Figure 1 - available via license: Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
Content may be subject to copyright.
![Schematic Representation of Extracellular Matrix Underlying Epithelial Cells. Image adapted from [1, 2].](publication/349487572/figure/fig1/AS:1022810013069319@1620868318117/Schematic-Representation-of-Extracellular-Matrix-Underlying-Epithelial-Cells-Image.jpg)
Schematic Representation of Extracellular Matrix Underlying Epithelial Cells. Image adapted from [1, 2].
Source publication
Type VI collagen (collagen VI) is an obligate extracellular matrix component found mainly in the basement membrane region of many mammalian tissues and organs, including skeletal muscle and throughout the respiratory system. Collagen VI is probably most recognized in medicine as the genetic cause of a spectrum of muscular dystrophies, including Ull...
Contexts in source publication
Context 1
... of epithelial and endothelial cells, as well as surrounding muscle and nerve cells [42,44]. The basement membrane is thought to serve as an interface between the cellular and matrix components of the lung epithelium, endothelium and musculature, and acts as a barrier between the epithelium and external environment, and the internal environment ( Fig. 1) ...
Citations
... X-FIB, similar to D-dimer, is a degradation product of fibrin, which is mainly present within the circulation during coagulation activity and released upon clot resolution [35]. Collagen type VI (C6M and PRO-C6) is a microfibrillar beaded collagen connects the basement membrane and interstitial matrix in all tissues [36,37]. Collagen type IV (C4Ma3 and PRO-C4) is located within the basement membrane of which the alpha3 chain is mainly found in the alveolar basement membrane [29], and produced by endothelial and epithelial cells [38,39]. ...
Background: Sepsis is associated with high morbidity and mortality, primarily due to systemic inflammation-induced tissue damage, resulting organ failure, and impaired recovery. Regulated extracellular matrix (ECM) turnover is crucial for maintaining tissue homeostasis in health and in response to disease-related changes in the tissue microenvironment. Conversely, uncontrolled turnover can contribute to tissue damage. Systemic Inflammation is implicated to play a role in the regulation of ECM turnover, but the relationship between the two is largely unclear.
Methods: We performed an exploratory study in 10 healthy male volunteers who were intravenously challenged with 2 ng/kg lipopolysaccharide (LPS, derived from Escherichia coli) to induce systemic inflammation. Plasma samples were collected before (T0) and after (T 1h, 3h, 6h and 24h) the LPS challenge. Furthermore, plasma was collected from 43 patients with septic shock on day 1 of ICU admission. Circulating neo-epitopes of extracellular matrix turnover, including ECM degradation neo-epitopes of collagen type I (C1M), type III (C3M), type IV (C4Ma3), and type VI (C6M), elastin (ELP-3) and fibrin (X-FIB), as well as the ECM synthesis neo-epitopes of collagen type III (PRO-C3), collagen type IV (PRO-C4) and collagen type VI (PRO-C6) were measured by ELISA. Patient outcome data were obtained from electronic patient records.
Results: Twenty-four hours after LPS administration, all measured ECM turnover neo-epitopes, except ELP-3, were increased compared to baseline levels. In septic shock patients, concentrations of all measured ECM neo-epitopes were higher compared to healthy controls. In addition, concentrations of C6M, ELP-3 and X-FIB were higher in patients with septic shock who ultimately did not survive (N=7) compared to those who recovered (N=36).
Conclusion: ECM turnover is induced in a model of systemic inflammation in healthy volunteers and was observed in patients with septic shock. Understanding interactions between systemic inflammation and ECM turnover may provide further insight into mechanisms underlying acute and persistent organ failure in sepsis.
... Several genome-wide association studies (GWAS) have previously linked this gene region to immune and respiratory related diseases including atopic dermatitis, asthma, atopy, and COPD [45][46][47]. Additional studies in animal models have suggested that collagen VI protein, comprised of three peptide chains which may include the α5 chain encoded by COL6A5, has a significant role in lung development [48]. Mice deficient for collagen VI protein exhibit simplified alveolar structure, similar to what is observed in bronchopulmonary dysplasia [49,50]. ...
