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Extracellular Matrix in Development and Disease 3.0
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Extracellular Matrix in Development and Disease 3.0

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 (15 July 2022) | Viewed by 61886

Special Issue Editor

Prof. Dr. Frank Zaucke

E-Mail Website
Guest Editor
Department of Orthopedics (Friedrichsheim), Medical Faculty, Goethe University Frankfurt, Frankfurt, Germany
Interests: extracellular matrix proteins; collagens; cartilage; bone; skeletal development; mouse models; chondrodysplasias; osteoarthritis; chondrogenesis; chondrocyte differentiation; skin homeostasis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue is a continuation of our previous Special Issue “Extracellular Matrix in Development and Disease” (https://www.mdpi.com/journal/ijms/special_issues/extracellular_matrix) and Special Issue "Extracellular Matrix in Development and Disease 2.0" (https://www.mdpi.com/journal/ijms/special_issues/extracellular_matrix2).

Extracellular matrix in development and disease 3.0. This Special Issue will deal with molecular and cellular aspects of the role of the extracellular matrix in development and disease. Cells exist in three-dimensional scaffolding called the extracellular matrix. The matrix holds together the millions of cells that make up our blood vessels, organs, skin, and all tissues of the body. The matrix serves as a reservoir of signaling molecules as well. In bacterial cultures, biofilms form as an extracellular matrix and play essential roles in disease and drug resistance. Topics such as matrix structure and function, cell attachment, and cell surface proteins mediating cell–matrix interactions, and the synthesis, regulation, composition, structure, assembly, remodeling, and function of the matrix are included.

A common thread uniting the topics is the essential nature that the matrix plays in normal development and pathophysiology. Providing new knowledge will lead us to improved diagnostics, preventions to disease progression, and therapeutic strategies for the repair and regeneration of tissues.

Prof. Dr. Frank Zaucke
Guest Editor

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Keywords

  • extracellular matrix
  • collagen
  • biofilm
  • embryonic development
  • degenerative disease
  • fibrosis
  • tissue engineering

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Published Papers (19 papers)

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18 pages, 2249 KiB  
Article
Integrins Increase Sarcoplasmic Reticulum Activity for Excitation—Contraction Coupling in Human Stem Cell-Derived Cardiomyocytes
by Brian X. Wang, Christopher Kane, Laura Nicastro, Oisín King, Worrapong Kit-Anan, Barrett Downing, Graziano Deidda, Liam S. Couch, Christian Pinali, Anna Mitraki, Kenneth T. MacLeod and Cesare M. Terracciano
Int. J. Mol. Sci. 2022, 23(18), 10940; https://doi.org/10.3390/ijms231810940 - 19 Sep 2022
Cited by 1 | Viewed by 2375
Abstract
Engagement of the sarcoplasmic reticulum (SR) Ca2+ stores for excitation–contraction (EC)-coupling is a fundamental feature of cardiac muscle cells. Extracellular matrix (ECM) proteins that form the extracellular scaffolding supporting cardiac contractile activity are thought to play an integral role in the modulation [...] Read more.
Engagement of the sarcoplasmic reticulum (SR) Ca2+ stores for excitation–contraction (EC)-coupling is a fundamental feature of cardiac muscle cells. Extracellular matrix (ECM) proteins that form the extracellular scaffolding supporting cardiac contractile activity are thought to play an integral role in the modulation of EC-coupling. At baseline, human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) show poor utilisation of SR Ca2+ stores, leading to inefficient EC-coupling, like developing or human CMs in cardiac diseases such as heart failure. We hypothesised that integrin ligand–receptor interactions between ECM proteins and CMs recruit the SR to Ca2+ cycling during EC-coupling. hiPSC-CM monolayers were cultured on fibronectin-coated glass before 24 h treatment with fibril-forming peptides containing the integrin-binding tripeptide sequence arginine–glycine–aspartic acid (2 mM). Micropipette application of 40 mM caffeine in standard or Na+/Ca2+-free Tyrode’s solutions was used to assess the Ca2+ removal mechanisms. Microelectrode recordings were conducted to analyse action potentials in current-clamp. Confocal images of labelled hiPSC-CMs were analysed to investigate hiPSC-CM morphology and ultrastructural arrangements in Ca2+ release units. This study demonstrates that peptides containing the integrin-binding sequence arginine–glycine–aspartic acid (1) abbreviate hiPSC-CM Ca2+ transient and action potential duration, (2) increase co-localisation between L-type Ca2+ channels and ryanodine receptors involved in EC-coupling, and (3) increase the rate of SR-mediated Ca2+ cycling. We conclude that integrin-binding peptides induce recruitment of the SR for Ca2+ cycling in EC-coupling through functional and structural improvements and demonstrate the importance of the ECM in modulating cardiomyocyte function in physiology. Full article
(This article belongs to the Special Issue Extracellular Matrix in Development and Disease 3.0)
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20 pages, 3455 KiB  
Article
The IRE1α–XBP1s Arm of the Unfolded Protein Response Activates N-Glycosylation to Remodel the Subepithelial Basement Membrane in Paramyxovirus Infection
by Yingxin Zhao, Dianhua Qiao, Melissa Skibba and Allan R. Brasier
Int. J. Mol. Sci. 2022, 23(16), 9000; https://doi.org/10.3390/ijms23169000 - 12 Aug 2022
Cited by 4 | Viewed by 1843
Abstract
Respiratory syncytial virus (RSV) causes severe lower respiratory tract infections (LRTI) associated with decreased pulmonary function, asthma, and allergy. Recently, we demonstrated that RSV induces the hexosamine biosynthetic pathway via the unfolded protein response (UPR), which is a pathway controlling protein glycosylation and [...] Read more.
