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Pathological Changes of the Extracellular Matrix as Diagnostic Target

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A special issue of Biology (ISSN 2079-7737). This special issue belongs to the section "Cell Biology".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 18150

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Special Issue Editors

Prof. Dr. Antje Ludwig

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Guest Editor

1. Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Medizinische Klinik für Kardiologie und Angiologie, Campus Mitte, Charitéplatz 1, 10117 Berlin, Germany
2. DZHK (German Centre for Cardiovascular Research), Partner Site, 10115 Berlin, Germany
Interests: inflammation in atherosclerosis; endothelial function; endothelial glycocalyx; proteasome

Prof. Dr. Carmen Infante-Duarte

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Guest Editor

1. Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany. Institute for Medical Immunology, Charité Virchow Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany
2. Experimental and Clinical Research Center, Max Delbrueck Center for Molecular Medicine and Charité - Universitätsmedizin Berlin, Berlin, Germany
Interests: neuroinflammation; blood-brain-barrier and blood-CSF-barrier; brain ECM; innate immunity; innate lymphoid cells

Special Issue Information

Dear Colleagues,

The extracellular matrix (ECM) is a dynamic non-cellular three-dimensional scaffold embedding the cells of all tissues. The ECM is a macromolecular network composed of collagens and elastin, fibronectin, laminins, proteoglycans/glycosaminoglycans, and various other glycoproteins. The components of the tissue ECM are involved in ECM-cell interactions and are important for cellular signal transduction. In this context, ECM regulates tissue homeostasis, including the regulation of the pH value and the hydration of the micromilieu, controls cell migration and differentiation and determines the biomechanical properties of a particular tissue. The ECM is a highly dynamic structure, in which the ratio of synthesis, degradation, and modification of its components determines its functional state. Pathological remodeling of the ECM is a hallmark of many diseases and is currently emerging as a potential diagnostic and prognostic target.

For this Special Issue, we encourage the submission of manuscripts on disease specific pathological changes affecting the ECM, which can serve as potential biomarker for diagnosis and/or for monitoring disease progression or treatment response. This includes all aspects of disease related changes of the molecular composition and biomechanical properties of the ECM, novel concepts for non-invasive imaging with ECM-directed probes, ECM related biomarkers in the circulation, ECM as target for therapeutic and regenerative approaches, and in vitro and in vivo models for the investigation of ECM biology.

The call is open to contributions in form of reviews and short- / full-size research papers dedicated to the above mentioned topics.

Prof. Dr. Antje Ludwig
Prof. Dr. Carmen Infante-Duarte
Guest Editors

Manuscript Submission Information

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Keywords

extracellular matrix
collagen
elastin
proteoglycans
glycosaminoglycans
biomarkers
imaging
theranostics

Published Papers (6 papers)

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Research

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13 pages, 3905 KiB

Open AccessArticle

Straightforward Analysis of Sulfated Glycosaminoglycans by MALDI-TOF Mass Spectrometry from Biological Samples

by Lynn Krüger, Karina Biskup, Vasileios Karampelas, Antje Ludwig, Antje-Susanne Kasper, Wolfram C. Poller and Véronique Blanchard

Biology 2022, 11(4), 506; https://0-doi-org.brum.beds.ac.uk/10.3390/biology11040506 - 25 Mar 2022

Cited by 1 | Viewed by 2196

Abstract

Glycosaminoglycans (GAGs) are considered to be the most difficult type of glycoconjugates to analyze as they are constituted of linear long polysaccharidic chains having molecular weights reaching up to several million daltons. Bottom-up analysis of glycosaminoglycans from biological samples is a long and work-extensive procedure due to the many preparation steps involved. In addition, so far, only few research articles have been dedicated to the analysis of GAGs by means of matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS) because their intact ionization can be problematic due to the presence of labile sulfate groups. In this work, we had the aim of exploring the sulfation pattern of monosulfated chondroitin/dermatan sulfate (CS/DS) disaccharides in human tissue samples because they represent the most abundant form of sulfation in disaccharides. We present here an optimized strategy to analyze on-target derivatized CS/DS disaccharides via MALDI-TOF-MS using a fast workflow that does not require any purification after enzymatic cleavage. For the first time, we show that MALDI-TOF/TOF experiments allow for discrimination between monosulfated CS disaccharide isomers via specific fragments corresponding to glycosidic linkages and to cross-ring cleavages. This proof of concept is illustrated via the analysis of CS/DS disaccharides of atherosclerotic lesions of different histological origins, in which we were able to identify their monosulfation patterns. Full article

(This article belongs to the Special Issue Pathological Changes of the Extracellular Matrix as Diagnostic Target)

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14 pages, 4869 KiB

Open AccessArticle

The Effects of EMMPRIN/CD147 on Late Function and Histopathological Lesions of the Renal Graft

by Magdalena Nalewajska, Martyna Opara-Bajerowicz, Krzysztof Safranow, Andrzej Pawlik, Kazimierz Ciechanowski, Sebastian Kwiatkowski and Ewa Kwiatkowska

