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The Role of Extracellular Matrix in Human Health and Disease

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 August 2023) | Viewed by 15428

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Special Issue Editor

Dr. Cornelia Tolg

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Guest Editor

London Regional Cancer Program, London Health Sciences Centre, Victoria Hospital, London, ON, Canada
Interests: hyaluronan; RHAMM; CD44; wound repair; fibrosis; breast cancer

Special Issue Information

Dear Colleagues,

The extracellular matrix (ECM) is not only a three-dimensional scaffold for residing cells, it is also an important part of the dynamic microenvironment and influences many aspects of cell biology and tissue function. Glycosaminoglycans (GAGs), including hyaluronan, chondroitin sulfates, heparan sulfates, dermatan sulfates and keratan sulfates, form complex networks that interact and communicate with cells via cell surface receptors or other ECM components and play important roles in physiological and pathological processes.

Injury-induced fibrosis, the abnormal deregulated production of extracellular matrix interfering with organ function, is only one example of a pathological process that is driven by aberrant GAG biology. For example, aberrant signaling via the hyaluronan receptor RHAMM (HMMR) plays an important role in skin or lung injury-induced fibrosis.

Other examples of processes that are affected by GAG functions are wound repair, degenerative disorders such as osteoarthritis, rheumatoid arthritis, neurogenerative disorders, viral infection, and aging. The genetic disease mucopolysaccharidosis, a lysosomal storage disorder, is caused by mutations in GAG-degrading enzymes.

Although pathologies associated with GAG function are generally not lethal, they have profound negative consequences on the quality of life and treatment strategies for GAG-based pathologies are only beginning to be explored.

This Special Issue highlights GAG biology in the context of disease and treatment.

Dr. Cornelia Tolg
Guest Editor

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Keywords

extracellular matrix
glycosaminoglycans
hyaluronan
chondroitin sulfate
heparan sulfate
dermatan sulfate
keratan sulfate
RHAMM
fibrosis
osteoarthritis
rheumatoid arthritis
neurogenerative disorders
viral infection
aging
mucopolysaccharidosis

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Published Papers (6 papers)

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Research

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16 pages, 1590 KiB

Open AccessArticle

Chemokine Binding to Tenascin-C Influences Chemokine-Induced Immune Cell Migration

by Alissa Domaingo, Philipp Jokesch, Alexandra Schweiger, Martha Gschwandtner, Tanja Gerlza, Manuel Koch, Kim S. Midwood and Andreas J. Kungl

Int. J. Mol. Sci. 2023, 24(19), 14694; https://doi.org/10.3390/ijms241914694 - 28 Sep 2023

Cited by 2 | Viewed by 1249

Abstract

Tenascin-C (TNC) is a complex glycoprotein of the extracellular matrix (ECM) involved in a plethora of (patho-)physiological processes, such as oncogenesis and inflammation. Since chemokines play an essential role in both disease processes, we have investigated here the binding of TNC to some of the key chemokines, namely CCL2, CCL26, CXCL8, CXCL10, and CXCL12. Thereby, a differential chemokine-TNC binding pattern was observed, with CCL26 exhibiting the highest and CCL2 the lowest affinity for TNC. Heparan sulfate (HS), another member of the ECM, proved to be a similarly high-affinity ligand of TNC, with a Kd value of 730 nM. Chemokines use glycosa-minoglycans such as HS as co-receptors to induce immune cell migration. Therefore, we assumed an influence of TNC on immune cell chemotaxis due to co-localization within the ECM. CCL26- and CCL2-induced mobilization experiments of eosinophils and monocytes, respectively, were thus performed in the presence and the absence of TNC. Pre-incubation of the immune cells with TNC resulted in a 3.5-fold increase of CCL26-induced eosinophil chemotaxis, whereas a 1.3-fold de-crease in chemotaxis was observed when monocytes were pre-incubated with CCL2. As both chemokines have similar HS binding but different TNC binding affinities, we speculate that TNC acts as an attenuator in monocyte and as an amplifier in eosinophil mobilization by impeding CCL2 from binding to HS on the one hand, and by reinforcing CCL26 to bind to HS on the other hand. Full article

(This article belongs to the Special Issue The Role of Extracellular Matrix in Human Health and Disease)

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24 pages, 4727 KiB

Open AccessArticle

Investigating Chemokine-Matrix Networks in Breast Cancer: Tenascin-C Sets the Tone for CCL2

by Martha Gschwandtner, Anís N. Gammage, Claire Deligne, Linda F. M. Mies, Alissa Domaingo, Devardarssen Murdamoothoo, Thomas Loustau, Anja Schwenzer, Rupert Derler, Raphael Carapito, Manuel Koch, Matthias Mörgelin, Gertraud Orend, Andreas J. Kungl and Kim S. Midwood

