Special Issue "Fibronectin in Health and Diseases"

A special issue of Cells (ISSN 2073-4409).

Deadline for manuscript submissions: closed (30 November 2019).

Special Issue Editors

Prof. Matthew A Nugent
E-Mail Website
Guest Editor
Department of Biological Sciences, University of Massachusetts Lowell, Olney Science Center, Lowell, MA 01854, USA
Interests: extracellular matrix; cardiovascular disease; cancer; cell biology; growth factors; enzymology; lung disease; COPD
Dr. Michael L. Smith
E-Mail Website
Guest Editor
Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA
Interests: matrix mechanotransduction; extracellular matrix; fibronectin
Dr. Maria Mitsi
E-Mail Website
Guest Editor
Laboratory of Food and Soft Materials, ETH Zurich, 8092 Zurich, Switzerland
Interests: extracellular matrix; fibronectin; growth factors; angiogenesis; structural biology

Special Issue Information

Dear Colleagues,

Fibronectin is a large multimodular protein, which is incorporated in a fibrillar form in the extracellular matrix of almost every cell type. It is a major substrate for cell adhesion and migration and plays important roles in a large number of physiological processes, including wound healing and tissue regeneration, neovascularization, and embryonic development. Thus, fibronectin has been implicated in many diseases where such physiological processes are dysregulated. The ability of fibronectin to carry all these diverse functionalities depends on interactions with a large number of molecules, including adhesive and signaling cell surface receptors, other components of the extracellular matrix, and growth factors and cytokines. The regulation and integration of such a large number of interactions depends on the modular architecture and flexibility of fibronectin, which allows a large number of conformations, exposing or destroying different binding sites. Both biochemical and mechanical factors have the ability to regulate fibronectin conformation and alter fibronectin functionality.

The aim of this Special Issue is to summarize our current knowledge of the role of fibronectin in health and disease and highlight the underlying mechanisms at the cellular and molecular level. Emphasis will be given on the biochemical and mechanical forces that regulate fibronectin conformation, affect its binding partners, and lead to the activation of biochemical pathways that control cell behavior. Furthermore, an overview of the use of fibronectin in various therapeutic approaches will be given, especially the design of fibronectin-based scaffolds for tissue engineering applications. We hope that such a Special Issue will provide valuable information to the scientific community, help to identify open questions, and drive the field forward.

Prof. Matthew A Nugent
Dr. Michael L. Smith
Dr. Maria Mitsi
Guest Editors

Manuscript Submission Information

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Keywords

  • fibronectin
  • conformational flexibility
  • binding sites
  • mechanical forces
  • scaffolds
  • tissue engineering

Published Papers (8 papers)

