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Extracellular Matrix Remodeling in Health, Regenerative Medicine and Disease

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Tissues and Organs".

Deadline for manuscript submissions: closed (15 May 2023) | Viewed by 18236

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Special Issue Editors

Dr. Michela Pozzobon

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Guest Editor

1. Department of Women and Children Health, University of Padova, 35128 Padova, Italy
2. Institute of Pediatric Research Città della Speranza, Corso Stati Uniti 4, 35129 Padova, Italy
Interests: muscle stem cells; perinatal cells; extracellular vesicles; muscle extracellular matrix; rhabdomyosarcoma; tissue engineering
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Victor S. Carriel

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Guest Editor

Departamento de Histología, Grupo de Ingeniería Tisular, Facultad de Medicina, Universidad de Granada, Granada, Spain
Interests: extracellular matrix biology; tissue engineering; scaffolds; experimental cancer biology; tissue repair and regeneration; histology; histochemistry & immunohistochemistry
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Sebastián San Martín

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Guest Editor

Centro de Investigaciones Biomédicas, Escuela de Medicina-Facultad de Medicina, Doctorado en Ciencias e Ingeniería para la Salud, Universidad de Valparaíso, Viña del Mar, Chile
Interests: embryology; cell migration; molecular biology; cell biology; extracellular matrix; physiology; endothelial cells; embryo biotechnology; anatomy; histology

Special Issue Information

Dear Colleagues,

It is with great pleasure and enthusiasm that we present to you this Special Issue of Cells. This issue aims at investigating the cross talk among cells, factors and extracellular matrix (ECM), with focus on the Extracellular Matrix Remodeling in Health and Disease. ECM is formed by fibrillar proteins, such as collagens, fibronectin, and elastin, and non-fibrillar molecules as proteoglycans, hyaluronan, and glyco-proteins including matricellular proteins. The complex network that these macromolecular components form, are interconnected and actively communicate with cells through binding to cell surface receptors and/or matrix effectors. ECM roles are paramount for structural tissue integrity, for specific mechanical properties in order to allow tissue functions, for regulation of cell phenotype and for maintenance of tissue homeostasis.

Cells and ECM components represent the multifaceted and dynamic environment that distinguishes each organ. In healthy condition, ECM is well organized and gives structure to the different tissues; when ECM composition become dysregulated, also the structure of organs change and pathological processes are sustained.

In this special issue we would like to highlight the multitasking role of ECM that give rise to different clinical phenotypes when mutation in matrix genes and proteins elicit genetic disorders, cancer, fibrosis, inflammatory diseases.

The present Special Issue aims to collect new aspects that are under exploration on the cross talk among cells, soluble factors and microenvironment in health and disease, considering the following aspects:

The microenvironment;
The immunoenvironment;
Trapped factors
Extracellular vesicles;
Regenerative medicine approaches
Tumor microenvironment

We look forward to receiving your contributions summarizing or explaining your research to this Special Issue.

Dr. Michela Pozzobon
Prof. Dr. Victor Carriel Araya
Prof. Dr. Sebastián San Martín
Guest Editors

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. Cells is an international peer-reviewed open access semimonthly 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 2700 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.

Keywords

proteoglycans
biological dysregulation processes
immune cells
cancer
collagens
elastic fibers
glycoproteins
ECM remodeling
regenerative medicine

Published Papers (8 papers)

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Research

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14 pages, 1033 KiB

Open AccessArticle

Expression of Adipose Tissue Extracellular Matrix-Related Genes Predicts Weight Loss after Bariatric Surgery

by Óscar Osorio-Conles, Romina Olbeyra, Josep Vidal, Ainitze Ibarzabal, José María Balibrea and Ana de Hollanda