Background
We previously reported in the “Vitamin C to Decrease the Effects of Smoking in Pregnancy on Infant Lung Function” randomized clinical trial (RCT) that vitamin C (500 mg/day) supplementation to pregnant smokers is associated with improved respiratory outcomes that persist through 5 years of age. The objective of this study was to assess whether buccal cell DNA methylation (DNAm), as a surrogate for airway epithelium, is associated with vitamin C supplementation, improved lung function, and decreased occurrence of wheeze.
Methods
We conducted epigenome-wide association studies (EWAS) using Infinium MethylationEPIC arrays and buccal DNAm from 158 subjects (80 placebo; 78 vitamin C) with pulmonary function testing (PFT) performed at the 5-year visit. EWAS were performed on (1) vitamin C treatment, (2) forced expiratory flow between 25 and 75% of expired volume (FEF25–75), and (3) offspring wheeze. Models were adjusted for sex, race, study site, gestational age at randomization (≤ OR > 18 weeks), proportion of epithelial cells, and latent covariates in addition to child length at PFT in EWAS for FEF25–75. We considered FDR p < 0.05 as genome-wide significant and nominal p < 0.001 as candidates for downstream analyses. Buccal DNAm measured in a subset of subjects at birth and near 1 year of age was used to determine whether DNAm signatures originated in utero, or emerged with age.
Results
Vitamin C treatment was associated with 457 FDR significant (q < 0.05) differentially methylated CpGs (DMCs; 236 hypermethylated; 221 hypomethylated) and 53 differentially methylated regions (DMRs; 26 hyper; 27 hypo) at 5 years of age. FEF25–75 was associated with one FDR significant DMC (cg05814800), 1,468 candidate DMCs (p < 0.001), and 44 DMRs. Current wheeze was associated with 0 FDR-DMCs, 782 candidate DMCs, and 19 DMRs (p < 0.001). In 365/457 vitamin C FDR significant DMCs at 5 years of age, there was no significant interaction between time and treatment.
Conclusions
Vitamin C supplementation to pregnant smokers is associated with buccal DNA methylation in offspring at 5 years of age, and most methylation signatures appear to be persistent from the prenatal period. Buccal methylation at 5 years was also associated with current lung function and occurrence of wheeze, and these functionally associated loci are enriched for vitamin C associated loci.
Clinical trial registration ClinicalTrials.gov, NCT01723696 and NCT03203603.
... Regulation of cell growth involved in acute lung injury, lung cancer progression and inflammation 73 . Collagen is the main ECM component and hence plays a critical role in lung development, pathogenesis and progression of chronic lung diseases 74 . Adenylribonucleotide binding may play a role as a key pathway of acute lung disease 75 . ...
Respiratory diseases (RD) are significant public health burdens and malignant diseases worldwide. However, the RD-related biological information and interconnection still need to be better understood. Thus, this study aims to detect common differential genes and potential hub genes (HubGs), emphasizing their actions, signaling pathways, regulatory biomarkers for diagnosing RD and candidate drugs for treating RD. In this paper we used integrated bioinformatics approaches (such as, gene ontology (GO) and KEGG pathway enrichment analysis, molecular docking, molecular dynamic simulation and network-based molecular interaction analysis). We discovered 73 common DEGs (CDEGs) and ten HubGs (ATAD2B, PPP1CB, FOXO1, AKT3, BCR, PDE4D, ITGB1, PCBP2, CD44 and SMARCA2). Several significant functions and signaling pathways were strongly related to RD. We recognized six transcription factor (TF) proteins (FOXC1, GATA2, FOXL1, YY1, POU2F2 and HINFP) and five microRNAs (hsa-mir-218-5p, hsa-mir-335-5p, hsa-mir-16-5p, hsa-mir-106b-5p and hsa-mir-15b-5p) as the important transcription and post-transcription regulators of RD. Ten HubGs and six major TF proteins were considered drug-specific receptors. Their binding energy analysis study was carried out with the 63 drug agents detected from network analysis. Finally, the five complexes (the PDE4D-benzo[a]pyrene, SMARCA2-benzo[a]pyrene, HINFP-benzo[a]pyrene, CD44-ketotifen and ATAD2B-ponatinib) were selected for RD based on their strong binding affinity scores and stable performance as the most probable repurposable protein-drug complexes. We believe our findings will give readers, wet-lab scientists, and pharmaceuticals a thorough grasp of the biology behind RD.
