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Biomedicines
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ECM Code in Physiological and Pathological Processes
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ECM Code in Physiological and Pathological Processes

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cell Biology and Pathology".

Deadline for manuscript submissions: closed (30 September 2023) | Viewed by 14155

Special Issue Editor

Dr. Nikolaos A. Afratis

E-Mail Website
Guest Editor
Laboratory of Biotechnology and Molecular Analysis, Department of Agricultural Development, Agrofood & Management of Natural Resources, National and Kapodistrian University of Athens Evripos Campus, 34400 Psachna, Greece
Interests: ECM pathobiology; ECM therapeutics

Special Issue Information

Dear Colleagues,

This Special Issue, “ECM Code in Physiological and Pathological Processes”, will mainly focus on the role of the extracellular matrix (ECM) during physiological tissue development and disease-state conditions.

The ECM is a complex network of macromolecules with a large role in cell behavior during development and organ pathology. ECM does not only provide physical support for tissue integrity and elasticity, but also controls tissue homeostasis by being constantly remodeled. Remodeling of ECM in physiological and pathological conditions is driven by local cells, as well as surrounding stroma tissue and immune cells. ECM remodeling enzymes orchestrate the reconstruction of the ECM. Specifically, it is performed by break-down enzymes, such as matrix metalloproteinases (MMPs), adamalysins, meprins, and cathepsins as well as matrix build-up enzymes, such as lysyl oxidases and hydroxylases. In addition, ECM proteins such as collagen, proteoglycans (PGs) and glycoproteins, known as matrisome, constitute the basement membrane and interstitial connective tissue with structural and functional role. A fast-growing field of ECM has highlighted the importance of microenvironment in healthy and pathological conditions and provide mechanistic understanding of many pathologies and novel therapeutic approaches in targeting ECM molecules.

In this Special Issue, authors from the ECM field are invited to submit original or review articles regarding the following topics:

  • Glycobiology in matrix pathobiology;
  • Extracellular matrix “omics”;
  • Therapeutic approaches targeting ECM functionality;
  • ECM-based advanced biomaterials;
  • Bioinformatic approaches for better understanding of ECM impact;
  • ECM-mediated immune response;
  • Matrix enzymology and paracrine interactions;
  • Cell-ECM interactions in matrix biology and pathology;
  • Functional role of ECM macromolecules and their role in cellular signaling.

Dr. Nikolaos A. Afratis
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomedicines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

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Published Papers (5 papers)

