domains and subsequent integrin activation by signaling molecules such as talin requires myosin II-dependent cell-generated tension, which is activated by force-induced conformational changes. 'Outside-in' signals can be translated into 'inside-out' signals via a feedback loop to regulate adhesion-complex formation, integrin affinity and FN-matrix assembly (Figure 3Aiii). 'Inside-out' signaling and integrin activation and clustering may precede FN binding during embryogenesis: integrin α5β1 activation and clustering was shown to be initiated by Eph/Ephrin signaling with subsequent FN-matrix assembly.

23Cell-surface heparan sulfate proteoglycans (HSPGs) have also been shown to play an important role in FN-matrix assembly (Figure 3A (iv)). The HepII domain of FN (FNIII12-14) can interact with heparin, and the FNIII13 module is the primary binding site, suggesting that this FN domain is involved in the binding of HSPGs. Syndecan-2, which is the major syndecan of fibroblasts, has been shown to be an important HSPG for FN fibrillogenesis during zebrafish development, and supports FN-matrix assembly.

24It should be noted that models of fibril initiation are often elucidated from two-dimensional cellular experiments, in which cells also form distinct adhesive structures. In three-dimensional cultures, cells that assemble FN do not form distinct focal or fibrillar adhesions, but instead form long, slender ECM attachments that contain both classic focal-adhesion and fibrillar-adhesion components: α5, paxillin, vinculin, focal-adhesion kinase, phosphotyrosine, and activated β1. These FN-assembly complexes probably involve a multitude of cell-surface receptors, HSPGs and signaling molecules that act in concert to facilitate FN-assembly initiation.

Fibronectin unfolding, elongation and fibril formation

25Upon binding to integrins and other cell-surface receptors, FN then has to be unfolded from its compact structure into an extended structure (Figure 3B).

26An intact actin cytoskeleton is essential to generate cell tension and a cytoskeletal force, which translates into a temporal change in traction force that induces conformational changes of the cell-surface-bound FN and allows integrin crosslinking, clustering and subsequent translocation (Figure 3Bi). FN unfolding is dependent on β1-FN translocation from focal contacts to central tensin-rich fibrillar-adhesion complexes (Figure 3Bii), and FN fibrils are shown to form from the continuous extension of FN molecules and their intermolecular associations. FN unfolding exposes binding sites buried in the soluble structure to promote the interaction of FN with other FN molecules and ECM components. Cell contractility may require a submembranous pool of myosin II, controlled by myosin light chain kinase via RhoA-Rho kinase II-dependent or RhoA-independent pathways. Cells in three-dimensional microenvironments may favor different isoforms of myosin II for generating intracellular forces compared with cells cultured in two-dimensional environments. The transduction of intracellular cytoskeleton-generated forces and extracellular mechanical stresses are communicated via cell-ECM contacts, allowing the cell to respond to changes in its microenvironment.

27During embryogenesis, an alternative mechanism for production of intracellular tension involves the activation of the non-canonical Wnt/PCP signaling pathway, Rho GTPase Rac, p21 activated kinase (Pak) and cadherins, which generate cytoskeletal tension via cell-cell adhesion. This tension is transmitted via β1 to cell-surface-bound FN to mediate fibril formation. In support of this process, inhibition of β1 function inhibits convergence extension tissue morphogenesis and cadherin-mediated cell adhesion. The presence of multiple pathways to mediate cell contractility demonstrates the importance of this generated force in FN-matrix assembly.

28FNI1-5, FNIII1-2, FNIII4-5 and FNIII12-14 are important domains for FN fibrillogenesis, and play a role in mediating and regulating intermolecular FN-FN interactions (Figure 3C). The EIIIA or EIIIB domains can also promote FN-matrix assembly, possibly by exposing integrin-binding sites in neighboring domains: FNIII10 (EIIIB) and IIICS region (EIIIA).

29FN module unfolding and exposure of cryptic FN-FN binding sites further promote FN fibrillogenesis. FN linker domains and the FNIII modules possess inherent elasticity. Domains shown to possess cryptic binding sites include FNIII1, FNIII1-2, FNIII10, FNIII7 and FNIII15 (Figure 3C). A peptide sequence derived from FNIII1 (FNIII1-C) can induce superfibronectin formation; that is, high-molecular-weight, crosslinked aggregates of FN, which resemble cell-assembled FN fibrils, indicating how effective these cryptic binding sequences are in promoting FN-FN interactions.

30FN molecules are organized into thin fibrils of 5 nm in diameter, formed from the overlapping and staggering of extended FN dimers and the crosslinking of FN into stable multimers. FN fibrils then become laterally associated into thicker fibrils of 6-22 nm in diameter. Further FN-fibril interactions allow the formation of high-molecular-weight, complex, branched, fibrillar FN matrices, which are detergent-insoluble. FN cross-linking and multimerization may occur via a partially cryptic endogenous protein disulfide isomerase activity present in FNI12, as reported by Lagenbach et al. in RNase refolding experiments. However, there is some question as to whether covalent disulfide crosslinking is a true phenomenon; there are suggestions that FN associates via non-covalent protein-protein interactions. The high-molecular-weight multimers seen in non-reduced SDS-PAGE gels are suggested to be a mixture of other ECM proteins such as fibrillin, which 'block' FN dimers from migrating through the gel. This is not unexpected as FN is known to interact with many different ECM components, and these protein-protein interactions may well attenuate its migration through SDS-PAGE gels.

31Once assembled, FN fibrils are continuously polymerized and remodeled within the fibrillar matrix on the cell surface. FN remodeling is a dynamic process, in which fibrils continuously detach, contract, bend, stretch, extend, retract and anneal to neighboring fibrils. In vivo, the fibrillar ECM structure is deformed by local cell migratory and protrusive activities, and large-scale tissue motion, particularly during embryogenesis. This strongly extensible behavior is due to mechanical unfolding and refolding of FNIII modules.

32Pre-existing three-dimensional matrices act as scaffolds for further FN deposition; new fibrils colocalize with pre-existing matrix. Cells cultured in native ECM scaffolds deposit more soluble FN onto pre-existing FN fibers, requiring lower concentrations of FN for initiation. New FN molecules deposited by cells onto a mature matrix are unfolded more than cells cultured on 'soft' polyacrylamide substrates. ECM crosslinking has also been shown to increase the rate of de novo FN stretching by cells but to reduce overall deposition of soluble FN molecules, suggesting that ECM maturation is a mechanism that regulates the rate of FN deposition.

Fibronectin and aberrant wound-healing conditions

33FN-matrix assembly has to be tightly regulated. Cellular FN homeostasis is maintained by continual FN assembly and loss from the pericellular matrix. Persistently high levels of FN promote cell proliferation, survival signals, and strong cell-ECM adhesions. Conversely, loss of FN-matrix assembly is observed in some transformed cells, and may be important during cell-migration events such as metastasis. In addition, loss of FN deposition would accentuate the loss in the assembly of other ECM components within the wound bed, as seen in chronic non-healing wounds, even though FN expression persists and is actually increased in the surrounding dermis.

Fibronectin in fibrotic conditions

34FN plays an important role in the development of fibrotic disease. Fibrosis is characterized by an excessive deposition of connective tissue that leads to the impairment of organ structure or function, and is considered a chronic inflammatory tissue-repair response, similar in structure and composition to granulation tissue. In fibrosis, there is a key interplay between the immune response, fibroblastic-cell response and ECM, which results in the formation of fibrotic lesions.