... Mutations in COL6A1 cause collagen VI-related muscular dystrophy and respiratory dysfunction (60). Simultaneously, while collagen VI assumes a pivotal role in establishing and maintaining lung structure and function, it also exerts a direct influence on lung epithelial cell phenotype in vitro (61). IPF patients exhibit heightened COL6 mRNA and protein deposition, signifying Collagen VI as a pivotal fibrosis driver and disease biomarker (62,63). ...
Background
Dermatomyositis (DM) is an autoimmune and inflammatory disease that can affect the lungs, causing interstitial lung diseases (ILD). However, the exact pathophysiological mechanisms underlying DM-ILD are unknown. Idiopathic pulmonary fibrosis (IPF) belongs to the broader spectrum of ILD and evidence shows that common pathologic pathways might lie between IPF and DM-ILD.
Methods
We retrieved gene expression profiles of DM and IPF from the Gene Expression Omnibus (GEO) and utilized weighted gene co-expression network analysis (WGCNA) to reveal their co-expression modules. We then performed a differentially expressed gene (DEG) analysis to identify common DEGs. Enrichment analyses were employed to uncover the hidden biological pathways. Additionally, we conducted protein-protein interaction (PPI) networks analysis, cluster analysis, and successfully found the hub genes, whose levels were further validated in DM-ILD patients. We also examined the relationship between hub genes and immune cell abundance in DM and IPF. Finally, we conducted a common transcription factors (TFs)-genes network by NetworkAnalyst.
Results
WGCNA revealed 258 intersecting genes, while DEG analysis identified 66 shared genes in DM and IPF. All of these genes were closely related to extracellular matrix and structure, cell-substrate adhesion, and collagen metabolism. Four hub genes (POSTN, THBS2, COL6A1, and LOXL1) were derived through intersecting the top 30 genes of the WGCNA and DEG sets. They were validated as active transcripts and showed diagnostic values for DM and IPF. However, ssGSEA revealed distinct infiltration patterns in DM and IPF. These four genes all showed a positive correlation with immune cells abundance in DM, but not in IPF. Finally, we identified one possible key transcription factor, MYC, that interact with all four hub genes.
Conclusion
Through bioinformatics analysis, we identified common hub genes and shared molecular pathways underlying DM and IPF, which provides valuable insights into the intricate mechanisms of these diseases and offers potential targets for diagnostic and therapeutic interventions.
... It is surprising that there are only a few complete studies regarding the possible alignment of collagens to each other. Their importance for ontogenesis and structure formation in the body is indisputable (Marro et al., 2016;Mereness & Mariani, 2021). ...
Collagens are structural proteins that are predominantly found in the extracellular matrix, where they are mainly responsible for the stability and structural integrity of various tissues. There are several different types of collagens, some of which differ significantly in form, function, and tissue specificity. Subdivisions into so-called collagen families exist, which are defined on the basis of mainly clinical research. Collagens contain polypeptide strands (ɑ-chains). Their sequences are often analysed in view of clinical aspects, but problems arise with highly homologous sequence segments. To increase the accuracy of collagen classification and prediction of their functions, the structure of these collagens and their expression in different tissues could result in a better focus on sequence segments of interest. Here, we analyse collagen families with different levels of conservation. As a result, families with strong interchain hydrogen bonds can be found, such as fibrillar collagens, network-forming collagens, and FACITs. Moreover, collagen IV α-chains form their own cluster, and other collagen α-chains do not bond at all.