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Research

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23 pages, 4531 KiB  
Article
Proteolytic Vesicles Derived from Salmonella enterica Serovar Typhimurium-Infected Macrophages: Enhancing MMP-9-Mediated Invasion and EV Accumulation
by Alon Nudelman, Anjana Shenoy, Hyla Allouche-Arnon, Michal Fisler, Irit Rosenhek-Goldian, Lior Dayan, Paula Abou Karam, Ziv Porat, Inna Solomonov, Neta Regev-Rudzki, Amnon Bar-Shir and Irit Sagi
Biomedicines 2024, 12(2), 434; https://doi.org/10.3390/biomedicines12020434 - 15 Feb 2024
Viewed by 1603
Abstract
Proteolysis of the extracellular matrix (ECM) by matrix metalloproteinases (MMPs) plays a crucial role in the immune response to bacterial infections. Here we report the secretion of MMPs associated with proteolytic extracellular vesicles (EVs) released by macrophages in response to Salmonella enterica serovar [...] Read more.
Proteolysis of the extracellular matrix (ECM) by matrix metalloproteinases (MMPs) plays a crucial role in the immune response to bacterial infections. Here we report the secretion of MMPs associated with proteolytic extracellular vesicles (EVs) released by macrophages in response to Salmonella enterica serovar Typhimurium infection. Specifically, we used global proteomics, in vitro, and in vivo approaches to investigate the composition and function of these proteolytic EVs. Using a model of S. Typhimurium infection in murine macrophages, we isolated and characterized a population of small EVs. Bulk proteomics analysis revealed significant changes in protein cargo of naïve and S. Typhimurium-infected macrophage-derived EVs, including the upregulation of MMP-9. The increased levels of MMP-9 observed in immune cells exposed to S. Typhimurium were found to be regulated by the toll-like receptor 4 (TLR-4)-mediated response to bacterial lipopolysaccharide. Macrophage-derived EV-associated MMP-9 enhanced the macrophage invasion through Matrigel as selective inhibition of MMP-9 reduced macrophage invasion. Systemic administration of fluorescently labeled EVs into immunocompromised mice demonstrated that EV-associated MMP activity facilitated increased accumulation of EVs in spleen and liver tissues. This study suggests that macrophages secrete proteolytic EVs to enhance invasion and ECM remodeling during bacterial infections, shedding light on an essential aspect of the immune response. Full article
(This article belongs to the Special Issue ECM Code in Physiological and Pathological Processes)
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19 pages, 4086 KiB  
Article
Colorectal Cancer Cell Invasion and Functional Properties Depend on Peri-Tumoral Extracellular Matrix
by Marco Franchi, Konstantinos-Athanasios Karamanos, Concettina Cappadone, Natalia Calonghi, Nicola Greco, Leonardo Franchi, Maurizio Onisto and Valentina Masola
Biomedicines 2023, 11(7), 1788; https://doi.org/10.3390/biomedicines11071788 - 22 Jun 2023
Cited by 1 | Viewed by 1794
Abstract
We investigated how the extracellular matrix (ECM) affects LoVo colorectal cancer cells behavior during a spatiotemporal invasion. Epithelial-to-mesenchymal transition (EMT) markers, matrix-degrading enzymes, and morphological phenotypes expressed by LoVo-S (doxorubicin-sensitive) and higher aggressive LoVo-R (doxorubicin-resistant) were evaluated in cells cultured for 3 and [...] Read more.
We investigated how the extracellular matrix (ECM) affects LoVo colorectal cancer cells behavior during a spatiotemporal invasion. Epithelial-to-mesenchymal transition (EMT) markers, matrix-degrading enzymes, and morphological phenotypes expressed by LoVo-S (doxorubicin-sensitive) and higher aggressive LoVo-R (doxorubicin-resistant) were evaluated in cells cultured for 3 and 24 h on Millipore filters covered by Matrigel, mimicking the basement membrane, or type I Collagen reproducing a desmoplastic lamina propria. EMT and invasiveness were investigated with RT-qPCR, Western blot, and scanning electron microscopy. As time went by, most gene expressions decreased, but in type I Collagen samples, a strong reduction and high increase in MMP-2 expression in LoVo-S and -R cells occurred, respectively. These data were confirmed by the development of an epithelial morphological phenotype in LoVo-S and invading phenotypes with invadopodia in LoVo-R cells as well as by protein-level analysis. We suggest that the duration of culturing and type of substrate influence the morphological phenotype and aggressiveness of both these cell types differently. In particular, the type I collagen meshwork, consisting of large fibrils confining inter fibrillar micropores, affects the two cell types differently. It attenuates drug-sensitive LoVo-S cell aggressiveness but improves a proteolytic invasion in drug-resistant LoVo-R cells as time goes by. Experimental studies on CRC cells should examine the peri-tumoral ECM components, as well as the dynamic physical conditions of TME, which affect the behavior and aggressiveness of both drug-sensitive and drug-resistant LoVo cells differently. Full article
(This article belongs to the Special Issue ECM Code in Physiological and Pathological Processes)
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19 pages, 3992 KiB  
Article
The Human Extracellular Matrix Diseasome Reveals Genotype–Phenotype Associations with Clinical Implications for Age-Related Diseases
by Cyril Statzer, Karan Luthria, Arastu Sharma, Maricel G. Kann and Collin Y. Ewald
Biomedicines 2023, 11(4), 1212; https://doi.org/10.3390/biomedicines11041212 - 19 Apr 2023
Cited by 6 | Viewed by 2812
Abstract
The extracellular matrix (ECM) is earning an increasingly relevant role in many disease states and aging. The analysis of these disease states is possible with the GWAS and PheWAS methodologies, and through our analysis, we aimed to explore the relationships between polymorphisms in [...] Read more.
The extracellular matrix (ECM) is earning an increasingly relevant role in many disease states and aging. The analysis of these disease states is possible with the GWAS and PheWAS methodologies, and through our analysis, we aimed to explore the relationships between polymorphisms in the compendium of ECM genes (i.e., matrisome genes) in various disease states. A significant contribution on the part of ECM polymorphisms is evident in various types of disease, particularly those in the core-matrisome genes. Our results confirm previous links to connective-tissue disorders but also unearth new and underexplored relationships with neurological, psychiatric, and age-related disease states. Through our analysis of the drug indications for gene–disease relationships, we identify numerous targets that may be repurposed for age-related pathologies. The identification of ECM polymorphisms and their contributions to disease will play an integral role in future therapeutic developments, drug repurposing, precision medicine, and personalized care. Full article
(This article belongs to the Special Issue ECM Code in Physiological and Pathological Processes)
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17 pages, 3383 KiB  
Article
Inflammation and Syndecan-4 Shedding from Cardiac Cells in Ischemic and Non-Ischemic Heart Disease
by Mari E. Strand, Maarten Vanhaverbeke, Michiel T. H. M. Henkens, Maurits A. Sikking, Karoline B. Rypdal, Bjørn Braathen, Vibeke M. Almaas, Theis Tønnessen, Geir Christensen, Stephane Heymans and Ida G. Lunde
Biomedicines 2023, 11(4), 1066; https://doi.org/10.3390/biomedicines11041066 - 1 Apr 2023
Cited by 4 | Viewed by 2422
Abstract
Circulating biomarkers reflecting cardiac inflammation are needed to improve the diagnostics and guide the treatment of heart failure patients. The cardiac production and shedding of the transmembrane proteoglycan syndecan-4 is upregulated by innate immunity signaling pathways. Here, we investigated the potential of syndecan-4 [...] Read more.
Circulating biomarkers reflecting cardiac inflammation are needed to improve the diagnostics and guide the treatment of heart failure patients. The cardiac production and shedding of the transmembrane proteoglycan syndecan-4 is upregulated by innate immunity signaling pathways. Here, we investigated the potential of syndecan-4 as a blood biomarker of cardiac inflammation. Serum syndecan-4 was measured in patients with (i) non-ischemic, non-valvular dilated cardiomyopathy (DCM), with (n = 71) or without (n = 318) chronic inflammation; (ii) acute myocarditis (n = 15), acute pericarditis (n = 3) or acute perimyocarditis (23) and (iii) acute myocardial infarction (MI) at day 0, 3 and 30 (n = 119). Syndecan-4 was investigated in cultured cardiac myocytes and fibroblasts (n = 6–12) treated with the pro-inflammatory cytokines interleukin (IL)-1β and its inhibitor IL-1 receptor antagonist (IL-1Ra), or tumor necrosis factor (TNF)α and its specific inhibitor infliximab, an antibody used in treatment of autoimmune diseases. The levels of serum syndecan-4 were comparable in all subgroups of patients with chronic or acute cardiomyopathy, independent of inflammation. Post-MI, syndecan-4 levels were increased at day 3 and 30 vs. day 0. IL-1Ra attenuated IL-1β-induced syndecan-4 production and shedding in vitro, while infliximab had no effect. In conclusion, syndecan-4 shedding from cardiac myocytes and fibroblasts was attenuated by immunomodulatory therapy. Although its circulating levels were increased post-MI, syndecan-4 did not reflect cardiac inflammatory status in patients with heart disease. Full article
(This article belongs to the Special Issue ECM Code in Physiological and Pathological Processes)
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Review