35Although collagen is the most predominant ECM component of fibrotic tissue, excessive deposition of FN also occurs, and precedes the collagen deposition (Table 1). In glomerular and interstitial fibrosis, there is markedly increased expression of total FN levels, with increased levels of EIIIA+, EIIIB+ and oncofetal (IIICS+) isoforms detected in distinct areas of the kidney and in areas of fibrosis. Fibrogenesis is driven by fibroblasts and myofibroblasts, which show increased migration, proliferation, ECM synthesis and assembly within affected tissues. The presence of both alternatively spliced EIIIA+FN and pro-inflammatory cytokines such as TGF-β1 have been shown to be required in the differentiation or transdifferentiation of cells to myofibroblasts. For example, experiments with EIIIA null mice suggest that EIIIA+ isoform of FN induces α-smooth-muscle actin myofibroblast differentiation in the presence of TGF-β1. In the absence of EIIIA+ FN, there is continuous interstitial fibrosis after bleomycin treatment, but no switch to a chronic fibrotic response mediated by myofibroblasts. Furthermore, these experiments also showed that EIIIA+FN is required for latent TGF-β1 activation, and plays a response in fibroblast response to TGF-β1. TGF-β1 and the TGF-β family have been shown to activate the Smad family of transcription factors (including Smad3), which are involved in the expression of profibrotic genes. Furthermore, mouse models of atherosclerosis have shown the essential role of FN in initima-media thickening in vivo. Using a 49-residue sequence from the FUD domain of the F1 adhesin protein produced by Streptococcus pyogenes (pUR4), which has been shown to inhibit FN-matrix assembly by binding to the N-terminal 70-kDa domain of FN, this study demonstrated that inhibiting FN-matrix assembly in vivo significantly reduced intimal, medial and adventitial thickening, collagen deposition, cell proliferation, and inflammatory-cell infiltration after induction of atherosclerosis. The results confirm the essential role FN plays in mediating ECM deposition and inflammatory response, which are corollaries of fibrosis. This study also showed promise for possible in vivo applications for inhibiting FN assembly.

36Recently clinical studies have shown that use of a 585 nm flashlamp-pumped pulsed-dye laser resulted in the regression or arrest of keloid development by reducing the expression of TGF-β1in keloid tissues and increasing the expression of matrix metalloproteinase (MMP)-13 (also called collagenase-3). As many fibrotic conditions are largely untreatable, it is imperative that the mechanisms involved in the development and maintenance of these diseases are understood so that effective therapies can be developed.

Regulation of fibronectin-matrix assembly

37FN expression and assembly is stimulated in a cell-specific manner by a multitude of molecules (Table 3). Stimulation of FN expression, secretion and assembly by these agents emphasizes the complexity and requirement for tight regulation of this process. As mentioned earlier, TGF-β1 and connective tissue growth factor are key cytokines involved in upregulating FN expression during fibrogenesis. FN deposition also requires RhoA-mediated cell contractility (Table 3). FN can also be degraded by multiple proteases including MMP-9. FN fragments and modules can also inhibit FN-matrix assembly by competing for FN-assembly sites, which could act as a feedback system to regulate FN levels on the cell surface. The increased levels of proteases such as neutrophil elastase in chronic wound exudate, which can act to degrade FN, could further contribute to this condition. Aged clots in chronic wounds contain highly crosslinked fibrin, which is stripped of other functional proteins by the strongly proteolytic environment. These examples illustrate the importance of FN and its assembly in regulating and resolving wound-healing processes to maintain tissue architecture.

38FN fibrils are continuously remodeled and turned over, which is mediated via a β1-dependent, caveolin-1-dependent and low-density lipoprotein receptor-related protein (LRP)-independent endocytic mechanism. FN becomes targeted to the lysosomes and degraded intracellularly. As FN is assembled into high-molecular-weight multimers by an endogenous disulfide isomerase activity, some reverse proteolytic activity must occur to allow FN endocytosis. Furthermore, β1 integrin clustering can induce polarized expression of membrane type 1 (MT1)-MMP to invasive structures to cause localized ECM degradation. Indeed, endocytosis of fibrillar FN from pre-assembled matrices was shown to be much slower than endocytosis of soluble FN. Interestingly, mature FN matrices are as highly dynamic as immature FN matrices, but ECM maturation has been reported to assemble less dynamic ECM networks over time, which loses this dynamic remodeling.

39Other ECM components can also influence FN-matrix assembly. Low levels of vitronectin (VN) have been shown to enhance FN-matrix assembly by increasing the expression of matrix-assembly sites on the cell surface. However, high concentrations of VN are inhibitory for FN-matrix assembly. The HepII domain of VN has been shown to interact with αvβ3 and αvβ5 integrins, preventing actin microfilament reorganization and causing loss of FN-matrix assembly sites. Loss of collagen type VI also impairs complex FN-matrix assembly; FN fibrils become oriented parallel to the long axis of the cell. As discussed earlier, the individual FN domains including 70-kDa can also inhibit FN-matrix assembly by interfering with fibril formation by the full-length molecules.

40Work carried out in our laboratory has also shown that smaller domains of TN-C, but not the full-length protein, can inhibit FN-matrix assembly. As TN-C is only coexpressed with FN in areas of physiological and pathological tissue remodeling and the presence of encrypted inhibitory activity within the individual TN-C domains suggests TN-C may also play an important role in regulating FN-matrix assembly. This highlights how ECM composition and the breakdown of ECM components can also act as a further level of control, which could be exploited to control pathological wound-healing events.

Future perspectives

41Current therapies used to treat fibrotic conditions are well summarized and discussed elsewhere. It is now appreciated that fibrosis can be considered an aberrant wound-healing response as the understanding of the mechanism of its development is better understood. For example, anti-TGF-β has been successfully shown to reduce skin and pulmonary fibrosis in mice with sclerodermatous graft-versus-host disease, a mouse model of the systemic fibrotic condition scleroderma. However, anti-TGF-β therapy has not been as successful in human systemic sclerosis (SSc): in a placebo-controlled phase I/II trial, systemic and repeated dosing of CAT-192, an antibody developed against active TGF-β1, showed no efficacy in a cohort of 45 patients with early-stage diffuse cutaneous SSc. That study also had higher mortality rates than shown in trials of other drugs to treat diffuse cutaneous SSc, although whether this is due to other factors was not clear. The lack of success might also have been due to the fact that other TGF-β isoforms have profibrotic effects, highlighting the complex interplay between the immune system, the ECM and cell signaling during wound healing and aberrant wounding responses. The interplay between cells and the ECM in the regulation of homeostasis and response to physiological and pathological events is complex, and it will be vital to understand these in order to develop therapies that can modify these processes.

42Further research into the mechanisms that regulate FN-matrix assembly will help us understand how we can regulate it to prevent aberrant deposition that contributes to pathological conditions. In particular, the effect of other ECM proteins on the FN-assembly process may comprise a regulatory mechanism that could be further explored and exploited therapeutically. For example, ECM proteins such as TN-C are re-expressed only in tissues undergoing active remodeling, such as in fibrotic lesions. However, the role of these molecules in fibrotic tissues and their effects on FN expression, deposition or assembly are still unclear. Elucidation of the complex interplay between resident ECM constituents is likely to reveal how physiological, synergistic control of matrix remodeling is mediated.

Conclusions

43The plasma and cellular forms of FN play temporally and spatially distinct and vital roles during the progression of wound healing. Plasma FN circulates in the blood plasma in an inactive form, and is stored in the α-granules of platelets until activated by the wound response and stimulation of the coagulation cascade. Plasma FN is then deposited and crosslinked to the provisional FN-rich matrix, and functions to stimulate platelet adhesion and aggregation, and fibroblast spreading and invasion into the clot. Cellular FN is then synthesized by the migrated cells within the clot, and assembled into a complex, fibrillar matrix on the cell surface, which directs the deposition of other ECM proteins and the migration, adhesion and differentiation of fibroblasts. Many mechanisms are involved to regulate FN-matrix assembly, and there is now also growing evidence that in addition to regulation via molecules, the ECM composition and structure itself are also important.