Biology 2022, 11(2), 232; https://0-doi-org.brum.beds.ac.uk/10.3390/biology11020232 - 01 Feb 2022

Cited by 1 | Viewed by 1469

Abstract

Chronic kidney disease (CKD) is associated with renal fibrosis, and develops with the participation of fibroblasts and myofibroblasts from epithelial-to-mesenchymal transition (EMT). In cancer research, the key role of the glycoprotein CD147/EMMPRIN (extracellular matrix metalloproteinase inducer) in EMT has been proven. In this study, we evaluate how serum CD147/EMMPRIN affects long-term renal graft function and renal biopsy specimen lesions. In total, 49 renal graft recipients who had a renal biopsy within the last 18 months were retrospectively reviewed. At their most recent appointments, their serum concentrations of CD147/EMMPRIN and renal function were assessed. The occurrence of delayed graft function (DGF), estimated glomerular filtration rate (eGFR) at 1-year post-kidney transplantation (Tx) and the subsequent years of the follow-up period, and renal biopsy specimen lesions, mainly those related to renal fibrosis and tubular atrophy, were also evaluated. Results: CD147/EMMPRIN serum concentration correlated negatively with eGFR at the most recent appointment (ME 69 months) and with eGFR at 1 and 2 years after Tx (p < 0.05, R = −0.69, R = −0.39, and R = −0.40, respectively). CD147/EMMPRIN serum levels correlated positively with urine protein concentrations (p < 0.05, R = 0.73). A positive correlation was further found with the severity of renal biopsy specimen lesions such as interstitial fibrosis (CI), tubular atrophy (CT), double contours of the GBM (CG), mesangial matrix expansion (MM), and arteriolar hyalinosis (AH) (p < 0.05, R = 0.39, R = 0.29, R = 0.41, R = 0.32 and R = 0.40, respectively). Patients with a history of DGF had higher CD147/EMMPRIN serum concentrations (<0.05). Conclusions: CD147/EMMPRIN is linked to poorer long-term renal graft function. Additionally, a high serum concentration of CD147/EMMPRIN affects interstitial fibrosis tubular atrophy (IF/TA) lesions and proteinuria. Full article

(This article belongs to the Special Issue Pathological Changes of the Extracellular Matrix as Diagnostic Target)

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17 pages, 4091 KiB

Open AccessArticle

Sexual Dimorphism in Extracellular Matrix Composition and Viscoelasticity of the Healthy and Inflamed Mouse Brain

by Clara Sophie Batzdorf, Anna Sophie Morr, Gergely Bertalan, Ingolf Sack, Rafaela Vieira Silva and Carmen Infante-Duarte

Biology 2022, 11(2), 230; https://0-doi-org.brum.beds.ac.uk/10.3390/biology11020230 - 31 Jan 2022

Cited by 13 | Viewed by 5449

Abstract

Magnetic resonance elastography (MRE) has revealed sexual dimorphism in brain stiffness in healthy individuals and multiple sclerosis (MS) patients. In an animal model of MS, named experimental autoimmune encephalomyelitis (EAE), we have previously shown that inflammation-induced brain softening was associated with alterations of the extracellular matrix (ECM). However, it remained unclear whether the brain ECM presents sex-specific properties that can be visualized by MRE. Therefore, here we aimed at quantifying sexual dimorphism in brain viscoelasticity in association with ECM changes in healthy and inflamed brains. Multifrequency MRE was applied to the midbrain of healthy and EAE mice of both sexes to quantitatively map regional stiffness. To define differences in brain ECM composition, the gene expression of the key basement membrane components laminin (Lama4, Lama5), collagen (Col4a1, Col1a1), and fibronectin (Fn1) were investigated by RT-qPCR. We showed that the healthy male cortex expressed less Lama4, Lama5, and Col4a1, but more Fn1 (all p < 0.05) than the healthy female cortex, which was associated with 9% softer properties (p = 0.044) in that region. At peak EAE cortical softening was similar in both sexes compared to healthy tissue, with an 8% difference remaining between males and females (p = 0.006). Cortical Lama4, Lama5 and Col4a1 expression increased 2 to 3-fold in EAE in both sexes while Fn1 decreased only in males (all p < 0.05). No significant sex differences in stiffness were detected in other brain regions. In conclusion, sexual dimorphism in the ECM composition of cortical tissue in the mouse brain is reflected by in vivo stiffness measured with MRE and should be considered in future studies by sex-specific reference values. Full article

(This article belongs to the Special Issue Pathological Changes of the Extracellular Matrix as Diagnostic Target)

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16 pages, 2175 KiB

Open AccessArticle

Assessment of Albumin ECM Accumulation and Inflammation as Novel In Vivo Diagnostic Targets for Multi-Target MR Imaging

by Jana Möckel, Julia Brangsch, Carolin Reimann, Jan O. Kaufmann, Ingolf Sack, Dilyana B. Mangarova, Avan Kader, Matthias Taupitz, Lisa C. Adams, Sarah Keller, Antje Ludwig, Bernd Hamm, Rene M. Botnar and Marcus R. Makowski