... The collagen superfamilies exhibit diverse functions within specific body tissues, bestowing upon them the potential for a range of biological activities. For instance, fibrillar collagen can provide intricate three-dimensional frameworks for tissues or organs [14], microfibrillar collagen can interact with fibrils and cells [15], and transmembrane collagen can contribute to the development and homeostasis of tissues [16]. Collagen is known for its complexity and variety, encompassing aspects such as structure, splice variants, non-helical domains, and self-assembly functions. ...
Collagen with a multi-hierarchical architecture exhibits powerful biological performance, thus being developed in biomedical applications as a processing building block. The isolated collagen after extraction from biological tissues can be processed into various forms such as fibrils, scaffolds, membranes, microspheres, hydrogels, and sponges for further use in specific applications. This review briefly discusses the multi-hierarchical structure, powerful biological performances, extraction, and processing approaches of collagen as a natural biomaterial. The processing of collagen including dissolution, self-assembly, cross-linking, and electrospinning, is discussed to show more feasibility for specific applications of collagen composite biomaterials. Further emphasis is directed towards the biomedical applications of drug and gene delivery, as well as tissue repair involving bone, cartilage, vascular, and corneal, along with wound healing. Additionally, there is a focus on the development of flexible sensors and electronic skins (e-skins). Furthermore, the potential challenges and perspectives for the development of collagen-based biomaterials are proposed. In short, collagen-based biomaterials are expected to facilitate sustainable development and the next generation of advanced biomaterial applications.
Graphical Abstract
... The latter suggests a possible role for tri-culture FBs in supporting AEC2 surfactant synthesis in bioengineered lungs 59 . ECM genes that were upregulated in tri-culture FBs, relative to AEC2/FB co-cultured mesenchyme, included proteoglycans that are critical for proper collagen fibril assembly (Dcn, Lum), as well as a basement membrane collagen (Col6a2) that is necessary for normal alveolar formation (Fig. 4d) 60 . Sirius red staining of triculture lungs revealed well-defined collagen within the alveolar septa with airspace preservationalbeit with some alteration of the original alveolar network (Fig. 4e). ...
Engineered whole lungs may one day expand therapeutic options for patients with end-stage lung disease. However, the feasibility of ex vivo lung regeneration remains limited by the inability to recapitulate mature, functional alveolar epithelium. Here, we modulate multimodal components of the alveolar epithelial type 2 cell (AEC2) niche in decellularized lung scaffolds in order to guide AEC2 behavior for epithelial regeneration. First, endothelial cells coordinate with fibroblasts, in the presence of soluble growth and maturation factors, to promote alveolar scaffold population with surfactant-secreting AEC2s. Subsequent withdrawal of Wnt and FGF agonism synergizes with tidal-magnitude mechanical strain to induce the differentiation of AEC2s to squamous type 1 AECs (AEC1s) in cultured alveoli, in situ. These results outline a rational strategy to engineer an epithelium of AEC2s and AEC1s contained within epithelial-mesenchymal-endothelial alveolar-like units, and highlight the critical interplay amongst cellular, biochemical, and mechanical niche cues within the reconstituting alveolus.
... Till this point in time, no treatment has been introduced to COL6A related muscular dystrophy, the symptoms are just managed as we cited before. Recent research in the mice model of collagen typeVI deficiency (Col6α1 − / − ) shows that CyclosporineA can revive at least part of affected tissue caused by mitochondrial deficiency [8]. ...
... Collagen typeVI deficiency is caused by a stop codon at the genome or frameshift including insertion, deletion, duplication, and splice changes, which could lead to mitochondrial defect (mitochondrial abnormality spanning from tubular cristae to electron-dense matrix with alteration of threshold voltage for PTP opening caused by F1F0-ATPase Inhibitor oligomycin), sarcoplasmic reticulum, decreased autophagy (a crucial reaction against muscle wasting), impaired muscle regeneration, and variation in fiber size atrophy, which are mostly replaced by fibrotic tissue in the diaphragm, and finally ending in maturation deficiency [8,9]. ...
Introduction
Ullrich congenital muscular dystrophy (UCMD) is a severe form of inherited muscle weakness at birth. Recent genetic studies discovered that different gene mutations are responsible for UCMD clinical manifestation.