44As ECM assembly is such a complex process, understanding the mechanisms involved is vital if we are to manipulate this process. The fact that other ECM components can affect the deposition and assembly levels of FN suggests further levels of control that could be exploited in cases of dysfunctional wound-healing events. It may be that modifying the microenvironment by altering the expression of other ECM components may be sufficient to induce the resolution of such aberrant tissue-repair processes, which can lead to conditions such as fibrosis.

List of abbreviations

45ECM: extracellular matrix; EIIIA: alternatively spliced fibronectin type III repeat A; EIIIB: alternatively spliced fibronectin type III repeat B; FN: fibronectin; FNI: fibronectin type I repeat; FNII: fibronectin type II repeat; FNIII: fibronectin type III repeat; HSPG: heparan sulfate proteoglycan; MMP: matrix metalloproteinase; PDGF: platelet-derived growth factor; SSc: systemic sclerosis; TGF: transforming growth factor; VEGF: vascular endothelial growth factor.

Competing interests

46The authors declare that they have no competing interests.

Authors' contributions

47WST and KSM drafted the manuscript. Both authors have read and approved the final manuscript.

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8.
Rocco M Infusini E Daga MG Gogioso L Cuniberti C Models of fibronectinEMBO J1987 623432349
Not in our library10.1002/j.1460-2075.1987.tb02510.x
9.
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Zardi L Cecconi C Barbieri O Carnemolla B Picca M Santi L Concentration of fibronectin in plasma of tumor-bearing mice and synthesis by Ehrlich ascites tumor cellsCancer Res1979 3937743779
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14.
Magnusson MK Mosher DF Fibronectin: structure, assembly, and cardiovascular implicationsArterioscler Thromb Vasc Biol1998 1813631370
Not in our library10.1161/01.atv.18.9.1363
15.
Tressel T McCarthy JB Calaycay J Lee TD Legesse K Shively JE Pande H Human plasma fibronectin. Demonstration of structural differences between the A- and B-chains in the III CS regionBiochem J1991 274Pt 3731738
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Wilson CL Schwarzbauer JE The alternatively spliced V region contributes to the differential incorporation of plasma and cellular fibronectins into fibrin clotsJ Cell Biol1992 119923933
Not in our library10.1083/jcb.119.4.923
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Chauhan AK Kisucka J Cozzi MR Walsh MT Moretti FA Battiston M Mazzucato M De Marco L Baralle FE Wagner DD Muro AF Prothrombotic effects of fibronectin isoforms containing the EDA domainArterioscler Thromb Vasc Biol2008 28296301
Not in our library10.1161/atvbaha.107.149146
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Peters JH Loredo GA Chen G Maunder R Hahn TJ Willits NH Hynes RO Plasma levels of fibronectin bearing the alternatively spliced EIIIB segment are increased after major traumaJ Lab Clin Med2003 141401410
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19.
Castellanos M Leira R Serena J Blanco M Pedraza S Castillo J Davalos A Plasma cellular-fibronectin concentration predicts hemorrhagic transformation after thrombolytic therapy in acute ischemic strokeStroke2004 3516711676
Not in our library10.1161/01.str.0000131656.47979.39
20.
Song KS Kim HK Shim W Jee SH Plasma fibronectin levels in ischemic heart diseaseAtherosclerosis2001 154449453
Not in our library10.1016/s0021-9150(00)00490-1
21.
Claudepierre P Allanore Y Belec L Larget-Piet B Zardi L Chevalier X Increased Ed-B fibronectin plasma levels in spondyloarthropathies: comparison with rheumatoid arthritis patients and a healthy populationRheumatology (Oxford)1999 3810991103
Not in our library10.1093/rheumatology/38.11.1099
22.
Mao Y Schwarzbauer JE Fibronectin fibrillogenesis, a cell-mediated matrix assembly processMatrix Biol2005 24389399
Not in our library10.1016/j.matbio.2005.06.008
23.
Hershberger RP Culp LA Cell-type-specific expression of alternatively spliced human fibronectin IIICS mRNAsMol Cell Biol1990 10662671
Not in our library10.1128/mcb.10.2.662-671.1990
24.
Khan ZA Chan BM Uniyal S Barbin YP Farhangkhoee H Chen S Chakrabarti S EDB fibronectin and angiogenesis-a novel mechanistic pathwayAngiogenesis2005 8183196
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26.
Van Vliet A Baelde HJ Vleming LJ de Heer E Bruijn JA Distribution of fibronectin isoforms in human renal diseaseJ Pathol2001 193256262
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27.
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28.
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Not in our library10.1016/j.jmb.2006.10.017
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Not in our library10.1016/s0092-8674(00)81002-8
31.
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Not in our library10.1006/jmbi.1996.0736
33.
Ventura E Sassi F Parodi A Balza E Borsi L Castellani P Carnemolla B Zardi L Alternative splicing of the angiogenesis associated extra-domain B of fibronectin regulates the accessibility of the B-C loop of the type III repeat 8PLoS One5e9145
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34.
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Not in our library10.1242/jcs.00059
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Not in our library10.1023/a:1026307731751
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Not in our library10.1172/jci109334
40.
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Not in our library10.1182/blood.v98.1.117
41.
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42.
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43.
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Not in our library10.1016/0092-8674(85)90101-1
44.
Plow EF Marguerie GA Ginsberg MH Fibronectin binding to thrombin-stimulated platelets: evidence for fibrin(ogen) independent and dependent pathwaysBlood1985 662632
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45.
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Not in our library10.2174/138161209787846702
46.
Schick PK Wojensk CM Bennett V Denisova L Fibronectin isoforms in megakaryocytesStem Cells1996 14Suppl 1212219
Not in our library10.1002/stem.5530140728
47.
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Not in our library10.1172/jci9896
48.
Ni H Papalia JM Degen JL Wagner DD Control of thrombus embolization and fibronectin internalization by integrin alpha IIb beta 3 engagement of the fibrinogen gamma chainBlood2003 10236093614
Not in our library10.1182/blood-2003-03-0850
49.
Ni H Yuen PS Papalia JM Trevithick JE Sakai T Fassler R Hynes RO Wagner DD Plasma fibronectin promotes thrombus growth and stability in injured arteriolesProc Natl Acad Sci USA2003 10024152419
Not in our library10.1073/pnas.2628067100
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Wencel-Drake JD Painter RG Zimmerman TS Ginsberg MH Ultrastructural localization of human platelet thrombospondin, fibrinogen, fibronectin, and von Willebrand factor in frozen thin sectionBlood1985 65929938
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Sakai T Johnson KJ Murozono M Sakai K Magnuson MA Wieloch T Cronberg T Isshiki A Erickson HP Fassler R Plasma fibronectin supports neuronal survival and reduces brain injury following transient focal cerebral ischemia but is not essential for skin-wound healing and hemostasisNat Med2001 7324330
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Matuskova J Chauhan AK Cambien B Astrof S Dole VS Piffath CL Hynes RO Wagner DD Decreased plasma fibronectin leads to delayed thrombus growth in injured arteriolesArterioscler Thromb Vasc Biol2006 2613911396