Respiratory syncytial virus (RSV) causes severe lower respiratory tract infections (LRTI) associated with decreased pulmonary function, asthma, and allergy. Recently, we demonstrated that RSV induces the hexosamine biosynthetic pathway via the unfolded protein response (UPR), which is a pathway controlling protein glycosylation and secretion of the extracellular matrix (ECM). Because the presence of matrix metalloproteinases and matricellular growth factors (TGF) is associated with severe LRTI, we studied the effect of RSV on ECM remodeling and found that RSV enhances the deposition of fibronectin-rich ECM by small airway epithelial cells in a manner highly dependent on the inositol requiring kinase (IRE1α)–XBP1 arm of the UPR. To understand this effect comprehensively, we applied pharmacoproteomics to understand the effect of the UPR on N-glycosylation and ECM secretion in RSV infection. We observe that RSV induces N-glycosylation and the secretion of proteins related to ECM organization, secretion, or proteins integral to plasma membranes, such as integrins, laminins, collagens, and ECM-modifying enzymes, in an IRE1α–XBP1 dependent manner. Using a murine paramyxovirus model that activates the UPR in vivo, we validate the IRE1α–XBP1-dependent secretion of ECM to alveolar space. This study extends understanding of the IRE1α–XBP1 pathway in regulating N-glycosylation coupled to structural remodeling of the epithelial basement membrane in RSV infection. Full article
(This article belongs to the Special Issue Extracellular Matrix in Development and Disease 3.0)
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15 pages, 477 KiB  
Article
Cellular Environment and Phenotypic Heterogeneity: How Data-Driven Modeling Finds the Smoking Gun
by Marie Guilbert, Emmanuel Courtade and Quentin Thommen
Int. J. Mol. Sci. 2022, 23(12), 6536; https://doi.org/10.3390/ijms23126536 - 10 Jun 2022
Viewed by 1481
Abstract
The cellular environment modifies cellular phenotypes, in particular, the stress response phenotype, which easily exhibits high phenotypic heterogeneity due to the common characteristics of its regulatory networks. The aim of this work is to quantify and interpret the impact of collagen type I, [...] Read more.
The cellular environment modifies cellular phenotypes, in particular, the stress response phenotype, which easily exhibits high phenotypic heterogeneity due to the common characteristics of its regulatory networks. The aim of this work is to quantify and interpret the impact of collagen type I, a major component of the cellular environment, on the phenotypic heterogeneity of the cellular response. Our approach combines in an original way the monitoring of the response of a single cell and the mathematical modeling of the network. After a detailed statistical description of the phenotypic heterogeneity of the cellular response, the mathematical modeling explains how the observed changes can be explained by an induced increase in the average expression of a central protein of the regulatory network. The predictions of the data-driven model are fully consistent with the biochemical measurements performed. The framework presented here is also a new general methodology to study phenotypic heterogeneity, although we focus here on the response to proteotoxic stress in HeLa cells. Full article
(This article belongs to the Special Issue Extracellular Matrix in Development and Disease 3.0)
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16 pages, 2415 KiB  
Article
The Thermal Stability of the Collagen Triple Helix Is Tuned According to the Environmental Temperature
by Kazunori K. Fujii, Yuki Taga, Yusuke K. Takagi, Ryo Masuda, Shunji Hattori and Takaki Koide
Int. J. Mol. Sci. 2022, 23(4), 2040; https://doi.org/10.3390/ijms23042040 - 12 Feb 2022
Cited by 10 | Viewed by 4439
Abstract
Triple helix formation of procollagen occurs in the endoplasmic reticulum (ER) where the single-stranded α-chains of procollagen undergo extensive post-translational modifications. The modifications include prolyl 4- and 3-hydroxylations, lysyl hydroxylation, and following glycosylations. The modifications, especially prolyl 4-hydroxylation, enhance the thermal stability of [...] Read more.