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Research

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Open AccessArticle
Extracellular Matrix Structure and Composition in the Early Four-Chambered Embryonic Heart
Cells 2020, 9(2), 285; https://doi.org/10.3390/cells9020285 (registering DOI) - 24 Jan 2020
Abstract
During embryonic development, the heart undergoes complex morphogenesis from a liner tube into the four chambers consisting of ventricles, atria and valves. At the same time, the cardiomyocytes compact into a dense, aligned, and highly vascularized myocardium. The extracellular matrix (ECM) is known [...] Read more.
During embryonic development, the heart undergoes complex morphogenesis from a liner tube into the four chambers consisting of ventricles, atria and valves. At the same time, the cardiomyocytes compact into a dense, aligned, and highly vascularized myocardium. The extracellular matrix (ECM) is known to play an important role in this process but understanding of the expression and organization remains incomplete. Here, we performed 3D confocal imaging of ECM in the left ventricle and whole heart of embryonic chick from stages Hamburger-Hamilton 28–35 (days 5–9) as an accessible model of heart formation. First, we observed the formation of a fibronectin-rich, capillary-like networks in the myocardium between day 5 and day 9 of development. Then, we focused on day 5 prior to vascularization to determine the relative expression of fibronectin, laminin, and collagen type IV. Cardiomyocytes were found to uniaxially align prior to vascularization and, while the epicardium contained all ECM components, laminin was reduced, and collagen type IV was largely absent. Quantification of fibronectin revealed highly aligned fibers with a mean diameter of ~500 nm and interfiber spacing of ~3 µm. These structural parameters (volume, spacing, fiber diameter, length, and orientation) provide a quantitative framework to describe the organization of the embryonic ECM. Full article
(This article belongs to the Special Issue Fibronectin in Health and Diseases)
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Open AccessArticle
HSP90 Interacts with the Fibronectin N-terminal Domains and Increases Matrix Formation
Cells 2020, 9(2), 272; https://doi.org/10.3390/cells9020272 - 22 Jan 2020
Abstract
Heat shock protein 90 (HSP90) is an evolutionarily conserved chaperone protein that controls the function and stability of a wide range of cellular client proteins. Fibronectin (FN) is an extracellular client protein of HSP90, and exogenous HSP90 or inhibitors of HSP90 alter the [...] Read more.
Heat shock protein 90 (HSP90) is an evolutionarily conserved chaperone protein that controls the function and stability of a wide range of cellular client proteins. Fibronectin (FN) is an extracellular client protein of HSP90, and exogenous HSP90 or inhibitors of HSP90 alter the morphology of the extracellular matrix. Here, we further characterized the HSP90 and FN interaction. FN bound to the M domain of HSP90 and interacted with both the open and closed HSP90 conformations; and the interaction was reduced in the presence of sodium molybdate. HSP90 interacted with the N-terminal regions of FN, which are known to be important for matrix assembly. The highest affinity interaction was with the 30-kDa (heparin-binding) FN fragment, which also showed the greatest colocalization in cells and accommodated both HSP90 and heparin in the complex. The strength of interaction with HSP90 was influenced by the inherent stability of the FN fragments, together with the type of motif, where HSP90 preferentially bound the type-I FN repeat over the type-II repeat. Exogenous extracellular HSP90 led to increased incorporation of both full-length and 70-kDa fragments of FN into fibrils. Together, our data suggested that HSP90 may regulate FN matrix assembly through its interaction with N-terminal FN fragments. Full article
(This article belongs to the Special Issue Fibronectin in Health and Diseases)
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Open AccessArticle
Fibronectin and Periostin as Prognostic Markers in Ovarian Cancer
Cells 2020, 9(1), 149; https://doi.org/10.3390/cells9010149 - 08 Jan 2020
Abstract
Previously, based on a DNA microarray experiment, we identified a 96-gene prognostic signature associated with the shorter survival of ovarian cancer patients. We hypothesized that some differentially expressed protein-coding genes from this signature could potentially serve as prognostic markers. The present study was [...] Read more.
