Common Denominators of Extracellular Matrix across Tissues as Inter-Tissue Messengers and Targets for Drug Repurposing

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Motility and Adhesion".

Deadline for manuscript submissions: closed (30 May 2022) | Viewed by 15054

Special Issue Editors


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Molecular Neuroplasticity Group, German Center for Neurodegenerative Diseases (DZNE), Leipziger Str. 44/64, 39120 Magdeburg, Germany
Interests: extracellular matrix; cell adhesion; synaptogenesis; synaptic plasticity; intrinsic plasticity; dementia; schizophrenia; mental retardation; epilepsy
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Department of Orthopaedic Surgery, Otto-Von-Guericke-University, 39120 Magdeburg, Germany
Interests: osteoarthritis; chondrocalcinosis; CPP crystals; BCP crystals; chondrocyte phenotype; inflammation; signaling cascades; cohort studies

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Guest Editor
Department of Nephrology and Hypertension, Diabetes and Endocrinology, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
Interests: inflammation; fibrosis; diabetic nephropathy; glomerular diseases; matrisome
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cells secrete diverse proteoglycans, glycans, and glycoproteins, which aggregate in the extracellular space and form extracellular matrix (ECM) structures. The ECM shapes cell differentiation and migration during early development, and provides mechanical support to cells and tissues. It serves as a diffusion barrier, extracellular scaffold for compartmentalization, and signaling platform for intercellular communications, and regulates diverse cellular functions in tissue homeostasis.

The molecular composition and organization of ECM in different tissues vary according to the tissue functions, so the ECM in cartilage is optimal for viscoelasticity and lubrication, while in bones it is a durable, strong, and stiff structure with low elasticity for shock absorption. Still, the molecular diversity of major ECM components is limited, and several forms of ECM can be distinguished in diverse tissues, with a remarkable similarity of organizational principles of basal lamina-like structures in the neuromuscular junctions and vasculature or hyaluronic acid-lectican-based scaffolds in the cartilage and the brain.

In this Special Issue, we aim to explore this similarity in the molecular organization as a potential basis for an exchange of ECM-targeting tools and therapeutics for diseases affecting the ECM in different organs, including the brain, cartilage, kidney, and vascular system. Differences between ECM in different tissues and ECM degradation products generated during disease are also of relevance, for instance, to understand how ECM structures can be targeted in a tissue-specific manner and which ECM molecules can be used as diagnostic biomarkers. Particularly (but not exclusively) we expect to collect reviews as well as experimental and bioinformatic studies with a focus on:

  • Cross-tissue comparison of signaling mechanisms impaired in human carriers of ECM mutations or corresponding animal models;
  • Bioinformatic analysis of common dysregulations in ECM molecules and related proteases and glycans across diseases;
  • Cross-signaling in and between organs via ECM molecules and their proteolytic products;
  • Immunomodulatory effects of ECM and its proteolytic products;
  • Drugs targeting biosynthesis, glycosylation, proteolysis, and other posttranslational modifications of ECM molecules and their receptors.

We anticipate that this Issue will promote interactions between experts working on ECM in different organs and tissues and will facilitate the transfer of targeting strategies across fields. As an example, beneficial effects by neural ECM modifications are envisioned given their multiple functional roles and relevance for neurological and psychiatric diseases; however, ECM-targeting therapeutics are still to be developed. For other organs, similar approaches are also foreseen, for example, to counteract aging and inflammatory diseases.