Triple helix formation of procollagen occurs in the endoplasmic reticulum (ER) where the single-stranded α-chains of procollagen undergo extensive post-translational modifications. The modifications include prolyl 4- and 3-hydroxylations, lysyl hydroxylation, and following glycosylations. The modifications, especially prolyl 4-hydroxylation, enhance the thermal stability of the procollagen triple helix. Procollagen molecules are transported to the Golgi and secreted from the cell, after the triple helix is formed in the ER. In this study, we investigated the relationship between the thermal stability of the collagen triple helix and environmental temperature. We analyzed the number of collagen post-translational modifications and thermal melting temperature and α-chain composition of secreted type I collagen in zebrafish embryonic fibroblasts (ZF4) cultured at various temperatures (18, 23, 28, and 33 °C). The results revealed that thermal stability and other properties of collagen were almost constant when ZF4 cells were cultured below 28 °C. By contrast, at a higher temperature (33 °C), an increase in the number of post-translational modifications and a change in α-chain composition of type I collagen were observed; hence, the collagen acquired higher thermal stability. The results indicate that the thermal stability of collagen could be autonomously tuned according to the environmental temperature in poikilotherms. Full article
(This article belongs to the Special Issue Extracellular Matrix in Development and Disease 3.0)
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12 pages, 5944 KiB  
Article
Osr1 Is Required for Mesenchymal Derivatives That Produce Collagen in the Bladder
by Vasikar Murugapoopathy, Philippe G. Cammisotto, Abubakr H. Mossa, Lysanne Campeau and Indra R. Gupta
Int. J. Mol. Sci. 2021, 22(22), 12387; https://doi.org/10.3390/ijms222212387 - 17 Nov 2021
Cited by 3 | Viewed by 1746
Abstract
The extracellular matrix of the bladder consists mostly of type I and III collagen, which are required during loading. During bladder injury, there is an accumulation of collagen that impairs bladder function. Little is known about the genes that regulate production of collagens [...] Read more.
The extracellular matrix of the bladder consists mostly of type I and III collagen, which are required during loading. During bladder injury, there is an accumulation of collagen that impairs bladder function. Little is known about the genes that regulate production of collagens in the bladder. We demonstrate that the transcription factor Odd-skipped related 1 (Osr1) is expressed in the bladder mesenchyme and epithelium at the onset of development. As development proceeds, Osr1 is mainly expressed in mesenchymal progenitors and their derivatives. We hypothesized that Osr1 regulates mesenchymal cell differentiation and production of collagens in the bladder. To test this hypothesis, we examined newborn and adult mice heterozygous for Osr1, Osr1+/−. The bladders of newborn Osr1+/− mice had a decrease in collagen I by western blot analysis and a global decrease in collagens using Sirius red staining. There was also a decrease in the cellularity of the lamina propria, where most collagen is synthesized. This was not due to decreased proliferation or increased apoptosis in this cell population. Surprisingly, the bladders of adult Osr1+/− mice had an increase in collagen that was associated with abnormal bladder function; they also had a decrease in bladder capacity and voided more frequently. The results suggest that Osr1 is important for the differentiation of mesenchymal cells that give rise to collagen-producing cells. Full article
(This article belongs to the Special Issue Extracellular Matrix in Development and Disease 3.0)
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16 pages, 1777 KiB  
Article
Fibrotic Changes to Schlemm’s Canal Endothelial Cells in Glaucoma
by Ruth A. Kelly, Kristin M. Perkumas, Matthew Campbell, G. Jane Farrar, W. Daniel Stamer, Pete Humphries, Jeffrey O’Callaghan and Colm J. O’Brien
Int. J. Mol. Sci. 2021, 22(17), 9446; https://doi.org/10.3390/ijms22179446 - 31 Aug 2021
Cited by 16 | Viewed by 2828
Abstract
Previous studies have shown that glaucomatous Schlemm’s canal endothelial cells (gSCECs) are stiffer and associated with reduced porosity and increased extracellular matrix (ECM) material compared to SCECs from healthy individuals. We hypothesised that Schlemm’s canal (SC) cell stiffening was a function of fibrotic [...] Read more.
Previous studies have shown that glaucomatous Schlemm’s canal endothelial cells (gSCECs) are stiffer and associated with reduced porosity and increased extracellular matrix (ECM) material compared to SCECs from healthy individuals. We hypothesised that Schlemm’s canal (SC) cell stiffening was a function of fibrotic changes occurring at the inner wall of SC in glaucoma. This study was performed in primary cell cultures isolated from the SC lumen of human donor eyes. RNA and protein quantification of both fibrotic and endothelial cell markers was carried out on both healthy and gSCECs. Functional assays to assess cell density, size, migration, proliferation, and mitochondrial function of these cells were also carried out. Indeed, we found that gSCECs deviate from typical endothelial cell characteristics and exhibit a more fibrotic phenotype. For example, gSCECs expressed significantly higher protein levels of the fibrotic markers α-SMA, collagen I-α1, and fibronectin, as well as significantly increased protein expression of TGFβ-2, the main driver of fibrosis, compared to healthy SCECs. Interestingly, we observed a significant increase in protein expression of endothelial marker VE-cadherin in gSCECs, compared to healthy SCECs. gSCECs also appeared to be significantly larger, and surprisingly proliferate and migrate at a significantly higher rate, as well as showing significantly reduced mitochondrial activity, compared to healthy SCECs. Full article
(This article belongs to the Special Issue Extracellular Matrix in Development and Disease 3.0)
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18 pages, 38820 KiB  
Article
Cardiac Extracellular Matrix Hydrogel Enriched with Polyethylene Glycol Presents Improved Gelation Time and Increased On-Target Site Retention of Extracellular Vesicles
by Lidia Gómez-Cid, María Luisa López-Donaire, Diego Velasco, Víctor Marín, María Isabel González, Beatriz Salinas, Lorena Cussó, Ángel García, Susana Belén Bravo, María Eugenia Fernández-Santos, Carlos Elvira, Johanna Sierra, Ester Arroba, Rafael Bañares, Lilian Grigorian-Shamagian and Francisco Fernández-Avilés
Int. J. Mol. Sci. 2021, 22(17), 9226; https://doi.org/10.3390/ijms22179226 - 26 Aug 2021
Cited by 12 | Viewed by 3251
Abstract
Stem-cell-derived extracellular vesicles (EVs) have demonstrated multiple beneficial effects in preclinical models of cardiac diseases. However, poor retention at the target site may limit their therapeutic efficacy. Cardiac extracellular matrix hydrogels (cECMH) seem promising as drug-delivery materials and could improve the retention of [...] Read more.