Not in our library10.1161/01.atv.0000216282.58291.c6
53.
Kamykowski GW Mosher DF Lorand L Ferry JD Modification of shear modulus and creep compliance of fibrin clots by fibronectinBiophys Chem1981 132528
Not in our library10.1016/0301-4622(81)80021-x
54.
Cho J Mosher DF Enhancement of thrombogenesis by plasma fibronectin cross-linked to fibrin and assembled in platelet thrombiBlood2006 10735553563
Not in our library10.1182/blood-2005-10-4168
55.
Tonnesen MG Feng X Clark RA Angiogenesis in wound healingJ Investig Dermatol Symp Proc2000 54046
Not in our library10.1046/j.1087-0024.2000.00014.x
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Knox P Crooks S Rimmer CS Role of fibronectin in the migration of fibroblasts into plasma clotsJ Cell Biol1986 10223182323
Not in our library10.1083/jcb.102.6.2318
57.
Manabe R Ohe N Maeda T Fukuda T Sekiguchi K Modulation of cell-adhesive activity of fibronectin by the alternatively spliced EDA segmentJ Cell Biol1997 139295307
Not in our library10.1083/jcb.139.1.295
58.
Sottile J Mosher DF N-terminal type I modules required for fibronectin binding to fibroblasts and to fibronectin's III1 moduleBiochem J1997 323Pt 15160
Not in our library10.1042/bj3230051
59.
Wang R Clark RA Mosher DF Ren XD Fibronectin's central cell-binding domain supports focal adhesion formation and Rho signal transductionJ Biol Chem2005 2802880328810
Not in our library10.1074/jbc.m501421200
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Friedland JC Lee MH Boettiger D Mechanically activated integrin switch controls alpha5beta1 functionScience2009 323642644
Not in our library10.1126/science.1168441
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Not in our library10.1091/mbc.e02-01-0048
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Cukierman E Pankov R Stevens DR Yamada KM Taking cell-matrix adhesions to the third dimensionScience2001 29417081712
Not in our library10.1126/science.1064829
63.
Johansson S Svineng G Wennerberg K Armulik A Lohikangas L Fibronectin-integrin interactionsFront Biosci1997 2d126146
Not in our library10.2741/a178
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Not in our library10.1074/jbc.270.39.23196
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Liao YF Gotwals PJ Koteliansky VE Sheppard D Van De Water L The EIIIA segment of fibronectin is a ligand for integrins alpha 9beta 1 and alpha 4beta 1 providing a novel mechanism for regulating cell adhesion by alternative splicingJ Biol Chem2002 2771446714474
Not in our library10.1074/jbc.m201100200
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Repesh LA Fitzgerald TJ Furcht LT Fibronectin involvement in granulation tissue and wound healing in rabbitsJ Histochem Cytochem1982 30351358
Not in our library10.1177/30.4.6174568
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Dallas SL Sivakumar P Jones CJ Chen Q Peters DM Mosher DF Humphries MJ Kielty CM Fibronectin regulates latent transforming growth factor-beta (TGF beta) by controlling matrix assembly of latent TGF beta-binding protein-1J Biol Chem2005 2801887118880
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Chiang HY Korshunov VA Serour A Shi F Sottile J Fibronectin is an important regulator of flow-induced vascular remodelingArterioscler Thromb Vasc Biol2009 2910741079Epub 2009 Apr 1030
Not in our library10.1161/atvbaha.108.181081
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Dzamba BJ Peters DM Arrangement of cellular fibronectin in noncollagenous fibrils in human fibroblast culturesJ Cell Sci1991 100Pt 3605612
Not in our library10.1242/jcs.100.3.605
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Dzamba BJ Wu H Jaenisch R Peters DM Fibronectin binding site in type I collagen regulates fibronectin fibril formationJ Cell Biol1993 12111651172
Not in our library10.1083/jcb.121.5.1165
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Li S Van Den Diepstraten C D'Souza SJ Chan BM Pickering JG Vascular smooth muscle cells orchestrate the assembly of type I collagen via alpha2beta1 integrin, RhoA, and fibronectin polymerizationAm J Pathol2003 16310451056
Not in our library10.1016/s0002-9440(10)63464-5
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McDonald JA Kelley DG Broekelmann TJ Role of fibronectin in collagen deposition: Fab' to the gelatin-binding domain of fibronectin inhibits both fibronectin and collagen organization in fibroblast extracellular matrixJ Cell Biol1982 92485492
Not in our library10.1083/jcb.92.2.485
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Sottile J Shi F Rublyevska I Chiang HY Lust J Chandler J Fibronectin-dependent collagen I deposition modulates the cell response to fibronectinAm J Physiol Cell Physiol2007 293C19341946
Not in our library10.1152/ajpcell.00130.2007
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Velling T Risteli J Wennerberg K Mosher DF Johansson S Polymerization of type I and III collagens is dependent on fibronectin and enhanced by integrins alpha 11beta 1 and alpha 2beta 1J Biol Chem2002 2773737737381
Not in our library10.1074/jbc.m206286200
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Pereira M Rybarczyk BJ Odrljin TM Hocking DC Sottile J Simpson-Haidaris PJ The incorporation of fibrinogen into extracellular matrix is dependent on active assembly of a fibronectin matrixJ Cell Sci2002 115609617
Not in our library10.1242/jcs.115.3.609
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Czirok A Zamir EA Filla MB Little CD Rongish BJ Extracellular matrix macroassembly dynamics in early vertebrate embryosCurr Top Dev Biol2006 73237258
Not in our library10.1016/s0070-2153(05)73008-8
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Kinsey R Williamson MR Chaudhry S Mellody KT McGovern A Takahashi S Shuttleworth CA Kielty CM Fibrillin-1 microfibril deposition is dependent on fibronectin assemblyJ Cell Sci2008 12126962704
Not in our library10.1242/jcs.029819
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Sabatier L Chen D Fagotto-Kaufmann C Hubmacher D McKee MD Annis DS Mosher DF Reinhardt DP Fibrillin assembly requires fibronectinMol Biol Cell2009 20846858
Not in our library10.1091/mbc.e08-08-0830
79.
Godyna S Mann DM Argraves WS A quantitative analysis of the incorporation of fibulin-1 into extracellular matrix indicates that fibronectin assembly is requiredMatrix Biol1995 14467477
Not in our library10.1016/0945-053x(95)90004-7
80.
Bazigou E Xie S Chen C Weston A Miura N Sorokin L Adams R Muro AF Sheppard D Makinen T Integrin-alpha9 is required for fibronectin matrix assembly during lymphatic valve morphogenesisDev Cell2009 17175186
Not in our library10.1016/j.devcel.2009.06.017
81.
Chung CY Zardi L Erickson HP Binding of tenascin-C to soluble fibronectin and matrix fibrilsJ Biol Chem1995 2702901229017
Not in our library10.1074/jbc.270.48.29012
82.
Ramos DM Chen B Regezi J Zardi L Pytela R Tenascin-C matrix assembly in oral squamous cell carcinomaInt J Cancer1998 75680687
Not in our library10.1002/(sici)1097-0215(19980302)75:5<680::aid-ijc4>3.0.co;2-v
83.
Huang G Zhang Y Kim B Ge G Annis DS Mosher DF Greenspan DS Fibronectin binds and enhances the activity of bone morphogenetic protein 1J Biol Chem2009 2842587925888
Not in our library10.1074/jbc.m109.024125
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Wijelath ES Rahman S Namekata M Murray J Nishimura T Mostafavi-Pour Z Patel Y Suda Y Humphries MJ Sobel M Heparin-II domain of fibronectin is a vascular endothelial growth factor-binding domain: enhancement of VEGF biological activity by a singular growth factor/matrix protein synergismCirc Res2006 99853860
Not in our library10.1161/01.res.0000246849.17887.66
85.