Cells 2023, 12(9), 1262; https://doi.org/10.3390/cells12091262 - 26 Apr 2023

Cited by 1 | Viewed by 1227

Abstract

Background: We evaluated the association between white adipose tissue parameters before bariatric surgery (BS) and post-surgical weight loss, with an especial focus on extracellular matrix (ECM) gene expression. Methods: Paired samples from subcutaneous (SAT) and visceral adipose tissue (VAT) were obtained from 144 subjects undergoing BS. The association between total body weight loss (%TBWL) at 12 months after BS and the histological characteristics and gene expression of selected genes in SAT and VAT was analyzed. Results: Fat cell area, size-frequency distribution, and fibrosis in SAT or VAT prior to surgery were not associated with %TBWL. On the contrary, the SAT expression of COL5A1 and COL6A3 was associated with %TBWL after BS (both p < 0.001), even after adjusting for age, gender, baseline BMI, and type 2 diabetes status (T2D). Furthermore, in logistic regression analyses, the expression of these genes was significantly associated with insufficient WL (IWL = TBWL < 20%) after BS (respectively, p = 0.030 and p = 0.031). Indeed, in ROC analysis, the prediction of IWL based on sex, age, BMI, T2D, and the type of surgery (AUC = 0.71) was significantly improved with the addition of SAT-COL5A1 gene expression (AUC = 0.88, Z = 2.13, p = 0.032). Conclusions: Our data suggest that the expression of SAT ECM-related genes may help explain the variability in TBWL following BS. Full article

(This article belongs to the Special Issue Extracellular Matrix Remodeling in Health, Regenerative Medicine and Disease)

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22 pages, 3569 KiB

Open AccessArticle

Comprehensive Characterization of Tissues Derived from Animals at Different Regenerative Stages: A Comparative Analysis between Fetal and Adult Mouse Skin

by Valentina Castillo, Pamela Díaz-Astudillo, Rocío Corrales-Orovio, Sebastián San Martín and José Tomás Egaña

Cells 2023, 12(9), 1215; https://doi.org/10.3390/cells12091215 - 22 Apr 2023

Cited by 4 | Viewed by 1537

Abstract

Tissue regeneration capabilities vary significantly throughout an organism’s lifespan. For example, mammals can fully regenerate until they reach specific developmental stages, after which they can only repair the tissue without restoring its original architecture and function. The high regenerative potential of fetal stages has been attributed to various factors, such as stem cells, the immune system, specific growth factors, and the presence of extracellular matrix molecules upon damage. To better understand the local differences between regenerative and reparative tissues, we conducted a comparative analysis of skin derived from mice at regenerative and reparative stages. Our findings show that both types of skin differ in their molecular composition, structure, and functionality. We observed a significant increase in cellular density, nucleic acid content, neutral lipid density, Collagen III, and glycosaminoglycans in regenerative skin compared with reparative skin. Additionally, regenerative skin had significantly higher porosity, metabolic activity, water absorption capacity, and elasticity than reparative skin. Finally, our results also revealed significant differences in lipid distribution, extracellular matrix pore size, and proteoglycans between the two groups. This study provides comprehensive data on the molecular and structural clues that enable full tissue regeneration in fetal stages, which could aid in developing new biomaterials and strategies for tissue engineering and regeneration. Full article

(This article belongs to the Special Issue Extracellular Matrix Remodeling in Health, Regenerative Medicine and Disease)

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41 pages, 17987 KiB

Open AccessArticle

Development and In Vitro/In Vivo Comparative Characterization of Cryopreserved and Decellularized Tracheal Grafts

by Elena Stocco, Silvia Barbon, Marco Mammana, Diletta Trojan, Alice Bianchin, Francesca Favaretto, Martina Contran, Giovanni Zambello, Andrea Vogliardi, Marta Confalonieri, Silvia Todros, Piero G. Pavan, Filippo Romanato, Maria Teresa Conconi, Veronica Macchi, Raffaele De Caro, Federico Rea and Andrea Porzionato