Stem-cell-derived extracellular vesicles (EVs) have demonstrated multiple beneficial effects in preclinical models of cardiac diseases. However, poor retention at the target site may limit their therapeutic efficacy. Cardiac extracellular matrix hydrogels (cECMH) seem promising as drug-delivery materials and could improve the retention of EVs, but may be limited by their long gelation time and soft mechanical properties. Our objective was to develop and characterize an optimized product combining cECMH, polyethylene glycol (PEG), and EVs (EVs–PEG–cECMH) in an attempt to overcome their individual limitations: long gelation time of the cECMH and poor retention of the EVs. The new combined product presented improved physicochemical properties (60% reduction in half gelation time, p < 0.001, and threefold increase in storage modulus, p < 0.01, vs. cECMH alone), while preserving injectability and biodegradability. It also maintained in vitro bioactivity of its individual components (55% reduction in cellular senescence vs. serum-free medium, p < 0.001, similar to EVs and cECMH alone) and increased on-site retention in vivo (fourfold increase vs. EVs alone, p < 0.05). In conclusion, the combination of EVs–PEG–cECMH is a potential multipronged product with improved gelation time and mechanical properties, increased on-site retention, and maintained bioactivity that, all together, may translate into boosted therapeutic efficacy. Full article
(This article belongs to the Special Issue Extracellular Matrix in Development and Disease 3.0)
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16 pages, 7523 KiB  
Article
Impact of Porcine Pancreas Decellularization Conditions on the Quality of Obtained dECM
by Marta Klak, Ilona Łojszczyk, Andrzej Berman, Grzegorz Tymicki, Anna Adamiok-Ostrowska, Maciej Sierakowski, Radosław Olkowski, Andrzej Antoni Szczepankiewicz, Artur Kamiński, Agnieszka Dobrzyń and Michał Wszoła
Int. J. Mol. Sci. 2021, 22(13), 7005; https://doi.org/10.3390/ijms22137005 - 29 Jun 2021
Cited by 12 | Viewed by 3351
Abstract
Due to the limited number of organ donors, 3D printing of organs is a promising technique. Tissue engineering is increasingly using xenogeneic material for this purpose. This study was aimed at assessing the safety of decellularized porcine pancreas, together with the analysis of [...] Read more.
Due to the limited number of organ donors, 3D printing of organs is a promising technique. Tissue engineering is increasingly using xenogeneic material for this purpose. This study was aimed at assessing the safety of decellularized porcine pancreas, together with the analysis of the risk of an undesirable immune response. We tested eight variants of the decellularization process. We determined the following impacts: rinsing agents (PBS/NH3·H2O), temperature conditions (4 °C/24 °C), and the grinding method of native material (ground/cut). To assess the quality of the extracellular matrix after the completed decellularization process, analyses of the following were performed: DNA concentration, fat content, microscopic evaluation, proteolysis, material cytotoxicity, and most importantly, the Triton X-100 content. Our analyses showed that we obtained a product with an extremely low detergent content with negligible residual DNA content. The obtained results confirmed the performed histological and immuno-fluorescence staining. Moreover, the TEM microscopic analysis proved that the correct collagen structure was preserved after the decellularization process. Based on the obtained results, we chose the most favorable variant in terms of quality and biology. The method we chose is an effective and safe method that gives a chance for the development of transplant and regenerative medicine. Full article
(This article belongs to the Special Issue Extracellular Matrix in Development and Disease 3.0)
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18 pages, 16837 KiB  
Article
Interactions via α2β1 Cell Integrin May Protect against the Progression of Airway Structural Changes in Asthma
by Stanislawa Bazan-Socha, Bogdan Jakiela, Joanna Zuk, Jacek Zarychta, Jerzy Soja, Krzysztof Okon, Sylwia Dziedzina, Lech Zareba, Jerzy Dropinski, Krzysztof Wojcik, Agnieszka Padjas, Cezary Marcinkiewicz and Jan G. Bazan
Int. J. Mol. Sci. 2021, 22(12), 6315; https://doi.org/10.3390/ijms22126315 - 12 Jun 2021
Cited by 2 | Viewed by 2438
Abstract
Increased airway wall thickness and remodeling of bronchial mucosa are characteristic of asthma and may arise from altered integrin signaling on airway cells. Here, we analyzed the expression of β1-subfamily integrins on blood and airway cells (flow cytometry), inflammatory biomarkers in [...] Read more.