Dallas SL Chen Q Sivakumar P Dynamics of assembly and reorganization of extracellular matrix proteinsCurr Top Dev Biol2006 75124
Not in our library10.1016/s0070-2153(06)75001-3
86.
Koli K Hyytiainen M Ryynanen MJ Keski-Oja J Sequential deposition of latent TGF-beta binding proteins (LTBPs) during formation of the extracellular matrix in human lung fibroblastsExp Cell Res2005 310370382
Not in our library10.1016/j.yexcr.2005.08.008
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Sivakumar P Czirok A Rongish BJ Divakara VP Wang YP Dallas SL New insights into extracellular matrix assembly and reorganization from dynamic imaging of extracellular matrix proteins in living osteoblastsJ Cell Sci2006 11913501360
Not in our library10.1242/jcs.02830
88.
Sottile J Chandler J Fibronectin matrix turnover occurs through a caveolin-1-dependent processMol Biol Cell2005 16757768
Not in our library10.1091/mbc.e04-08-0672
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Serini G Bochaton-Piallat ML Ropraz P Geinoz A Borsi L Zardi L Gabbiani G The fibronectin domain ED-A is crucial for myofibroblastic phenotype induction by transforming growth factor-beta1J Cell Biol1998 142873881
Not in our library10.1083/jcb.142.3.873
90.
Muro AF Chauhan AK Gajovic S Iaconcig A Porro F Stanta G Baralle FE Regulated splicing of the fibronectin EDA exon is essential for proper skin wound healing and normal lifespanJ Cell Biol2003 162149160
Not in our library10.1083/jcb.200212079
91.
Hashimoto-Uoshima M Yan YZ Schneider G Aukhil I The alternatively spliced domains EIIIB and EIIIA of human fibronectin affect cell adhesion and spreadingJ Cell Sci1997 110Pt 1822712280
Not in our library10.1242/jcs.110.18.2271
92.
Chen W Culp LA Adhesion mediated by fibronectin's alternatively spliced EDb (EIIIB) and its neighboring type III repeatsExp Cell Res1996 223919
Not in our library10.1006/excr.1996.0053
93.
Fukuda T Yoshida N Kataoka Y Manabe R Mizuno-Horikawa Y Sato M Kuriyama K Yasui N Sekiguchi K Mice lacking the EDB segment of fibronectin develop normally but exhibit reduced cell growth and fibronectin matrix assembly in vitroCancer Res2002 6256035610
Not in our library
94.
Guan JL Trevithick JE Hynes RO Retroviral expression of alternatively spliced forms of rat fibronectinJ Cell Biol1990 110833847
Not in our library10.1083/jcb.110.3.833
95.
Singh P Reimer CL Peters JH Stepp MA Hynes RO Van De Water L The spatial and temporal expression patterns of integrin alpha9beta1 and one of its ligands, the EIIIA segment of fibronectin, in cutaneous wound healingJ Invest Dermatol2004 12311761181
Not in our library10.1111/j.0022-202x.2004.23485.x
96.
Kalluri R Basement membranes: structure, assembly and role in tumour angiogenesisNat Rev Cancer2003 3422433
Not in our library10.1038/nrc1094
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Fernandez-Sauze S Grall D Cseh B Van Obberghen-Schilling E Regulation of fibronectin matrix assembly and capillary morphogenesis in endothelial cells by Rho family GTPasesExp Cell Res2009 31520922104
Not in our library10.1016/j.yexcr.2009.03.017
98.
Jarnagin WR Rockey DC Koteliansky VE Wang SS Bissell DM Expression of variant fibronectins in wound healing: cellular source and biological activity of the EIIIA segment in rat hepatic fibrogenesisJ Cell Biol1994 12720372048
Not in our library10.1083/jcb.127.6.2037
99.
Clark RA An JQ Greiling D Khan A Schwarzbauer JE Fibroblast migration on fibronectin requires three distinct functional domainsJ Invest Dermatol2003 121695705
Not in our library10.1046/j.1523-1747.2003.12484.x
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Wakui S Furusato M Nikaido T Yokota K Sekiguchi J Ohmori K Kano Y Ushigome S Ultrastructural localization of fibronectin and laminin in human granulation tissue in relation to capillary developmentCell Struct Funct1990 15201210
Not in our library10.1247/csf.15.201
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Gui L Wojciechowski K Gildner CD Nedelkovska H Hocking DC Identification of the heparin-binding determinants within fibronectin repeat III1: role in cell spreading and growthJ Biol Chem2006 2813481634825
Not in our library10.1074/jbc.m608611200
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Jiang ST Chiang HC Cheng MH Yang TP Chuang WJ Tang MJ Role of fibronectin deposition in cystogenesis of Madin-Darby canine kidney cellsKidney Int1999 5692103
Not in our library10.1046/j.1523-1755.1999.00520.x
103.
Sechler JL Schwarzbauer JE Control of cell cycle progression by fibronectin matrix architectureJ Biol Chem1998 2732553325536
Not in our library10.1074/jbc.273.40.25533
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Couchman JR Rees DA Green MR Smith CG Fibronectin has a dual role in locomotion and anchorage of primary chick fibroblasts and can promote entry into the division cycleJ Cell Biol1982 93402410
Not in our library10.1083/jcb.93.2.402
105.
Hocking DC Chang CH Fibronectin matrix polymerization regulates small airway epithelial cell migrationAm J Physiol Lung Cell Mol Physiol2003 285L169179
Not in our library10.1152/ajplung.00371.2002
106.
Rozario T Dzamba B Weber GF Davidson LA DeSimone DW The physical state of fibronectin matrix differentially regulates morphogenetic movements in vivoDev Biol2009 327386398
Not in our library10.1016/j.ydbio.2008.12.025
107.
Natal C Oses-Prieto JA Pelacho B Iraburu MJ Lopez-Zabalza MJ Regulation of apoptosis by peptides of fibronectin in human monocytesApoptosis2006 11209219
Not in our library10.1007/s10495-006-3761-y
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Tafolla E Wang S Wong B Leong J Kapila YL JNK1 and JNK2 oppositely regulate p53 in signaling linked to apoptosis triggered by an altered fibronectin matrix: JNK links FAK and p53J Biol Chem2005 2801999219999
Not in our library10.1074/jbc.m500331200
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Zhou X Rowe RG Hiraoka N George JP Wirtz D Mosher DF Virtanen I Chernousov MA Weiss SJ Fibronectin fibrillogenesis regulates three-dimensional neovessel formationGenes Dev2008 2212311243
Not in our library10.1101/gad.1643308
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Kaczmarek J Castellani P Nicolo G Spina B Allemanni G Zardi L Distribution of oncofetal fibronectin isoforms in normal, hyperplastic and neoplastic human breast tissuesInt J Cancer1994 591116
Not in our library10.1002/ijc.2910590104
111.
Tomasek JJ Gabbiani G Hinz B Chaponnier C Brown RA Myofibroblasts and mechano-regulation of connective tissue remodellingNat Rev Mol Cell Biol2002 3349363
Not in our library10.1038/nrm809
112.
Gabbiani G The Evolution of the Myofibroblast Concept: a Key Cell for Wound Healing and fibrotic diseases. I processi di repiarazione e fibrosiGiornale di Gerontologia2004 52280282
Not in our library
113.
Hinz B Masters and servants of the force: the role of matrix adhesions in myofibroblast force perception and transmissionEur J Cell Biol2006 85175181
Not in our library10.1016/j.ejcb.2005.09.004
114.
Hinz B Phan SH Thannickal VJ Galli A Bochaton-Piallat ML Gabbiani G The myofibroblast: one function, multiple originsAm J Pathol2007 17018071816
Not in our library10.2353/ajpath.2007.070112
115.
Hayman EG Ruoslahti E Distribution of fetal bovine serum fibronectin and endogenous rat cell fibronectin in extracellular matrixJ Cell Biol1979 83255259
Not in our library10.1083/jcb.83.1.255
116.
Mao Y Schwarzbauer JE Stimulatory effects of a three-dimensional microenvironment on cell-mediated fibronectin fibrillogenesisJ Cell Sci2005 11844274436
Not in our library10.1242/jcs.02566
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Peters DM Portz LM Fullenwider J Mosher DF Co-assembly of plasma and cellular fibronectins into fibrils in human fibroblast culturesJ Cell Biol1990 111249256