Biology 2021, 10(10), 964; https://0-doi-org.brum.beds.ac.uk/10.3390/biology10100964 - 27 Sep 2021

Cited by 2 | Viewed by 2362

Abstract

Atherosclerosis is a progressive inflammatory vascular disease characterized by endothelial dysfunction and plaque burden. Extracellular matrix (ECM)-associated plasma proteins play an important role in disease development. Our magnetic resonance imaging (MRI) study investigates the feasibility of using two different molecular MRI probes for the simultaneous assessment of ECM-associated intraplaque albumin deposits caused by endothelial damage and progressive inflammation in atherosclerosis. Male apolipoprotein E-deficient (ApoE^-/-)-mice were fed a high-fat diet (HFD) for 2 or 4 months. Another ApoE^-/--group was treated with pravastatin and received a HFD for 4 months. T1- and T2*-weighted MRI was performed before and after albumin-specific MRI probe (gadofosveset) administration and a macrophage-specific contrast agent (ferumoxytol). Thereafter, laser ablation inductively coupled plasma mass spectrometry and histology were performed. With advancing atherosclerosis, albumin-based MRI signal enhancement and ferumoxytol-induced signal loss areas in T2*-weighted MRI increased. Significant correlations between contrast-to-noise-ratio (CNR) post-gadofosveset and albumin stain (R² = 0.78, p < 0.05), and signal loss areas in T2*-weighted MRI with Perls’ Prussian blue stain (R² = 0.83, p < 0.05) were observed. No interference of ferumoxytol with gadofosveset enhancement was detectable. Pravastatin led to decreased inflammation and intraplaque albumin. Multi-target MRI combining ferumoxytol and gadofosveset is a promising method to improve diagnosis and treatment monitoring in atherosclerosis. Full article

(This article belongs to the Special Issue Pathological Changes of the Extracellular Matrix as Diagnostic Target)

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15 pages, 3609 KiB

Open AccessArticle

Immuno-Electron and Confocal Laser Scanning Microscopy of the Glycocalyx

by Shailey Gale Twamley, Anke Stach, Heike Heilmann, Berit Söhl-Kielczynski, Verena Stangl, Antje Ludwig and Agnieszka Münster-Wandowski

Biology 2021, 10(5), 402; https://0-doi-org.brum.beds.ac.uk/10.3390/biology10050402 - 04 May 2021

Cited by 3 | Viewed by 3688

Abstract

The glycocalyx (GCX), a pericellular carbohydrate rich hydrogel, forms a selective barrier that shields the cellular membrane, provides mechanical support, and regulates the transport and diffusion of molecules. The GCX is a fragile structure, making it difficult to study by transmission electron microscopy (TEM) and confocal laser scanning microscopy (CLSM). Sample preparation by conventional chemical fixation destroys the GCX, giving a false impression of its organization. An additional challenge is to process the GCX in a way that preserves its morphology and enhanced antigenicity to study its cell-specific composition. The aim of this study was to provide a protocol to preserve both antigen accessibility and the unique morphology of the GCX. We established a combined high pressure freezing (HPF), osmium-free freeze substitution (FS), rehydration, and pre-embedding immunogold labeling method for TEM. Our results showed specific immunogold labeling of GCX components expressed in human monocytic THP-1 cells, hyaluronic acid receptor (CD44) and chondroitin sulfate (CS), and maintained a well-preserved GCX morphology. We adapted the protocol for antigen localization by CLSM and confirmed the specific distribution pattern of GCX components. The presented combination of HPF, FS, rehydration, and immunolabeling for both TEM and CLSM offers the possibility for analyzing the morphology and composition of the unique GCX structure. Full article

(This article belongs to the Special Issue Pathological Changes of the Extracellular Matrix as Diagnostic Target)

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Review

Jump to: Research

13 pages, 918 KiB

Open AccessReview

Extracellular Matrix Components as Diagnostic Tools in Inflammatory Bowel Disease

by Laura Golusda, Anja A. Kühl, Britta Siegmund and Daniela Paclik

Biology 2021, 10(10), 1024; https://doi.org/10.3390/biology10101024 - 11 Oct 2021

Cited by 4 | Viewed by 2111

Abstract

Work from the last years indicates that the extracellular matrix (ECM) plays a direct role in various cellular processes, including proliferation, migration and differentiation. Besides homeostatic processes, its regulatory function in inflammation becomes more and more evident. In inflammation, such as inflammatory bowel disease, the ECM composition is constantly remodeled, and this can result in a structuring of fistulizing disease course. Thus, tracking early ECM changes might bear the potential to predict the disease course. In this review, we provide an overview of relevant diagnostic methods, focusing on ECM changes. Full article

(This article belongs to the Special Issue Pathological Changes of the Extracellular Matrix as Diagnostic Target)

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