Increased airway wall thickness and remodeling of bronchial mucosa are characteristic of asthma and may arise from altered integrin signaling on airway cells. Here, we analyzed the expression of β1-subfamily integrins on blood and airway cells (flow cytometry), inflammatory biomarkers in serum and bronchoalveolar lavage, reticular basement membrane (RBM) thickness and collagen deposits in the mucosa (histology), and airway geometry (CT-imaging) in 92 asthma patients (persistent airflow limitation subtype: n = 47) and 36 controls. Persistent airflow limitation was associated with type-2 inflammation, elevated soluble α2 integrin chain, and changes in the bronchial wall geometry. Both subtypes of asthma showed thicker RBM than control, but collagen deposition and epithelial α1 and α2 integrins staining were similar. Type-I collagen accumulation and RBM thickness were inversely related to the epithelial expression of the α2 integrin chain. Expression of α2β1 integrin on T-cells and eosinophils was not altered in asthma. Collagen I deposits were, however, more abundant in patients with lower α2β1 integrin on blood and airway CD8+ T-cells. Thicker airway walls in CT were associated with lower α2 integrin chain on blood CD4+ T-cells and airway eosinophils. Our data suggest that α2β1 integrin on inflammatory and epithelial cells may protect against airway remodeling advancement in asthma. Full article
(This article belongs to the Special Issue Extracellular Matrix in Development and Disease 3.0)
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23 pages, 5062 KiB  
Article
Decellularized Porcine Cartilage Scaffold; Validation of Decellularization and Evaluation of Biomarkers of Chondrogenesis
by Roxanne N. Stone, Stephanie M. Frahs, Makenna J. Hardy, Akina Fujimoto, Xinzhu Pu, Cynthia Keller-Peck and Julia Thom Oxford
Int. J. Mol. Sci. 2021, 22(12), 6241; https://doi.org/10.3390/ijms22126241 - 9 Jun 2021
Cited by 10 | Viewed by 4039
Abstract
Osteoarthritis is a major concern in the United States and worldwide. Current non-surgical and surgical approaches alleviate pain but show little evidence of cartilage restoration. Cell-based treatments may hold promise for the regeneration of hyaline cartilage-like tissue at the site of injury or [...] Read more.
Osteoarthritis is a major concern in the United States and worldwide. Current non-surgical and surgical approaches alleviate pain but show little evidence of cartilage restoration. Cell-based treatments may hold promise for the regeneration of hyaline cartilage-like tissue at the site of injury or wear. Cell–cell and cell–matrix interactions have been shown to drive cell differentiation pathways. Biomaterials for clinically relevant applications can be generated from decellularized porcine auricular cartilage. This material may represent a suitable scaffold on which to seed and grow chondrocytes to create new cartilage. In this study, we used decellularization techniques to create an extracellular matrix scaffold that supports chondrocyte cell attachment and growth in tissue culture conditions. Results presented here evaluate the decellularization process histologically and molecularly. We identified new and novel biomarker profiles that may aid future cartilage decellularization efforts. Additionally, the resulting scaffold was characterized using scanning electron microscopy, fluorescence microscopy, and proteomics. Cellular response to the decellularized scaffold was evaluated by quantitative real-time PCR for gene expression analysis. Full article
(This article belongs to the Special Issue Extracellular Matrix in Development and Disease 3.0)
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19 pages, 17974 KiB  
Article
Heparan Sulfate Deficiency in Cartilage: Enhanced BMP-Sensitivity, Proteoglycan Production and an Anti-Apoptotic Expression Signature after Loading
by Matthias Gerstner, Ann-Christine Severmann, Safak Chasan, Andrea Vortkamp and Wiltrud Richter
Int. J. Mol. Sci. 2021, 22(7), 3726; https://doi.org/10.3390/ijms22073726 - 2 Apr 2021
Cited by 4 | Viewed by 3513
Abstract
Osteoarthritis (OA) represents one major cause of disability worldwide still evading efficient pharmacological or cellular therapies. Severe degeneration of extracellular cartilage matrix precedes the loss of mobility and disabling pain perception in affected joints. Recent studies showed that a reduced heparan sulfate (HS) [...] Read more.