Not in our library10.1083/jcb.111.1.249
118.
Tate CC Garcia AJ LaPlaca MC Plasma fibronectin is neuroprotective following traumatic brain injuryExp Neurol2007 2071322Epub 2007 May 2018
Not in our library10.1016/j.expneurol.2007.05.008
119.
Tan MH Sun Z Opitz SL Schmidt TE Peters JH George EL Deletion of the alternatively spliced fibronectin EIIIA domain in mice reduces atherosclerosisBlood2004 1041118Epub 2004 Feb 2019
Not in our library10.1182/blood-2003-09-3363
120.
Mosher DF Johnson RB Specificity of fibronectin-fibrin cross-linkingAnn N Y Acad Sci1983 408583594
Not in our library10.1111/j.1749-6632.1983.tb23275.x
121.
Force-Induced Unfolding of Fibronectin in the Extracellular Matrix of Living Cells · 2007
No notice
122.
Choi MG Hynes RO Biosynthesis and processing of fibronectin in NIL.8 hamster cellsJ Biol Chem1979 2541205012055
Not in our library
123.
McKeown-Longo PJ Mosher DF Binding of plasma fibronectin to cell layers of human skin fibroblastsJ Cell Biol1983 97466472
Not in our library10.1083/jcb.97.2.466
124.
Schwarzbauer JE Identification of the fibronectin sequences required for assembly of a fibrillar matrixJ Cell Biol1991 11314631473
Not in our library10.1083/jcb.113.6.1463
125.
Singh P Carraher C Schwarzbauer JE Assembly of fibronectin extracellular matrixAnnu Rev Cell Dev Biol26397419
Not in our library10.1146/annurev-cellbio-100109-104020
126.
Takahashi S Leiss M Moser M Ohashi T Kitao T Heckmann D Pfeifer A Kessler H Takagi J Erickson HP Fassler R The RGD motif in fibronectin is essential for development but dispensable for fibril assemblyJ Cell Biol2007 178167178
Not in our library10.1083/jcb.200703021
127.
Yang JT Rayburn H Hynes RO Embryonic mesodermal defects in alpha 5 integrin-deficient miceDevelopment1993 11910931105
Not in our library10.1242/dev.119.4.1093
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Lee SE Kamm RD Mofrad MR Force-induced activation of talin and its possible role in focal adhesion mechanotransductionJ Biomech2007 4020962106
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Ingham KC Brew SA Migliorini MM Busby TF Binding of heparin by type III domains and peptides from the carboxy terminal hep-2 region of fibronectinBiochemistry1993 321254812553
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Davidson LA Dzamba BD Keller R Desimone DW Live imaging of cell protrusive activity, and extracellular matrix assembly and remodeling during morphogenesis in the frog, Xenopus laevisDev Dyn2008 23726842692
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Yoneda A Ushakov D Multhaupt HA Couchman JR Fibronectin matrix assembly requires distinct contributions from Rho kinases I and -IIMol Biol Cell2007 186675
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Zhang Q Magnusson MK Mosher DF Lysophosphatidic acid and microtubule-destabilizing agents stimulate fibronectin matrix assembly through Rho-dependent actin stress fiber formation and cell contractionMol Biol Cell1997 814151425
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Brenner KA Corbett SA Schwarzbauer JE Regulation of fibronectin matrix assembly by activated Ras in transformed cellsOncogene2000 1931563163
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Marsden M DeSimone DW Integrin-ECM interactions regulate cadherin-dependent cell adhesion and are required for convergent extension in XenopusCurr Biol2003 1311821191
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Sechler JL Rao H Cumiskey AM Vega-Colon I Smith MS Murata T Schwarzbauer JE A novel fibronectin binding site required for fibronectin fibril growth during matrix assemblyJ Cell Biol2001 15410811088
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Maqueda A Moyano JV Hernandez Del Cerro M Peters DM Garcia-Pardo A The heparin III-binding domain of fibronectin (III4-5 repeats) binds to fibronectin and inhibits fibronectin matrix assemblyMatrix Biol2007 26642651
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Abe Y Bui-Thanh NA Ballantyne CM Burns AR Extra domain A and type III connecting segment of fibronectin in assembly and cleavageBiochem Biophys Res Commun2005 33816401647
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Chen Y Wu Y Cai J Atomic force microscopic investigation on the potential early intermediate stages of fibrillogenesis of fibronectin within fibrilsBiochem Biophys Res Commun2007 361391397
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Craig D Krammer A Schulten K Vogel V Comparison of the early stages of forced unfolding for fibronectin type III modulesProc Natl Acad Sci USA2001 9855905595
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Gao M Craig D Lequin O Campbell ID Vogel V Schulten K Structure and functional significance of mechanically unfolded fibronectin type III1 intermediatesProc Natl Acad Sci USA2003 1001478414789
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Oberhauser AF Badilla-Fernandez C Carrion-Vazquez M Fernandez JM The mechanical hierarchies of fibronectin observed with single-molecule AFMJ Mol Biol2002 319433447
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Hocking DC Sottile J McKeown-Longo PJ Fibronectin's III-1 module contains a conformation-dependent binding site for the amino-terminal region of fibronectinJ Biol Chem1994 2691918319187
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Hocking DC Smith RK McKeown-Longo PJ A novel role for the integrin-binding III-10 module in fibronectin matrix assemblyJ Cell Biol1996 133431444
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Morla A Zhang Z Ruoslahti E Superfibronectin is a functionally distinct form of fibronectinNature1994 367193196
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186.
Ingham KC Brew SA Huff S Litvinovich SV Cryptic self-association sites in type III modules of fibronectinJ Biol Chem1997 27217181724
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Bourdoulous S Orend G MacKenna DA Pasqualini R Ruoslahti E Fibronectin matrix regulates activation of RHO and CDC42 GTPases and cell cycle progressionJ Cell Biol1998 143267276
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Langenbach KJ Sottile J Identification of protein-disulfide isomerase activity in fibronectinJ Biol Chem1999 27470327038
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Chen H Mosher DF Formation of sodium dodecyl sulfate-stable fibronectin multimers. Failure to detect products of thiol-disulfide exchange in cyanogen bromide or limited acid digests of stabilized matrix fibronectinJ Biol Chem1996 27190849089
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Ohashi T Erickson HP Revisiting the mystery of fibronectin multimers: the fibronectin matrix is composed of fibronectin dimers cross-linked by non-covalent bondsMatrix Biol2009 28170175Epub 2009 Mar 2012
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De Jong KL MacLeod HC Norton PR Petersen NO Fibronectin organization under and near cellsEur Biophys J2006 35695708
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Ohashi T Kiehart DP Erickson HP Dynamics and elasticity of the fibronectin matrix in living cell culture visualized by fibronectin-green fluorescent proteinProc Natl Acad Sci USA1999 9621532158
Not in our library10.1073/pnas.96.5.2153
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Kubow KE Klotzsch E Smith ML Gourdon D Little WC Vogel V Crosslinking of cell-derived 3D scaffolds up-regulates the stretching and unfolding of new extracellular matrix assembled by reseeded cellsIntegr Biol (Camb)2009 1635648
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Klotzsch E Smith ML Kubow KE Muntwyler S Little WC Beyeler F Gourdon D Nelson BJ Vogel V Fibronectin forms the most extensible biological fibers displaying switchable force-exposed cryptic binding sitesProc Natl Acad Sci USA2009 1061826718272