Cells 2023, 12(6), 888; https://doi.org/10.3390/cells12060888 - 13 Mar 2023

Cited by 4 | Viewed by 1942

Abstract

Tracheal reconstruction represents a challenge when primary anastomosis is not feasible. Within this scenario, the study aim was to develop a new pig-derived decellularized trachea (DecellT) to be compared with the cryopreserved counterpart (CryoT) for a close predictive analysis. Tracheal segments underwent decellularization by a physical + enzymatic + chemical method (12 cycles); in parallel, cryopreserved samples were also prepared. Once decellularized (histology/DNA quantification), the two groups were characterized for Alpha-Gal epitopes/structural proteins (immunohistochemistry/histology/biochemical assays/second harmonic generation microscopy)/ultrastructure (Scanning Electron Microscopy (SEM))/mechanical behaviour. Cytotoxicity absence was assessed in vitro (extract-test assay/direct seeding, HM1SV40 cell line) while biocompatibility was verified in BALB/c mice, followed by histological/immunohistochemical analyses and SEM (14 days). Decellularization effectively removed Alpha-Gal epitopes; cartilage histoarchitecture was retained in both groups, showing chondrocytes only in the CryoT. Cryopreservation maintained few respiratory epithelium sparse cilia, not detectable in DecellT. Focusing on ECM, preserved structural/ultrastructural organization and collagen content were observed in the cartilage of both; conversely, the GAGs were significantly reduced in DecellT, as confirmed by mechanical study results. No cytotoxicity was highlighted by CryoT/DecellT in vitro, as they were also corroborated by a biocompatibility assay. Despite some limitations (cells presence/GAGs reduction), CryoT/DecellT are both appealing options, which warrant further investigation in comparative in vivo studies. Full article

(This article belongs to the Special Issue Extracellular Matrix Remodeling in Health, Regenerative Medicine and Disease)

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17 pages, 7716 KiB

Open AccessArticle

Expression of Basement Membrane Molecules by Wharton Jelly Stem Cells (WJSC) in Full-Term Human Umbilical Cords, Cell Cultures and Microtissues

by David Sánchez-Porras, Daniel Durand-Herrera, Ramón Carmona, Cristina Blanco-Elices, Ingrid Garzón, Michela Pozzobon, Sebastián San Martín, Miguel Alaminos, Óscar Darío García-García, Jesús Chato-Astrain and Víctor Carriel

Cells 2023, 12(4), 629; https://doi.org/10.3390/cells12040629 - 15 Feb 2023

Cited by 1 | Viewed by 1478

Abstract

Wharton’s jelly stem cells (WJSC) from the human umbilical cord (UC) are one of the most promising mesenchymal stem cells (MSC) in tissue engineering (TE) and advanced therapies. The cell niche is a key element for both, MSC and fully differentiated tissues, to preserve their unique features. The basement membrane (BM) is an essential structure during embryonic development and in adult tissues. Epithelial BMs are well-known, but similar structures are present in other histological structures, such as in peripheral nerve fibers, myocytes or chondrocytes. Previous studies suggest the expression of some BM molecules within the Wharton’s Jelly (WJ) of UC, but the distribution pattern and full expression profile of these molecules have not been yet elucidated. In this sense, the aim of this histological study was to evaluate the expression of main BM molecules within the WJ, cultured WJSC and during WJSC microtissue (WJSC-MT) formation process. Results confirmed the presence of a pericellular matrix composed by the main BM molecules—collagens (IV, VII), HSPG2, agrin, laminin and nidogen—around the WJSC within UC. Additionally, ex vivo studies demonstrated the synthesis of these BM molecules, except agrin, especially during WJSC-MT formation process. The WJSC capability to synthesize main BM molecules could offer new alternatives for the generation of biomimetic-engineered substitutes where these molecules are particularly needed. Full article

(This article belongs to the Special Issue Extracellular Matrix Remodeling in Health, Regenerative Medicine and Disease)

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20 pages, 1000 KiB

Open AccessArticle

Blood-Brain Barrier-Associated Proteins Are Elevated in Serum of Epilepsy Patients

by Elżbieta Bronisz, Agnieszka Cudna, Aleksandra Wierzbicka and Iwona Kurkowska-Jastrzębska