Previously, based on a DNA microarray experiment, we identified a 96-gene prognostic signature associated with the shorter survival of ovarian cancer patients. We hypothesized that some differentially expressed protein-coding genes from this signature could potentially serve as prognostic markers. The present study was aimed to validate two proteins, namely fibronectin (FN1) and periostin (POSTN), in the independent set of ovarian cancer samples. Both proteins are mainly known as extracellular matrix proteins with many important functions in physiology. However, there are also indications that they are implicated in cancer, including ovarian cancer. The expression of these proteins was immunohistochemically analyzed in 108 surgical samples of advanced ovarian cancer (majority: high-grade serous) and additionally on tissue arrays representing different stages of the progression of ovarian and fallopian tube epithelial tumors, from normal epithelia, through benign tumors, to adenocarcinomas of different stages. The correlation with clinical, pathological, and molecular features was evaluated. Kaplan–Meier survival analysis and Cox-proportional hazards models were used to estimate the correlation of the expression levels these proteins with survival. We observed that the higher expression of fibronectin in the tumor stroma was highly associated with shorter overall survival (OS) (Kaplan–Meier analysis, log-rank test p = 0.003). Periostin was also associated with shorter OS (p = 0.04). When we analyzed the combined score, calculated by adding together individual scores for stromal fibronectin and periostin expression, Cox regression demonstrated that this joint FN1&POSTN score was an independent prognostic factor for OS (HR = 2.16; 95% CI: 1.02–4.60; p = 0.044). The expression of fibronectin and periostin was also associated with the source of ovarian tumor sample: metastases showed higher expression of these proteins than primary tumor samples (χ2 test, p = 0.024 and p = 0.032). Elevated expression of fibronectin and periostin was also more common in fallopian cancers than in ovarian cancers. Our results support some previous observations that fibronectin and periostin have a prognostic significance in ovarian cancer. In addition, we propose the joint FN1&POSTN score as an independent prognostic factor for OS. Based on our results, it may also be speculated that these proteins are related to tumor progression and/or may indicate fallopian–epithelial origin of the tumor. Full article
(This article belongs to the Special Issue Fibronectin in Health and Diseases)
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Open AccessArticle
A Matricryptic Conformation of the Integrin-Binding Domain of Fibronectin Regulates Platelet-Derived Growth Factor-Induced Intracellular Calcium Release
Cells 2019, 8(11), 1351; https://doi.org/10.3390/cells8111351 - 30 Oct 2019
Abstract
Platelet-derived growth factor (PDGF) signaling is dysregulated in a wide variety of diseases, making PDGF an attractive therapeutic target. However, PDGF also affects numerous signaling cascades essential for tissue homeostasis, limiting the development of PDGF-based therapies that lack adverse side-effects. Recent studies showed [...] Read more.
Platelet-derived growth factor (PDGF) signaling is dysregulated in a wide variety of diseases, making PDGF an attractive therapeutic target. However, PDGF also affects numerous signaling cascades essential for tissue homeostasis, limiting the development of PDGF-based therapies that lack adverse side-effects. Recent studies showed that fibroblast-mediated assembly of extracellular matrix (ECM) fibronectin fibrils attenuates PDGF-induced intracellular calcium release by selectively inhibiting phosphoinositol 3-kinase (PI3K) activation while leaving other PDGF-mediated signaling cascades intact. In the present study, a series of recombinant fibronectin-derived fusion proteins were used to localize the sequences in fibronectin that are responsible for this inhibition. Results demonstrate that attenuation of PDGF-induced intracellular calcium release by the fibronectin matrix mimetic, FNIII1H,8-10 requires α5β1 integrin ligation, but is not dependent upon the matricryptic, heparin-binding site of FNIII1. Intact cell-binding fibronectin fragments were also unable to attenuate PDGF-induced intracellular calcium release. In contrast, a novel integrin-binding fragment that adopts an extended and aligned conformational state, inhibited both PI3K activation and intracellular calcium release in response to PDGF. Taken together, these studies provide evidence that attenuation of PDGF-induced intracellular calcium release by fibronectin is mediated by a novel conformation of the α5β1 integrin-binding, FNIII9-10 modules, that is expressed by fibrillar fibronectin. Full article
(This article belongs to the Special Issue Fibronectin in Health and Diseases)
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Review