Case report
In this study, we carried out whole exome sequencing (WES) to recognize probable gene defects in an Iranian boy with UCMD. We found a novel disease-causing COL6α1 gene mutation (c.2551_2562del; p.Phe851_Arg854del), located in exon35 (NM_001848.3), causing a deletion mutation that has eliminated 12 bp. The WES-identified variant that was confirmed by Sanger sequencing for the patient and his consanguineous parents. Here, we report the clinical manifestations of 4-year-old Iranian patient who presented with muscle weakness since birth and proved compound homozygous mutation of the COL6A1 gene.
Conclusion
Our findings established that this detected COL6α1 mutation is the pathogenic variant for UCMD. This is the first genetic study indicating that c.2551_2562 mutation in homozygous state in COL6α1 gene is responsible for the UCMD phenotype.
... TNXB mRNA is most expressed in musculoskeletal, cardiac and dermal tissues, but also found at varying quantities in the tissues of the lung, kidney, mammary gland, blood vessels, testis, ovaries, and digestive tract (Bristow et al., 1993;Matsumoto et al., 1994;Valcourt et al., 2015). Specifically, the lung interstitial matrix is comprised of mostly collagen and elastin, which form a three-dimensional framework and impart most of the mechanical attributes (Mereness & Mariani, 2021). TNXB-protein has been shown to regulate collagen metabolism, specifically reducing the deposition of fibrils independent of collagen synthesis or fibrillogensis, as well as play a critical role in stabilization of fibrillar-collagen matrix (Mao et al., 2002;Minamitani et al., 2004;Veit et al., 2006). ...
The genomic region surrounding the Tenascin‐XB gene (TNXB) is a complex and duplicated region, with several pseudogenes that predispose to high rates of homologous recombination. Classical‐like Ehlers–Danlos syndrome (clEDS) is the result of tenascin‐X deficiency due to biallelic loss of function variants in the TNXB gene. Here we present a patient with clEDS and spontaneous pneumothorax, a feature not previously reported to be associated with this condition. Two inherited pathogenic/likely pathogenic variants were identified; a previously reported deletion resulting in a TNXA/TNXB chimeric gene and a novel frameshift variant. The Tenascin‐XB gene is well described in the literature to be associated with collagen metabolism, stabilization of the fibrillar‐collagen matrix and is expressed abundantly in the extracellular matrix. We propose that tenascin‐X deficiency is directly related to pneumothorax predisposition. This case expands the phenotypic spectrum of clEDS and highlights the challenges with molecular analysis and diagnosis
... The main components of the matrix are elastin, fibronectin, collagens I, III, IV, VI, and XVII, laminins, proteoglycans, and glycoproteins. Many diseases that affect the structure and function of the lung are accompanied by the dysregulation of basement membrane components [107][108][109]. While it is well known that the overexpression of collagen fibers causes lung fibrosis, there is not much information on the role of collagens in alveologenesis. ...
The simplification of alveoli leads to various lung pathologies such as bronchopulmonary dysplasia and emphysema. Deep insight into the process of emergence of the secondary septa during development and regeneration after pneumonectomy, and into the contribution of the drivers of alveologenesis and neo-alveolarization is required in an efficient search for therapeutic approaches. In this review, we describe the formation of the gas exchange units of the lung as a multifactorial process, which includes changes in the actomyosin cytoskeleton of alveocytes and myofibroblasts, elastogenesis, retinoic acid signaling, and the contribution of alveolar mesenchymal cells in secondary septation. Knowledge of the mechanistic context of alveologenesis remains incomplete. The characterization of the mechanisms that govern the emergence and depletion of αSMA will allow for an understanding of how the niche of fibroblasts is changing. Taking into account the intense studies that have been performed on the pool of lung mesenchymal cells, we present data on the typing of interstitial fibroblasts and their role in the formation and maintenance of alveoli. On the whole, when identifying cell subpopulations in lung mesenchyme, one has to consider the developmental context, the changing cellular functions, and the lability of gene signatures.