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21 pages, 1735 KiB  
Review
Collagens Regulating Adipose Tissue Formation and Functions
by Iida Jääskeläinen, Tiina Petäistö, Elahe Mirzarazi Dahagi, Mahdokht Mahmoodi, Taina Pihlajaniemi, Mari T. Kaartinen and Ritva Heljasvaara
Biomedicines 2023, 11(5), 1412; https://doi.org/10.3390/biomedicines11051412 - 10 May 2023
Cited by 16 | Viewed by 4525
Abstract
The globally increasing prevalence of obesity is associated with the development of metabolic diseases such as type 2 diabetes, dyslipidemia, and fatty liver. Excess adipose tissue (AT) often leads to its malfunction and to a systemic metabolic dysfunction because, in addition to storing [...] Read more.
The globally increasing prevalence of obesity is associated with the development of metabolic diseases such as type 2 diabetes, dyslipidemia, and fatty liver. Excess adipose tissue (AT) often leads to its malfunction and to a systemic metabolic dysfunction because, in addition to storing lipids, AT is an active endocrine system. Adipocytes are embedded in a unique extracellular matrix (ECM), which provides structural support to the cells as well as participating in the regulation of their functions, such as proliferation and differentiation. Adipocytes have a thin pericellular layer of a specialized ECM, referred to as the basement membrane (BM), which is an important functional unit that lies between cells and tissue stroma. Collagens form a major group of proteins in the ECM, and some of them, especially the BM-associated collagens, support AT functions and participate in the regulation of adipocyte differentiation. In pathological conditions such as obesity, AT often proceeds to fibrosis, characterized by the accumulation of large collagen bundles, which disturbs the natural functions of the AT. In this review, we summarize the current knowledge on the vertebrate collagens that are important for AT development and function and include basic information on some other important ECM components, principally fibronectin, of the AT. We also briefly discuss the function of AT collagens in certain metabolic diseases in which they have been shown to play central roles. Full article
(This article belongs to the Special Issue ECM Code in Physiological and Pathological Processes)
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