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Open AccessReview
Profile of Matrix-Remodeling Proteinases in Osteoarthritis: Impact of Fibronectin
Cells 2020, 9(1), 40; https://doi.org/10.3390/cells9010040 - 22 Dec 2019
Abstract
The extracellular matrix (ECM) is a complex and specialized three-dimensional macromolecular network, present in nearly all tissues, that also interacts with cell surface receptors on joint resident cells. Changes in the composition and physical properties of the ECM lead to the development of [...] Read more.
The extracellular matrix (ECM) is a complex and specialized three-dimensional macromolecular network, present in nearly all tissues, that also interacts with cell surface receptors on joint resident cells. Changes in the composition and physical properties of the ECM lead to the development of many diseases, including osteoarthritis (OA). OA is a chronic degenerative rheumatic disease characterized by a progressive loss of synovial joint function as a consequence of the degradation of articular cartilage, also associated with alterations in the synovial membrane and subchondral bone. During OA, ECM-degrading enzymes, including urokinase-type plasminogen activator (uPA), matrix metalloproteinases (MMPs), and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs), cleave ECM components, such as fibronectin (Fn), generating fibronectin fragments (Fn-fs) with catabolic properties. In turn, Fn-fs promote activation of these proteinases, establishing a degradative and inflammatory feedback loop. Thus, the aim of this review is to update the contribution of ECM-degrading proteinases to the physiopathology of OA as well as their modulation by Fn-fs. Full article
(This article belongs to the Special Issue Fibronectin in Health and Diseases)
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Open AccessReview
Fibronectin in Cancer: Friend or Foe
Cells 2020, 9(1), 27; https://doi.org/10.3390/cells9010027 - 20 Dec 2019
Cited by 1
Abstract
The role of fibronectin (FN) in tumorigenesis and malignant progression has been highly controversial. Cancerous FN plays a tumor-suppressive role, whereas it is pro-metastatic and associated with poor prognosis. Interestingly, FN matrix deposited in the tumor microenvironments (TMEs) promotes tumor progression but is [...] Read more.
The role of fibronectin (FN) in tumorigenesis and malignant progression has been highly controversial. Cancerous FN plays a tumor-suppressive role, whereas it is pro-metastatic and associated with poor prognosis. Interestingly, FN matrix deposited in the tumor microenvironments (TMEs) promotes tumor progression but is paradoxically related to a better prognosis. Here, we justify how FN impacts tumor transformation and subsequently metastatic progression. Next, we try to reconcile and rationalize the seemingly conflicting roles of FN in cancer and TMEs. Finally, we propose future perspectives for potential FN-based therapeutic strategies. Full article
(This article belongs to the Special Issue Fibronectin in Health and Diseases)
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Open AccessReview
Role of Fibronectin in Primary Open Angle Glaucoma
Cells 2019, 8(12), 1518; https://doi.org/10.3390/cells8121518 - 26 Nov 2019
Abstract
Primary open angle glaucoma (POAG) is the most common form of glaucoma and the 2nd most common cause of irreversible vision loss in the United States. Nearly 67 million people have the disease worldwide including >3 million in the United States. A major [...] Read more.
Primary open angle glaucoma (POAG) is the most common form of glaucoma and the 2nd most common cause of irreversible vision loss in the United States. Nearly 67 million people have the disease worldwide including >3 million in the United States. A major risk factor for POAG is an elevation in intraocular pressure (IOP). The increase in IOP is believed to be caused by an increase in the deposition of extracellular matrix proteins, in particular fibronectin, in a region of the eye known as the trabecular meshwork (TM). How fibronectin contributes to the increase in IOP is not well understood. The increased density of fibronectin fibrils is thought to increase IOP by altering the compliance of the trabecular meshwork. Recent studies, however, also suggest that the composition and organization of fibronectin fibrils would affect IOP by changing the cell-matrix signaling events that control the functional properties of the cells in the trabecular meshwork. In this article, we will discuss how changes in the properties of fibronectin and fibronectin fibrils could contribute to the regulation of IOP. Full article
(This article belongs to the Special Issue Fibronectin in Health and Diseases)
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Open AccessFeature PaperReview
Fibronectin and Its Role in Human Infective Diseases
Cells 2019, 8(12), 1516; https://doi.org/10.3390/cells8121516 - 26 Nov 2019
Abstract
Fibronectin is a multidomain glycoprotein ubiquitously detected in extracellular fluids and matrices of a variety of animal and human tissues where it functions as a key link between matrices and cells. Fibronectin has also emerged as the target for a large number of [...] Read more.
Fibronectin is a multidomain glycoprotein ubiquitously detected in extracellular fluids and matrices of a variety of animal and human tissues where it functions as a key link between matrices and cells. Fibronectin has also emerged as the target for a large number of microorganisms, particularly bacteria. There are clear indications that the binding of microorganism’ receptors to fibronectin promotes attachment to and infection of host cells. Each bacterium may use different receptors which recognize specific fibronectin domains, mostly the N-terminal domain and the central cell-binding domain. In many cases, fibronectin receptors have actions over and above that of simple adhesion: In fact, adhesion is often the prerequisite for invasion and internalization of microorganisms in the cells of colonized tissues. This review updates the current understanding of fibronectin receptors of several microorganisms with emphasis on their biochemical and structural properties and the role they can play in the onset and progression of host infection diseases. Furthermore, we describe the antigenic profile and discuss the possibility of designing adhesion inhibitors based on the structure of the fibronectin-binding site in the receptor or the receptor-binding site in fibronectin. Full article
(This article belongs to the Special Issue Fibronectin in Health and Diseases)
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