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Antia M Baneyx G Kubow KE Vogel V Fibronectin in aging extracellular matrix fibrils is progressively unfolded by cells and elicits an enhanced rigidity responseFaraday Discuss2008 139229249discussion 309-225, 419-220
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Sakai T Larsen M Yamada KM Fibronectin requirement in branching morphogenesisNature2003 423876881
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Ongenae KC Phillips TJ Park HY Level of fibronectin mRNA is markedly increased in human chronic woundsDermatol Surg2000 26447451
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199.
Diegelmann RF Cellular and biochemical aspects of normal and abnormal wound healing: an overviewJ Urol1997 157298302
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van der Straaten HM Canninga-van Dijk MR Verdonck LF Castigliego D Borst HP Aten J Fijnheer R Extra-domain-A fibronectin: a new marker of fibrosis in cutaneous graft-versus-host diseaseJ Invest Dermatol2004 12310571062
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Muro AF Moretti FA Moore BB Yan M Atrasz RG Wilke CA Flaherty KR Martinez FJ Tsui JL Sheppard D An essential role for fibronectin extra type III domain A in pulmonary fibrosisAm J Respir Crit Care Med2008 177638645
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Barnes VL Musa J Mitchell RJ Barnes JL Expression of embryonic fibronectin isoform EIIIA parallels alpha-smooth muscle actin in maturing and diseased kidneyJ Histochem Cytochem1999 47787798
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Oomura A Nakamura T Arakawa M Ooshima A Isemura M Alterations in the extracellular matrix components in human glomerular diseasesVirchows Arch A Pathol Anat Histopathol1989 415151159
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Buyukbabani N Droz D Distribution of the extracellular matrix components in human glomerular lesionsJ Pathol1994 172199207
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Babu M Diegelmann R Oliver N Fibronectin is overproduced by keloid fibroblasts during abnormal wound healingMol Cell Biol1989 916421650
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Chin GS Liu W Steinbrech D Hsu M Levinson H Longaker MT Cellular signaling by tyrosine phosphorylation in keloid and normal human dermal fibroblastsPlast Reconstr Surg2000 10615321540
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McCarty SM Syed F Bayat A Influence of the human leukocyte antigen complex on the development of cutaneous fibrosis: an immunogenetic perspectiveActa Derm Venereol90563574
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Kischer CW Hendrix MJ Fibronectin (FN) in hypertrophic scars and keloidsCell Tissue Res1983 2312937
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Strutz F Muller GA Renal fibrosis and the origin of the renal fibroblastNephrol Dial Transplant2006 2133683370
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White ES Lazar MH Thannickal VJ Pathogenetic mechanisms in usual interstitial pneumonia/idiopathic pulmonary fibrosisJ Pathol2003 201343354
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White ES Baralle FE Muro AF New insights into form and function of fibronectin splice variantsJ Pathol2008 216114
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Leask A Abraham DJ TGF-beta signaling and the fibrotic responseFASEB J2004 18816827
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Tomasini-Johansson BR Kaufman NR Ensenberger MG Ozeri V Hanski E Mosher DF A 49-residue peptide from adhesin F1 of Streptococcus pyogenes inhibits fibronectin matrix assemblyJ Biol Chem2001 2762343023439Epub 22001 Apr 23425
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Kuo YR Wu WS Jeng SF Wang FS Huang HC Lin CZ Yang KD Suppressed TGF-beta1 expression is correlated with up-regulation of matrix metalloproteinase-13 in keloid regression after flashlamp pulsed-dye laser treatmentLasers Surg Med2005 363842
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Gabrielli A Avvedimento EV Krieg T SclerodermaN Engl J Med2009 36019892003
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Ihn H Scleroderma, fibroblasts, signaling, and excessive extracellular matrixCurr Rheumatol Rep2005 7156162
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Kusubata M Hirota A Ebihara T Kuwaba K Matsubara Y Sasaki T Kusakabe M Tsukada T Irie S Koyama Y Spatiotemporal changes of fibronectin, tenascin-C, fibulin-1, and fibulin-2 in the skin during the development of chronic contact dermatitisJ Invest Dermatol1999 113906912
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Grinnell F Zhu M Fibronectin degradation in chronic wounds depends on the relative levels of elastase, alpha1-proteinase inhibitor, and alpha2-macroglobulinJ Invest Dermatol1996 106335341
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Latijnhouwers MA Bergers M Veenhuis RT Beekman B Ankersmit-Ter Horst MF Schalkwijk J Tenascin-C degradation in chronic wounds is dependent on serine proteinase activityArch Dermatol Res1998 290490496
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Palolahti M Lauharanta J Stephens RW Kuusela P Vaheri A Proteolytic activity in leg ulcer exudateExp Dermatol1993 22937
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Rao CN Ladin DA Liu YY Chilukuri K Hou ZZ Woodley DT Alpha 1-antitrypsin is degraded and non-functional in chronic wounds but intact and functional in acute wounds: the inhibitor protects fibronectin from degradation by chronic wound fluid enzymesJ Invest Dermatol1995 105572578
Not in our library10.1111/1523-1747.ep12323503
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Trengove NJ Stacey MC MacAuley S Bennett N Gibson J Burslem F Murphy G Schultz G Analysis of the acute and chronic wound environments: the role of proteases and their inhibitorsWound Repair Regen1999 7442452
Not in our library10.1046/j.1524-475x.1999.00442.x
223.
Clark RAF The Molecular and Cellular Biology of Wound Repair1996 2New York, N. Y.: Plenum Pres
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224.
Shi F Sottile J Caveolin-1-dependent beta1 integrin endocytosis is a critical regulator of fibronectin turnoverJ Cell Sci2008 12123602371
Not in our library10.1242/jcs.014977
225.
Bravo-Cordero JJ Marrero-Diaz R Megias D Genis L Garcia-Grande A Garcia MA Arroyo AG Montoya MC MT1-MMP proinvasive activity is regulated by a novel Rab8-dependent exocytic pathwayEMBO J2007 2614991510
Not in our library10.1038/sj.emboj.7601606
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Zheng M Ambesi A Yu L McKeown-Longo PJ Quantification of fibronectin matrix assembly sites using a novel ELISA assayMatrix Biol2007 26330333
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227.
Rivera-Torres A Fibronectin matrix assembly: localization of β1 integrin and effects of laminin on formation of 70-kda fragment linear arrays or fibronectin fibrilsIntegrated Biological Sciences Summer Research Program2001 University of Wisconsin
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228.
Hocking DC Sottile J Reho T Fassler R McKeown-Longo PJ Inhibition of fibronectin matrix assembly by the heparin-binding domain of vitronectinJ Biol Chem1999 2742725727264
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Sabatelli P Bonaldo P Lattanzi G Braghetta P Bergamin N Capanni C Mattioli E Columbaro M Ognibene A Pepe G Collagen VI deficiency affects the organization of fibronectin in the extracellular matrix of cultured fibroblastsMatrix Biol2001 20475486