Prof. Dr. Alexander Dityatev
Prof. Dr. Jessica Bertrand
Prof. Dr. Peter R. Mertens
Guest Editors

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Keywords

  • proteoglycans
  • glycans
  • glycoproteins
  • matricellular proteins
  • integrins
  • matrix metalloproteinases
  • extracellular scaffold
  • cell signaling
  • ECM remodeling

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Published Papers (3 papers)

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Research

25 pages, 3722 KiB  
Article
Aging-Associated Changes in Cognition, Expression and Epigenetic Regulation of Chondroitin 6-Sulfotransferase Chst3
by David Baidoe-Ansah, Sadman Sakib, Shaobo Jia, Hadi Mirzapourdelavar, Luisa Strackeljan, Andre Fischer, Stepan Aleshin, Rahul Kaushik and Alexander Dityatev
Cells 2022, 11(13), 2033; https://doi.org/10.3390/cells11132033 - 27 Jun 2022
Cited by 6 | Viewed by 3101
Abstract
Understanding changes in the expression of genes involved in regulating various components of the neural extracellular matrix (ECM) during aging can provide an insight into aging-associated decline in synaptic and cognitive functions. Hence, in this study, we compared the expression levels of ECM-related [...] Read more.
Understanding changes in the expression of genes involved in regulating various components of the neural extracellular matrix (ECM) during aging can provide an insight into aging-associated decline in synaptic and cognitive functions. Hence, in this study, we compared the expression levels of ECM-related genes in the hippocampus of young, aged and very aged mice. ECM gene expression was downregulated, despite the accumulation of ECM proteoglycans during aging. The most robustly downregulated gene was carbohydrate sulfotransferase 3 (Chst3), the enzyme responsible for the chondroitin 6-sulfation (C6S) of proteoglycans. Further analysis of epigenetic mechanisms revealed a decrease in H3K4me3, three methyl groups at the lysine 4 on the histone H3 proteins, associated with the promoter region of the Chst3 gene, resulting in the downregulation of Chst3 expression in non-neuronal cells. Cluster analysis revealed that the expression of lecticans—substrates of CHST3—is tightly co-regulated with this enzyme. These changes in ECM-related genes were accompanied by an age-confounded decline in cognitive performance. Despite the co-directional impairment in cognitive function and average Chst3 expression in the studied age groups, at the individual level we found a negative correlation between mRNA levels of Chst3 and cognitive performance within the very aged group. An analysis of correlations between the expression of ECM-related genes and cognitive performance in novel object versus novel location recognition tasks revealed an apparent trade-off in the positive gene effects in one task at the expense of another. Further analysis revealed that, despite the reduction in the Chst3 mRNA, the expression of CHST3 protein is increased in glial cells but not in neurons, which, however, does not lead to changes in the absolute level of C6S and even results in the decrease in C6S in perineuronal, perisynaptic and periaxonal ECM relative to the elevated expression of its protein carrier versican. Full article
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13 pages, 16819 KiB  
Article
Comparative Analysis of Gene Expression in Fibroblastic Foci in Patients with Idiopathic Pulmonary Fibrosis and Pulmonary Sarcoidosis
by Jan C. Kamp, Lavinia Neubert, Helge Stark, Jan B. Hinrichs, Caja Boekhoff, Allison D. Seidel, Fabio Ius, Axel Haverich, Jens Gottlieb, Tobias Welte, Peter Braubach, Florian Laenger, Marius M. Hoeper, Mark P. Kuehnel and Danny D. Jonigk
Cells 2022, 11(4), 664; https://doi.org/10.3390/cells11040664 - 14 Feb 2022
Cited by 16 | Viewed by 3784
Abstract
Background: Fibroblastic foci (FF) are characteristic features of usual interstitial pneumonia (UIP)/idiopathic pulmonary fibrosis (IPF) and one cardinal feature thought to represent a key mechanism of pathogenesis. Hence, FF have a high impact on UIP/IPF diagnosis in current guidelines. However, although less frequent, [...] Read more.