Osteoarthritis (OA) represents one major cause of disability worldwide still evading efficient pharmacological or cellular therapies. Severe degeneration of extracellular cartilage matrix precedes the loss of mobility and disabling pain perception in affected joints. Recent studies showed that a reduced heparan sulfate (HS) content protects cartilage from degradation in OA-animal models of joint destabilization but the underlying mechanisms remained unclear. We aimed to clarify whether low HS-content alters the mechano-response of chondrocytes and to uncover pathways relevant for HS-related chondro-protection in response to loading. Tissue-engineered cartilage with HS-deficiency was generated from rib chondrocytes of mice carrying a hypomorphic allele of Exostosin 1 (Ext1), one of the main HS-synthesizing enzymes, and wildtype (WT) littermate controls. Engineered cartilage matured for 2 weeks was exposed to cyclic unconfined compression in a bioreactor. The molecular loading response was determined by transcriptome profiling, bioinformatic data processing, and qPCR. HS-deficient chondrocytes expressed 3–6% of WT Ext1-mRNA levels. Both groups similarly raised Sox9, Col2a1 and Acan levels during maturation. However, HS-deficient chondrocytes synthesized and deposited 50% more GAG/DNA. TGFβ and FGF2-sensitivity of Ext1gt/gt chondrocytes was similar to WT cells but their response to BMP-stimulation was enhanced. Loading induced similar activation of mechano-sensitive ERK and P38-signaling in WT and HS-reduced chondrocytes. Transcriptome analysis reflected regulation of cell migration as major load-induced biological process with similar stimulation of common (Fosl1, Itgα5, Timp1, and Ngf) as well as novel mechano-regulated genes (Inhba and Dhrs9). Remarkably, only Ext1-hypomorphic cartilage responded to loading by an expression signature of negative regulation of apoptosis with pro-apoptotic Bnip3 being selectively down-regulated. HS-deficiency enhanced BMP-sensitivity, GAG-production and fostered an anti-apoptotic expression signature after loading, all of which may protect cartilage from load-induced erosion. Full article
(This article belongs to the Special Issue Extracellular Matrix in Development and Disease 3.0)
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14 pages, 3866 KiB  
Article
Hypoxia Inducible Factor 1A Supports a Pro-Fibrotic Phenotype Loop in Idiopathic Pulmonary Fibrosis
by Gali Epstein Shochet, Becky Bardenstein-Wald, Mary McElroy, Andrew Kukuy, Mark Surber, Evgeny Edelstein, Barak Pertzov, Mordechai Reuven Kramer and David Shitrit
Int. J. Mol. Sci. 2021, 22(7), 3331; https://doi.org/10.3390/ijms22073331 - 24 Mar 2021
Cited by 25 | Viewed by 3731
Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with poor prognosis. The IPF-conditioned matrix (IPF-CM) system enables the study of matrix–fibroblast interplay. While effective at slowing fibrosis, nintedanib has limitations and the mechanism is not fully elucidated. In the current work, we [...] Read more.
Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with poor prognosis. The IPF-conditioned matrix (IPF-CM) system enables the study of matrix–fibroblast interplay. While effective at slowing fibrosis, nintedanib has limitations and the mechanism is not fully elucidated. In the current work, we explored the underlying signaling pathways and characterized nintedanib involvement in the IPF-CM fibrotic process. Results were validated using IPF patient samples and bleomycin-treated animals with/without oral and inhaled nintedanib. IPF-derived primary human lung fibroblasts (HLFs) were cultured on Matrigel and then cleared using NH4OH, creating the IPF-CM. Normal HLF-CM served as control. RNA-sequencing, PCR and western-blots were performed. HIF1α targets were evaluated by immunohistochemistry in bleomycin-treated rats with/without nintedanib and in patient samples with IPF. HLFs cultured on IPF-CM showed over-expression of ‘HIF1α signaling pathway’ (KEGG, p < 0.0001), with emphasis on SERPINE1 (PAI-1), VEGFA and TIMP1. IPF patient samples showed high HIF1α staining, especially in established fibrous tissue. PAI-1 was overexpressed, mainly in alveolar macrophages. Nintedanib completely reduced HIF1α upregulation in the IPF-CM and rat-bleomycin models. IPF-HLFs alter the extracellular matrix, thus creating a matrix that further propagates an IPF-like phenotype in normal HLFs. This pro-fibrotic loop includes the HIF1α pathway, which can be blocked by nintedanib. Full article
(This article belongs to the Special Issue Extracellular Matrix in Development and Disease 3.0)
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14 pages, 3031 KiB  
Article
The Glycoprotein/Cytokine Erythropoietin Promotes Rapid Alveolar Ridge Regeneration In Vivo by Promoting New Bone Extracellular Matrix Deposition in Conjunction with Coupled Angiogenesis/Osteogenesis
by Mirali Pandya, Matthew Saxon, John Bozanich, Connie Tillberg, Xianghong Luan and Thomas G.H. Diekwisch
Int. J. Mol. Sci. 2021, 22(6), 2788; https://doi.org/10.3390/ijms22062788 - 10 Mar 2021
Cited by 16 | Viewed by 3137
Abstract
The loss of bone following tooth extraction poses a significant clinical problem for maxillofacial esthetics, function, and future implant placement. In the present study, the efficacy of an erythropoietin-impregnated collagen scaffold as an alveolar ridge augmentation material versus a conventional collagen scaffold and [...] Read more.