Not in our library10.1016/s0945-053x(01)00160-3
230.
To WS Midwood KS Cryptic domains of tenascin-C differentially control fibronectin fibrillogenesisMatrix Biol2010
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231.
To WS Midwood KS Identification of novel and distinct binding sites within tenascin-C for soluble and fibrillar fibronectinJ Biol Chem
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232.
Hospenthal MA Diagnosis and management of idiopathic pulmonary fibrosis: Implications for respiratory careRespir Care2006 51382391
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233.
Horan GS Wood S Ona V Li DJ Lukashev ME Weinreb PH Simon KJ Hahm K Allaire NE Rinaldi NJ Partial inhibition of integrin alpha(v)beta6 prevents pulmonary fibrosis without exacerbating inflammationAm J Respir Crit Care Med2008 1775665
Not in our library10.1164/rccm.200706-805oc
234.
Maher TM Wells AU Optimal treatment for idiopathic pulmonary fibrosisThorax2008 6311201121author reply 1121
Not in our library10.1136/thx.2008.102566
235.
McCormick LL Zhang Y Tootell E Gilliam AC Anti-TGF-beta treatment prevents skin and lung fibrosis in murine sclerodermatous graft-versus-host disease: a model for human sclerodermaJ Immunol1999 16356935699
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236.
Denton CP Merkel PA Furst DE Khanna D Emery P Hsu VM Silliman N Streisand J Powell J Akesson A Recombinant human anti-transforming growth factor beta1 antibody therapy in systemic sclerosis: a multicenter, randomized, placebo-controlled phase I/II trial of CAT-192Arthritis Rheum2007 56323333
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Fujimoto T Fujigaki Y Sun DF Togawa A Yonemura K Hishida A Important role for fibronectin-EIIIA during renal tubular repair and cellular recovery in uranyl acetate-induced acute renal failure of ratsVirchows Arch2003 443194205
Not in our library10.1007/s00428-003-0846-7
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Maniscalco WM Watkins RH Chess PR Sinkin RA Horowitz S Toia L Cell-specific expression of fibronectin and EIIIA and EIIIB splice variants after oxygen injuryAm J Physiol1998 274L599609
Not in our library10.1152/ajplung.1998.274.4.l599
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Havrlikova K Mellott M Kaufman AH Loredo GA Peters JH Colvin RB Foster CS Expression of fibronectin isoforms bearing the alternatively spliced EIIIA, EIIIB, and V segments in corneal alkali burn and keratectomy wound models in the ratCornea2004 23812818
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Tominaga K Higuchi K Watanabe T Fujiwara Y Kim S Arakawa T Iwao H Kuroki T Expression of gene for EIIIA- and EIIIB- fibronectin, fetal types of fibronectin, during gastric ulcer healing in ratsDig Dis Sci2001 46311317
Not in our library10.1023/a:1005541305255
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Vitale AT Pedroza-Seres M Arrunategui-Correa V Lee SJ DiMeo S Foster CS Colvin RB Differential expression of alternatively spliced fibronectin in normal and wounded rat corneal stroma versus epitheliumInvest Ophthalmol Vis Sci1994 3536643672
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Matsui S Takahashi T Oyanagi Y Takahashi S Boku S Takahashi K Furukawa K Arai F Asakura H Expression, localization and alternative splicing pattern of fibronectin messenger RNA in fibrotic human liver and hepatocellular carcinomaJ Hepatol1997 27843853
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Carnemolla B Balza E Siri A Zardi L Nicotra MR Bigotti A Natali PG A tumor-associated fibronectin isoform generated by alternative splicing of messenger RNA precursorsJ Cell Biol1989 10811391148
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Birchler MT Milisavlijevic D Pfaltz M Neri D Odermatt B Schmid S Stoeckli SJ Expression of the extra domain B of fibronectin, a marker of angiogenesis, in head and neck tumorsLaryngoscope2003 11312311237
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Kosmehl H Berndt A Strassburger S Borsi L Rousselle P Mandel U Hyckel P Zardi L Katenkamp D Distribution of laminin and fibronectin isoforms in oral mucosa and oral squamous cell carcinomaBr J Cancer1999 8110711079
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Mhawech P Dulguerov P Assaly M Ares C Allal AS EB-D fibronectin expression in squamous cell carcinoma of the head and neckOral Oncol2005 418288
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247.
Astrof S Crowley D George EL Fukuda T Sekiguchi K Hanahan D Hynes RO Direct test of potential roles of EIIIA and EIIIB alternatively spliced segments of fibronectin in physiological and tumor angiogenesisMol Cell Biol2004 2486628670
Not in our library10.1128/mcb.24.19.8662-8670.2004
248.
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Not in our library10.1016/s0959-8049(98)00041-0
249.
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Not in our library10.1161/01.hyp.20.1.20
251.
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Not in our library10.1242/jcs.00670
252.
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Not in our library10.1021/bi010503x
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Not in our library10.1093/emboj/18.5.1345
254.
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Not in our library10.1152/ajprenal.00013.2006
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Not in our library
256.
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Not in our library10.1006/cbir.1995.1096
257.
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Not in our library10.1006/excr.1998.4107
258.
Lam S Verhagen NA Strutz F van der Pijl JW Daha MR van Kooten C Glucose-induced fibronectin and collagen type III expression in renal fibroblasts can occur independent of TGF-beta1Kidney Int2003 63878888
Not in our library10.1046/j.1523-1755.2003.00824.x
259.
Oh JH Ha H Yu MR Lee HB Sequential effects of high glucose on mesangial cell transforming growth factor-beta 1 and fibronectin synthesisKidney Int1998 5418721878
Not in our library10.1046/j.1523-1755.1998.00193.x
260.
Oliver N Babu M Diegelmann R Fibronectin gene transcription is enhanced in abnormal wound healingJ Invest Dermatol1992 99579586
Not in our library10.1111/1523-1747.ep12667776
261.
Zhang Q Peyruchaud O French KJ Magnusson MK Mosher DF Sphingosine 1-phosphate stimulates fibronectin matrix assembly through a Rho-dependent signal pathwayBlood1999 9329842990
Not in our library
262.
Quinn JA Graeber CT Frackelton AR Jr Kim M Schwarzbauer JE Filardo EJ Coordinate regulation of estrogen-mediated fibronectin matrix assembly and epidermal growth factor receptor transactivation by the G protein-coupled receptor, GPR30Mol Endocrinol2009 2310521064
Not in our library10.1210/me.2008-0262
263.
Vial D Monaghan-Benson E McKeown-Longo PJ Coordinate regulation of fibronectin matrix assembly by the plasminogen activator system and vitronectin in human osteosarcoma cellsCancer Cell Int2006 68
Not in our library10.1186/1475-2867-6-8
264.
Vial D McKeown-Longo PJ PAI1 stimulates assembly of the fibronectin matrix in osteosarcoma cells through crosstalk between the alphavbeta5 and alpha5beta1 integrinsJ Cell Sci2008 12116611670
Not in our library10.1242/jcs.020149
265.
Monaghan-Benson E Mastick CC McKeown-Longo PJ A dual role for caveolin-1 in the regulation of fibronectin matrix assembly by uPARJ Cell Sci2008 12136933703
Not in our library10.1242/jcs.028423
266.
Weston BS Wahab NA Mason RM CTGF mediates TGF-beta-induced fibronectin matrix deposition by upregulating active alpha5beta1 integrin in human mesangial cellsJ Am Soc Nephrol2003 14601610
Not in our library10.1097/01.asn.0000051600.53134.b9

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