Int. J. Mol. Sci. 2023, 24(9), 8365; https://doi.org/10.3390/ijms24098365 - 6 May 2023

Cited by 3 | Viewed by 2684

Abstract

Bidirectional dialogue between cellular and non-cellular components of the tumor microenvironment (TME) drives cancer survival. In the extracellular space, combinations of matrix molecules and soluble mediators provide external cues that dictate the behavior of TME resident cells. Often studied in isolation, integrated cues from complex tissue microenvironments likely function more cohesively. Here, we study the interplay between the matrix molecule tenascin-C (TNC) and chemokine CCL2, both elevated in and associated with the progression of breast cancer and playing key roles in myeloid immune responses. We uncover a correlation between TNC/CCL2 tissue levels in HER2+ breast cancer and examine the physical and functional interactions of these molecules in a murine disease model with tunable TNC levels and in in vitro cellular and cell-free models. TNC supported sustained CCL2 synthesis, with chemokine binding to TNC via two distinct domains. TNC dominated the behavior of tumor-resident myeloid cells; CCL2 did not impact macrophage survival/activation whilst TNC facilitated an immune suppressive macrophage phenotype that was not dependent on or altered by CCL2 co-expression. Together, these data map new binding partners within the TME and demonstrate that whilst the matrix exerts transcriptional control over the chemokine, each plays a distinct role in subverting anti-tumoral immunity. Full article

(This article belongs to the Special Issue The Role of Extracellular Matrix in Human Health and Disease)

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15 pages, 20531 KiB

Open AccessArticle

Spatial Gradients of E-Cadherin and Fibronectin in TGF-β1-Treated Epithelial Colonies Are Independent of Fibronectin Fibril Assembly

by Lauren A. Griggs and Christopher A. Lemmon

Int. J. Mol. Sci. 2023, 24(7), 6679; https://doi.org/10.3390/ijms24076679 - 3 Apr 2023

Cited by 1 | Viewed by 1382

Abstract

Epithelial to Mesenchymal Transition (EMT) is a dynamic, morphogenetic process characterized by a phenotypic shift in epithelial cells towards a motile and often invasive mesenchymal phenotype. We have previously demonstrated that EMT is associated with an increase in assembly of the extracellular matrix [...] Read more.

β

1 (TGF-

β

1) localizes to FN fibrils, and disruption of FN assembly or disruption of TGF-

β

1 localization to FN fibrils attenuates EMT. Previous studies have shown that TGF-

β

1 induces spatial gradients of EMT in mammary epithelial cells cultured on FN islands, with cells at free edges of the island preferentially undergoing EMT. In the current work, we sought to investigate: (a) whether FN fibril assembly is also spatially patterned in response to TGF-

β

1, and (b) what effects FN fibril inhibition has on spatial gradients of E-Cadherin and FN fibrillogenesis. We demonstrate that mammary epithelial cells cultured on square micropatterns have fewer E-Cadherin-containing adherens junctions and assemble more FN fibrils at the periphery of the micropattern in response to increasing TGF-

β

1 concentration, indicating that TGF-

β

1 induces a spatial gradient of both E-Cadherin and FN fibrils. Inhibition of FN fibril assembly globally diminished E-Cadherin-containing adherens junctions and FN fibrillogenesis, but did not eliminate the spatial gradient of either. This suggests that global inhibition of FN reduces the degree of both FN fibrillogenesis and E-Cadherin-containing adherens junctions, but does not eliminate the spatial gradient of either, suggesting that spatial gradients of EMT and FN fibrillogenesis are influenced by additional factors. Full article

(This article belongs to the Special Issue The Role of Extracellular Matrix in Human Health and Disease)

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19 pages, 4085 KiB

Open AccessArticle

Extracellular Matrix Changes in Subcellular Brain Fractions and Cerebrospinal Fluid of Alzheimer’s Disease Patients

by Lukas Höhn, Wilhelm Hußler, Anni Richter, Karl-Heinz Smalla, Anna-Maria Birkl-Toeglhofer, Christoph Birkl, Stefan Vielhaber, Stefan L. Leber, Eckart D. Gundelfinger, Johannes Haybaeck, Stefanie Schreiber and Constanze I. Seidenbecher

Int. J. Mol. Sci. 2023, 24(6), 5532; https://doi.org/10.3390/ijms24065532 - 14 Mar 2023