The loss of bone following tooth extraction poses a significant clinical problem for maxillofacial esthetics, function, and future implant placement. In the present study, the efficacy of an erythropoietin-impregnated collagen scaffold as an alveolar ridge augmentation material versus a conventional collagen scaffold and a BioOss inorganic bovine bone xenograft was examined. The collagen/Erythropoietin (EPO) scaffold exhibited significantly more rapid and complete osseous regeneration of the alveolar defect when compared to bone xenograft and the collagen membrane alone. The new EPO induced extracellular matrix was rich in Collagen I, Collagen III, Fibronectin (Fn) and E-cadherin, and featured significantly increased levels of the osteogenic transcription factors Runt-related transcription factor 2 (Runx2) and Osterix (Osx). Histomorphometric evaluation revealed a significant two-fold increase in the number of capillaries between the EPO and the BioOss group. Moreover, there was a highly significant 3.5-fold higher level of vascular endothelial growth factor (VEGF) in the collagen/EPO-treated group compared to controls. The significant effect of EPO on VEGF, FN, and RUNX2 upregulation was confirmed in vitro, and VEGF pathway analysis using VEGF inhibitors confirmed that EPO modulated extracellular matrix protein expression through VEGF even in the absence of blood vessels. Together, these data demonstrate the effectiveness of an EPO-impregnated collagen scaffold for bone regeneration as it induces rapid matrix production and osseoinduction adjacent to new capillaries via VEGF. Full article
(This article belongs to the Special Issue Extracellular Matrix in Development and Disease 3.0)
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Review

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17 pages, 665 KiB  
Review
Matrix Metalloproteinases in Dental and Periodontal Tissues and Their Current Inhibitors: Developmental, Degradational and Pathological Aspects
by Moataz Elgezawi, Rasha Haridy, Khalid Almas, Moamen A. Abdalla, Omar Omar, Hatem Abuohashish, Abeer Elembaby, Uta Christine Wölfle, Yasir Siddiqui and Dalia Kaisarly
Int. J. Mol. Sci. 2022, 23(16), 8929; https://doi.org/10.3390/ijms23168929 - 11 Aug 2022
Cited by 16 | Viewed by 3777
Abstract
Objectives: This review article aims to describe some of the roles of Matrix metalloproteinases (MMPs) in enamel, dentine, dental caries, hybrid layer degradation, pulp and periodontal tissues, throwing light on their current inhibitors. The article addresses the potential of MMPs to serve as [...] Read more.
Objectives: This review article aims to describe some of the roles of Matrix metalloproteinases (MMPs) in enamel, dentine, dental caries, hybrid layer degradation, pulp and periodontal tissues, throwing light on their current inhibitors. The article addresses the potential of MMPs to serve as biomarkers with diagnostic and therapeutic value. Design: The sections of this review discuss MMPs’ involvement in developmental, remodeling, degradational and turnover aspects of dental and periodontal tissues as well as their signals in the pathogenesis, progress of different lesions and wound healing of these tissues. The literature was searched for original research articles, review articles and theses. The literature search was conducted in PubMed and MEDLINE for articles published in the last 20 years. Results: 119 published papers, two textbooks and two doctoral theses were selected for preparing the current review. Conclusions: MMPs are significant proteases, of evident contribution in dental and periapical tissue development, health and disease processes, with promising potential for use as diagnostic and prognostic disease biomarkers. Continuing understanding of their role in pathogenesis and progress of different dental, periapical and periodontal lesions, as well as in dentine-pulp wound healing could be a keystone to future diagnostic and therapeutic regimens. Full article
(This article belongs to the Special Issue Extracellular Matrix in Development and Disease 3.0)
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16 pages, 1652 KiB  
Review
Molecular Mechanisms of Changes in Homeostasis of the Dermal Extracellular Matrix: Both Involutional and Mediated by Ultraviolet Radiation
by Alla Zorina, Vadim Zorin, Dmitry Kudlay and Pavel Kopnin
Int. J. Mol. Sci. 2022, 23(12), 6655; https://doi.org/10.3390/ijms23126655 - 15 Jun 2022
Cited by 18 | Viewed by 5939
Abstract
Skin aging is a multi-factorial process that affects nearly every aspect of skin biology and function. With age, an impairment of structures, quality characteristics, and functions of the dermal extracellular matrix (ECM) occurs in the skin, which leads to disrupted functioning of dermal [...] Read more.
Skin aging is a multi-factorial process that affects nearly every aspect of skin biology and function. With age, an impairment of structures, quality characteristics, and functions of the dermal extracellular matrix (ECM) occurs in the skin, which leads to disrupted functioning of dermal fibroblasts (DFs), the main cells supporting morphofunctional organization of the skin. The DF functioning directly depends on the state of the surrounding collagen matrix (CM). The intact collagen matrix ensures proper adhesion and mechanical tension in DFs, which allows these cells to maintain collagen homeostasis while ECM correctly regulates cellular processes. When the integrity of CM is destroyed, mechanotransduction is disrupted, which is accompanied by impairment of DF functioning and destruction of collagen homeostasis, thereby contributing to the progression of aging processes in skin tissues. This article considers in detail the processes of skin aging and associated changes in the skin layers, as well as the mechanisms of these processes at the molecular level. Full article
(This article belongs to the Special Issue Extracellular Matrix in Development and Disease 3.0)
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20 pages, 4765 KiB  
Review
Understanding the Renal Fibrotic Process in Leptospirosis
by Luan Gavião Prado and Angela Silva Barbosa
Int. J. Mol. Sci. 2021, 22(19), 10779; https://doi.org/10.3390/ijms221910779 - 5 Oct 2021
Cited by 3 | Viewed by 2894 | Correction
Abstract
Leptospirosis is a neglected infectious disease caused by pathogenic species of the genus Leptospira. The acute disease is well-described, and, although it resembles other tropical diseases, it can be diagnosed through the use of serological and molecular methods. While the chronic renal [...] Read more.