Cells 2023, 12(3), 368; https://doi.org/10.3390/cells12030368 - 19 Jan 2023

Cited by 5 | Viewed by 1610

Abstract

Blood–brain barrier (BBB) dysfunction emerges as one of the mechanisms underlying the induction of seizures and epileptogenesis. There is growing evidence that seizures also affect BBB, yet only scarce data is available regarding serum levels of BBB-associated proteins in chronic epilepsy. In this study, we aimed to assess serum levels of molecules associated with BBB in patients with epilepsy in the interictal period. Serum levels of MMP-9, MMP-2, TIMP-1, TIMP-2, S100B, CCL-2, ICAM-1, P-selectin, and TSP-2 were examined in a group of 100 patients who were seizure-free for a minimum of seven days and analyzed by ELISA. The results were compared with an age- and sex-matched control group. Serum levels of MMP-9, MMP-2, TIMP-1, TIMP-2 and S100B were higher in patients with epilepsy in comparison to control group (p < 0.0001; <0.0001; 0.001; <0.0001; <0.0001, respectively). Levels of CCL-2, ICAM-1, P-selectin and TSP-2 did not differ between the two groups. Serum levels of MMP-9, MMP-2, TIMP-1, TIMP-2 and S100B are elevated in patients with epilepsy in the interictal period, which suggests chronic processes of BBB disruption and restoration. The pathological process initiating epilepsy, in addition to seizures, is probably the factor contributing to the elevation of serum levels of the examined molecules. Full article

(This article belongs to the Special Issue Extracellular Matrix Remodeling in Health, Regenerative Medicine and Disease)

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17 pages, 6171 KiB

Open AccessArticle

RNA-Seq of Dermal Fibroblasts from Patients with Hypermobile Ehlers–Danlos Syndrome and Hypermobility Spectrum Disorders Supports Their Categorization as a Single Entity with Involvement of Extracellular Matrix Degrading and Proinflammatory Pathomechanisms

by Marco Ritelli, Nicola Chiarelli, Valeria Cinquina, Nicoletta Zoppi, Valeria Bertini, Marina Venturini and Marina Colombi

Cells 2022, 11(24), 4040; https://doi.org/10.3390/cells11244040 - 14 Dec 2022

Cited by 4 | Viewed by 5159

Abstract

Hypermobile Ehlers–Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD) are clinically overlapping connective tissue disorders of unknown etiology and without any validated diagnostic biomarker and specific therapies. Herein, we in-depth characterized the cellular phenotype and gene expression profile of hEDS and HSD dermal fibroblasts by immunofluorescence, amplicon-based RNA-seq, and qPCR. We demonstrated that both cell types show a common cellular trait, i.e., generalized extracellular matrix (ECM) disarray, myofibroblast differentiation, and dysregulated gene expression. Functional enrichment and pathway analyses clustered gene expression changes in different biological networks that are likely relevant for the disease pathophysiology. Specifically, the complex gene expression dysregulation (mainly involving growth factors, structural ECM components, ECM-modifying enzymes, cytoskeletal proteins, and different signal transducers), is expected to perturb many ECM-related processes including cell adhesion, migration, proliferation, and differentiation. Based on these findings, we propose a disease model in which an unbalanced ECM remodeling triggers a vicious cycle with a synergistic contribution of ECM degradation products and proinflammatory mediators leading to a functional impairment of different connective tissues reflecting the multisystemic presentation of hEDS/HSD patients. Our results offer many promising clues for translational research aimed to define molecular bases, diagnostic biomarkers, and specific therapies for these challenging connective tissue disorders. Full article

(This article belongs to the Special Issue Extracellular Matrix Remodeling in Health, Regenerative Medicine and Disease)

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25 pages, 5209 KiB

Open AccessArticle

Bio-Engineered Scaffolds Derived from Decellularized Human Esophagus for Functional Organ Reconstruction

by Silvia Barbon, Andrea Biccari, Elena Stocco, Giovanni Capovilla, Edoardo D’Angelo, Martina Todesco, Deborah Sandrin, Andrea Bagno, Filippo Romanato, Veronica Macchi, Raffaele De Caro, Marco Agostini, Stefano Merigliano, Michele Valmasoni and Andrea Porzionato