Background: Fibroblastic foci (FF) are characteristic features of usual interstitial pneumonia (UIP)/idiopathic pulmonary fibrosis (IPF) and one cardinal feature thought to represent a key mechanism of pathogenesis. Hence, FF have a high impact on UIP/IPF diagnosis in current guidelines. However, although less frequent, these histomorphological hallmarks also occur in other fibrotic pulmonary diseases. Currently, there is therefore a gap in knowledge regarding the underlying molecular similarities and differences of FF in different disease entities. Methods: In this work, we analyzed the compartment-specific gene expression profiles of FF in IPF and sarcoidosis in order to elucidate similarities and differences as well as shared pathomechanisms. For this purpose, we used laser capture microdissection, mRNA and protein expression analysis. Biological pathway analysis was performed using two different gene expression databases. As control samples, we used healthy lung tissue that was donated but not used for lung transplantation. Results: Based on Holm Bonferroni corrected expression data, mRNA expression analysis revealed a significantly altered expression signature for 136 out of 760 genes compared to healthy controls while half of these showed a similar regulation in both groups. Immunostaining of selected markers from each group corroborated these results. However, when comparing all differentially expressed genes with the fdr-based expression data, only 2 of these genes were differentially expressed between sarcoidosis and IPF compared to controls, i.e., calcium transport protein 1 (CAT1) and SMAD specific E3 ubiquitin protein ligase 1 (SMURF1), both in the sarcoidosis group. Direct comparison of sarcoidosis and IPF did not show any differentially regulated genes independent from the statistical methodology. Biological pathway analysis revealed a number of fibrosis-related pathways pronounced in IPF without differences in the regulatory direction. Conclusions: These results demonstrate that FF of end-stage IPF and sarcoidosis lungs, although different in initiation, are similar in gene and protein expression, encouraging further studies on the use of antifibrotic agents in sarcoidosis. Full article
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17 pages, 3902 KiB  
Article
Matrix Metalloproteinases Inhibition by Doxycycline Rescues Extracellular Matrix Organization and Partly Reverts Myofibroblast Differentiation in Hypermobile Ehlers-Danlos Syndrome Dermal Fibroblasts: A Potential Therapeutic Target?
by Nicola Chiarelli, Nicoletta Zoppi, Marina Venturini, Daniele Capitanio, Cecilia Gelfi, Marco Ritelli and Marina Colombi
Cells 2021, 10(11), 3236; https://doi.org/10.3390/cells10113236 - 19 Nov 2021
Cited by 9 | Viewed by 6974
Abstract
Hypermobile Ehlers-Danlos syndrome (hEDS) is the most frequent type of EDS and is characterized by generalized joint hypermobility and musculoskeletal manifestations which are associated with chronic pain, and mild skin involvement along with the presence of more than a few comorbid conditions. Despite [...] Read more.
Hypermobile Ehlers-Danlos syndrome (hEDS) is the most frequent type of EDS and is characterized by generalized joint hypermobility and musculoskeletal manifestations which are associated with chronic pain, and mild skin involvement along with the presence of more than a few comorbid conditions. Despite numerous research efforts, no causative gene(s) or validated biomarkers have been identified and insights into the disease-causing mechanisms remain scarce. Variability in the spectrum and severity of symptoms and progression of hEDS patients’ phenotype likely depend on a combination of age, gender, lifestyle, and the probable multitude of genes involved in hEDS. However, considering the clinical overlap with other EDS forms, which lead to abnormalities in extracellular matrix (ECM), it is plausible that the mechanisms underlying hEDS pathogenesis also affect the ECM to a certain extent. Herein, we performed a series of in vitro studies on the secretome of hEDS dermal fibroblasts that revealed a matrix metalloproteinases (MMPs) dysfunction as one of the major disease drivers by causing a detrimental feedback loop of excessive ECM degradation coupled with myofibroblast differentiation. We demonstrated that doxycycline-mediated inhibition of MMPs rescues in hEDS cells a control-like ECM organization and induces a partial reversal of their myofibroblast-like features, thus offering encouraging clues for translational studies confirming MMPs as a potential therapeutic target in hEDS with the expectation to improve patients’ quality of life and alleviate their disabilities. Full article
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