Leptospirosis is a neglected infectious disease caused by pathogenic species of the genus Leptospira. The acute disease is well-described, and, although it resembles other tropical diseases, it can be diagnosed through the use of serological and molecular methods. While the chronic renal disease, carrier state, and kidney fibrosis due to Leptospira infection in humans have been the subject of discussion by researchers, the mechanisms involved in these processes are still overlooked, and relatively little is known about the establishment and maintenance of the chronic status underlying this infectious disease. In this review, we highlight recent findings regarding the cellular communication pathways involved in the renal fibrotic process, as well as the relationship between renal fibrosis due to leptospirosis and CKD/CKDu. Full article
(This article belongs to the Special Issue Extracellular Matrix in Development and Disease 3.0)
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22 pages, 2310 KiB  
Review
Mechanotransducive Biomimetic Systems for Chondrogenic Differentiation In Vitro
by Ilona Uzieliene, Daiva Bironaite, Paulius Bernotas, Arkadij Sobolev and Eiva Bernotiene
Int. J. Mol. Sci. 2021, 22(18), 9690; https://doi.org/10.3390/ijms22189690 - 7 Sep 2021
Cited by 24 | Viewed by 4320
Abstract
Osteoarthritis (OA) is a long-term chronic joint disease characterized by the deterioration of bones and cartilage, which results in rubbing of bones which causes joint stiffness, pain, and restriction of movement. Tissue engineering strategies for repairing damaged and diseased cartilage tissue have been [...] Read more.
Osteoarthritis (OA) is a long-term chronic joint disease characterized by the deterioration of bones and cartilage, which results in rubbing of bones which causes joint stiffness, pain, and restriction of movement. Tissue engineering strategies for repairing damaged and diseased cartilage tissue have been widely studied with various types of stem cells, chondrocytes, and extracellular matrices being on the lead of new discoveries. The application of natural or synthetic compound-based scaffolds for the improvement of chondrogenic differentiation efficiency and cartilage tissue engineering is of great interest in regenerative medicine. However, the properties of such constructs under conditions of mechanical load, which is one of the most important factors for the successful cartilage regeneration and functioning in vivo is poorly understood. In this review, we have primarily focused on natural compounds, particularly extracellular matrix macromolecule-based scaffolds and their combinations for the chondrogenic differentiation of stem cells and chondrocytes. We also discuss different mechanical forces and compression models that are used for In Vitro studies to improve chondrogenic differentiation. Summary of provided mechanical stimulation models In Vitro reviews the current state of the cartilage tissue regeneration technologies and to the potential for more efficient application of cell- and scaffold-based technologies for osteoarthritis or other cartilage disorders. Full article
(This article belongs to the Special Issue Extracellular Matrix in Development and Disease 3.0)
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16 pages, 3816 KiB  
Review
Targeting the Extracellular Matrix in Abdominal Aortic Aneurysms Using Molecular Imaging Insights
by Lisa Adams, Julia Brangsch, Bernd Hamm, Marcus R. Makowski and Sarah Keller
Int. J. Mol. Sci. 2021, 22(5), 2685; https://doi.org/10.3390/ijms22052685 - 7 Mar 2021
Cited by 10 | Viewed by 3379
Abstract
This review outlines recent preclinical and clinical advances in molecular imaging of abdominal aortic aneurysms (AAA) with a focus on molecular magnetic resonance imaging (MRI) of the extracellular matrix (ECM). In addition, developments in pharmacologic treatment of AAA targeting the ECM will be [...] Read more.
This review outlines recent preclinical and clinical advances in molecular imaging of abdominal aortic aneurysms (AAA) with a focus on molecular magnetic resonance imaging (MRI) of the extracellular matrix (ECM). In addition, developments in pharmacologic treatment of AAA targeting the ECM will be discussed and results from animal studies will be contrasted with clinical trials. Abdominal aortic aneurysm (AAA) is an often fatal disease without non-invasive pharmacologic treatment options. The ECM, with collagen type I and elastin as major components, is the key structural component of the aortic wall and is recognized as a target tissue for both initiation and the progression of AAA. Molecular imaging allows in vivo measurement and characterization of biological processes at the cellular and molecular level and sets forth to visualize molecular abnormalities at an early stage of disease, facilitating novel diagnostic and therapeutic pathways. By providing surrogate criteria for the in vivo evaluation of the effects of pharmacological therapies, molecular imaging techniques targeting the ECM can facilitate pharmacological drug development. In addition, molecular targets can also be used in theranostic approaches that have the potential for timely diagnosis and concurrent medical therapy. Recent successes in preclinical studies suggest future opportunities for clinical translation. However, further clinical studies are needed to validate the most promising molecular targets for human application. Full article
(This article belongs to the Special Issue Extracellular Matrix in Development and Disease 3.0)
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Other

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3 pages, 214 KiB  
Correction
Correction: Prado, L.G.; Barbosa, A.S. Understanding the Renal Fibrotic Process in Leptospirosis. Int. J. Mol. Sci. 2021, 22, 10779
by Luan Gavião Prado and Angela Silva Barbosa
Int. J. Mol. Sci. 2022, 23(16), 9233; https://doi.org/10.3390/ijms23169233 - 17 Aug 2022
Cited by 1 | Viewed by 1045
Abstract
The authors wish to make the following corrections to this paper [...] Full article
(This article belongs to the Special Issue Extracellular Matrix in Development and Disease 3.0)
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