Cells 2022, 11(19), 2945; https://doi.org/10.3390/cells11192945 - 20 Sep 2022

Cited by 7 | Viewed by 1900

Abstract

Esophageal reconstruction through bio-engineered allografts that highly resemble the peculiar properties of the tissue extracellular matrix (ECM) is a prospective strategy to overcome the limitations of current surgical approaches. In this work, human esophagus was decellularized for the first time in the literature by comparing three detergent-enzymatic protocols. After decellularization, residual DNA quantification and histological analyses showed that all protocols efficiently removed cells, DNA (<50 ng/mg of tissue) and muscle fibers, preserving collagen/elastin components. The glycosaminoglycan fraction was maintained (70–98%) in the decellularized versus native tissues, while immunohistochemistry showed unchanged expression of specific ECM markers (collagen IV, laminin). The proteomic signature of acellular esophagi corroborated the retention of structural collagens, basement membrane and matrix–cell interaction proteins. Conversely, decellularization led to the loss of HLA-DR expression, producing non-immunogenic allografts. According to hydroxyproline quantification, matrix collagen was preserved (2–6 µg/mg of tissue) after decellularization, while Second-Harmonic Generation imaging highlighted a decrease in collagen intensity. Based on uniaxial tensile tests, decellularization affected tissue stiffness, but sample integrity/manipulability was still maintained. Finally, the cytotoxicity test revealed that no harmful remnants/contaminants were present on acellular esophageal matrices, suggesting allograft biosafety. Despite the different outcomes showed by the three decellularization methods (regarding, for example, tissue manipulability, DNA removal, and glycosaminoglycans/hydroxyproline contents) the ultimate validation should be provided by future repopulation tests and in vivo orthotopic implant of esophageal scaffolds. Full article

(This article belongs to the Special Issue Extracellular Matrix Remodeling in Health, Regenerative Medicine and Disease)

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Review

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33 pages, 2480 KiB

Open AccessFeature PaperReview

Untangling the Extracellular Matrix of Idiopathic Epiretinal Membrane: A Path Winding among Structure, Interactomics and Translational Medicine

by Laura Bianchi, Annalisa Altera, Virginia Barone, Denise Bonente, Tommaso Bacci, Elena De Benedetto, Luca Bini, Gian Marco Tosi, Federico Galvagni and Eugenio Bertelli

Cells 2022, 11(16), 2531; https://doi.org/10.3390/cells11162531 - 15 Aug 2022

Cited by 8 | Viewed by 2403

Abstract

Idiopathic epiretinal membranes (iERMs) are fibrocellular sheets of tissue that develop at the vitreoretinal interface. The iERMs consist of cells and an extracellular matrix (ECM) formed by a complex array of structural proteins and a large number of proteins that regulate cell–matrix interaction, matrix deposition and remodelling. Many components of the ECM tend to produce a layered pattern that can influence the tractional properties of the membranes. We applied a bioinformatics approach on a list of proteins previously identified with an MS-based proteomic analysis on samples of iERM to report the interactome of some key proteins. The performed pathway analysis highlights interactions occurring among ECM molecules, their cell receptors and intra- or extracellular proteins that may play a role in matrix biology in this special context. In particular, integrin β1, cathepsin B, epidermal growth factor receptor, protein-glutamine gamma-glutamyltransferase 2 and prolow-density lipoprotein receptor-related protein 1 are key hubs in the outlined protein–protein cross-talks. A section on the biomarkers that can be found in the vitreous humor of patients affected by iERM and that can modulate matrix deposition is also presented. Finally, translational medicine in iERM treatment has been summed up taking stock of the techniques that have been proposed for pharmacologic vitreolysis. Full article

(This article belongs to the Special Issue Extracellular Matrix Remodeling in Health, Regenerative Medicine and Disease)

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