Cited by 6 | Viewed by 3059

Abstract

The brain’s extracellular matrix (ECM) is assumed to undergo rearrangements in Alzheimer’s disease (AD). Here, we investigated changes of key components of the hyaluronan-based ECM in independent samples of post-mortem brains (N = 19), cerebrospinal fluids (CSF; N = 70), and RNAseq data (N = 107; from The Aging, Dementia and TBI Study) of AD patients and non-demented controls. Group comparisons and correlation analyses of major ECM components in soluble and synaptosomal fractions from frontal, temporal cortex, and hippocampus of control, low-grade, and high-grade AD brains revealed a reduction in brevican in temporal cortex soluble and frontal cortex synaptosomal fractions in AD. In contrast, neurocan, aggrecan and the link protein HAPLN1 were up-regulated in soluble cortical fractions. In comparison, RNAseq data showed no correlation between aggrecan and brevican expression levels and Braak or CERAD stages, but for hippocampal expression of HAPLN1, neurocan and the brevican-interaction partner tenascin-R negative correlations with Braak stages were detected. CSF levels of brevican and neurocan in patients positively correlated with age, total tau, p-Tau, neurofilament-L and Aβ1-40. Negative correlations were detected with the Aβ ratio and the IgG index. Altogether, our study reveals spatially segregated molecular rearrangements of the ECM in AD brains at RNA or protein levels, which may contribute to the pathogenic process. Full article

(This article belongs to the Special Issue The Role of Extracellular Matrix in Human Health and Disease)

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17 pages, 2773 KiB

Open AccessArticle

First Characterization of Human Dermal Fibroblasts Showing a Decreased Xylosyltransferase-I Expression Induced by the CRISPR/Cas9 System

by Bastian Fischer, Vanessa Schmidt, Thanh-Diep Ly, Anika Kleine, Cornelius Knabbe and Isabel Faust-Hinse

Int. J. Mol. Sci. 2022, 23(9), 5045; https://doi.org/10.3390/ijms23095045 - 2 May 2022

Cited by 4 | Viewed by 2484

Abstract

Background: Xylosyltransferases-I and II (XT-I and XT-II) catalyze the initial and rate limiting step of the proteoglycan (PG) biosynthesis and therefore have an import impact on the homeostasis of the extracellular matrix (ECM). The reason for the occurrence of two XT-isoforms in all higher organisms remains unknown and targeted genome-editing strategies could shed light on this issue. Methods: XT-I deficient neonatal normal human dermal fibroblasts were generated by using the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR-associated proteins (Cas) 9 system. We analyzed if a reduced XT-I activity leads to abnormalities regarding ECM-composition, myofibroblast differentiation, cellular senescence and skeletal and cartilage tissue homeostasis. Results: We successfully introduced compound heterozygous deletions within exon 9 of the XYLT1 gene. Beside XYLT1, we detected altered gene-expression levels of further, inter alia ECM-related, genes. Our data further reveal a dramatically reduced XT-I protein activity. Abnormal myofibroblast-differentiation was demonstrated by elevated alpha-smooth muscle actin expression on both, mRNA- and protein level. In addition, wound-healing capability was slightly delayed. Furthermore, we observed an increased cellular-senescence of knockout cells and an altered expression of target genes knowing to be involved in skeletonization. Conclusion: Our data show the tremendous relevance of the XT-I isoform concerning myofibroblast-differentiation and ECM-homeostasis as well as the pathophysiology of skeletal disorders. Full article

(This article belongs to the Special Issue The Role of Extracellular Matrix in Human Health and Disease)

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Review

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25 pages, 925 KiB

Open AccessReview

The Role of Extracellular Matrix in Human Neurodegenerative Diseases

by Panka Pintér and Alán Alpár

Int. J. Mol. Sci. 2022, 23(19), 11085; https://doi.org/10.3390/ijms231911085 - 21 Sep 2022

Cited by 18 | Viewed by 3421

Abstract

The dense neuropil of the central nervous system leaves only limited space for extracellular substances free. The advent of immunohistochemistry, soon followed by advanced diagnostic tools, enabled us to explore the biochemical heterogeneity and compartmentalization of the brain extracellular matrix in exploratory and clinical research alike. The composition of the extracellular matrix is critical to shape neuronal function; changes in its assembly trigger or reflect brain/spinal cord malfunction. In this study, we focus on extracellular matrix changes in neurodegenerative disorders. We summarize its phenotypic appearance and biochemical characteristics, as well as the major enzymes which regulate and remodel matrix establishment in disease. The specifically built basement membrane of the central nervous system, perineuronal nets and perisynaptic axonal coats can protect neurons from toxic agents, and biochemical analysis revealed how the individual glycosaminoglycan and proteoglycan components interact with these molecules. Depending on the site, type and progress of the disease, select matrix components can either proactively trigger the formation of disease-specific harmful products, or reactively accumulate, likely to reduce tissue breakdown and neuronal loss. We review the diagnostic use and the increasing importance of medical screening of extracellular matrix components, especially enzymes, which informs us about disease status and, better yet, allows us to forecast illness. Full article

(This article belongs to the Special Issue The Role of Extracellular Matrix in Human Health and Disease)

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