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Cells
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Modeling Extracellular Matrix-Cell Interactions in Lung Repair and Chronic Disease
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Modeling Extracellular Matrix-Cell Interactions in Lung Repair and Chronic Disease

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Motility and Adhesion".

Deadline for manuscript submissions: closed (30 October 2022) | Viewed by 58673

Special Issue Editors

Prof. Tillie-Louise Hackett

E-Mail Website
Guest Editor
The University of British Columbia, Vancouver, BC, Canada
Interests: epithelial-mesenchymal trophic unit; lung disease;airway microenvironment; asthma; chronic obstructive pulmonary disease
Dr. Emmanuel Twumasi Osei

E-Mail Website
Guest Editor
Department of Anesthesiology Pharmacology and Therapeutics, The University of British Columbia, Vancouver, BC, Canada
Interests: 3D mechano-relevant culture models; lung disease

Special Issue Information

Dear Colleagues,

The extracellular matrix (ECM) provides tissue architecture in the lung by providing mechanical stability and elastic recoil, which are essential for normal lung physiology. In addition to biomechanical signals through ECM-cell attachment, the lung ECM also directs cell functions through its biochemical composition and reservoir function for several growth factors and cytokines. ECM-cell interactions within the lung are essential for cell proliferation, differentiation, motility, cell–cell communication, and survival and are, therefore, essential in the mechanisms of tissue inflammation and repair. The progression of several chronic lung diseases including asthma, chronic obstructive pulmonary disease (COPD), interstitial pulmonary fibrosis (IPF), and acute respiratory distress syndrome (ARDS) have been associated with alterations in lung ECM–cell interactions. The ECM is a complex mixture of fibrous proteins that provide tensile strength (collagen, elastin), adhesive glycoproteins (fibronectin, laminin), and glycosaminoglycans and the proteoglycans (heparin, chondroitin sulfate) that resist compressive forces. The lung ECM is organized into two main structural types: 1) basement membranes, which are thin, dense sheets of specialized, self-assembled ECM proteins that sit between epithelial tissues (including mesothelium and endothelium), and the underlying connective tissue; which consists of 2) an interstitial matrix that is formed of a porous ECM that forms a 3-dimensionl lattice around cells. A recent proteomics study on the mouse lung ECM demonstrated over 150 different ECM proteins, glycosaminoglycans, and modifying enzymes. In recent years, the use of 3-dimensional tissue engineered in vitro model systems such as air–liquid interface cultures, lung organoids, precision-cut lung slices, lung-on-a-chip models, ECM gels, and co-culture systems, as well as animal studies have been used to model the complex cell–cell–ECM interactions within the lung. The primary focus of this Special Issue will be an exploration of how different disease models are elucidating ECM repair mechanisms in healthy and chronically diseased lungs. The reviews and research articles will assess the contribution of different cytokine and growth factor signaling pathways, gene regulation, epigenetic mechanisms, biomechanical signaling to cell-EM repair responses through a myriad of disease-relevant models.

Prof. Tillie-Louise Hackett
Dr. Emmanuel Twumasi Osei
Guest Editors

Manuscript Submission Information

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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

  • extracellular matrix
  • cell–cell communication
  • tissue inflammation
  • tissue repair
  • asthma
  • chronic obstructive pulmonary disease
  • interstitial pulmonary fibrosis
  • acute respiratory distress syndrome

Published Papers (12 papers)

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Editorial

Jump to: Research, Review

10 pages, 288 KiB  
Editorial
Modeling Extracellular Matrix-Cell Interactions in Lung Repair and Chronic Disease
by Tillie Louise Hackett and Emmanuel Twumasi Osei
Cells 2021, 10(8), 2145; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10082145 - 20 Aug 2021
Cited by 16 | Viewed by 3141
Abstract
The lung extracellular matrix (ECM) is a complex and dynamic mixture of fibrous proteins (collagen, elastin), glycoproteins (fibronectin, laminin), glycosaminoglycans (heparin, hyaluronic acid) and proteoglycans (perlecan, versican), that are essential for normal lung development and organ health [...] Full article
(This article belongs to the Special Issue Modeling Extracellular Matrix-Cell Interactions in Lung Repair and Chronic Disease)

Research

Jump to: Editorial, Review

17 pages, 1177 KiB  
Article
Hedgehog Signaling as a Therapeutic Target for Airway Remodeling and Inflammation in Allergic Asthma
by Anthony Tam, Emmanuel Twumasi Osei, Chung Y. Cheung, Michael Hughes, Chen X. Yang, Kelly M. McNagny, Delbert R. Dorscheid, Gurpreet K. Singhera, Teal S. Hallstrand, Stephanie Warner, James C. Hogg, Tillie L. Hackett, Chinten J. Lim and Don D. Sin
Cells 2022, 11(19), 3016; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11193016 - 27 Sep 2022
Cited by 2 | Viewed by 2149
Abstract
Genome-wide association studies (GWAS) have shown that variants of patched homolog 1 (PTCH1) are associated with lung function abnormalities in the general population. It has also been shown that sonic hedgehog (SHH), an important ligand for PTCH1, is upregulated in the [...] Read more.
Genome-wide association studies (GWAS) have shown that variants of patched homolog 1 (PTCH1) are associated with lung function abnormalities in the general population. It has also been shown that sonic hedgehog (SHH), an important ligand for PTCH1, is upregulated in the airway epithelium of patients with asthma and is suggested to be involved in airway remodeling. The contribution of hedgehog signaling to airway remodeling and inflammation in asthma is poorly described. To determine the biological role of hedgehog signaling-associated genes in asthma, gene silencing, over-expression, and pharmacologic inhibition studies were conducted after stimulating human airway epithelial cells or not with transforming growth factor β1 (TGFβ1), an important fibrotic mediator in asthmatic airway remodeling that also interacts with SHH pathway. TGFβ1 increased hedgehog-signaling-related gene expression including SHH, GLI1 and GLI2. Knockdown of PTCH1 or SMO with siRNA, or use of hedgehog signaling inhibitors, consistently attenuated COL1A1 expression induced by TGFβ1 stimulation. In contrast, Ptch1 over-expression augmented TGFβ1-induced an increase in COL1A1 and MMP2 gene expression. We also showed an increase in hedgehog-signaling-related gene expression in primary airway epithelial cells from controls and asthmatics at different stages of cellular differentiation. GANT61, an inhibitor of GLI1/2, attenuated TGFβ1-induced increase in COL1A1 protein expression in primary airway epithelial cells differentiated in air–liquid interface. Finally, to model airway tissue remodeling in vivo, C57BL/6 wildtype (WT) and Ptch1+/− mice were intranasally challenged with house dust mite (HDM) or phosphate-buffered saline (PBS) control. Ptch1+/− mice showed reduced sub-epithelial collagen expression and serum inflammatory proteins compared to WT mice in response to HDM challenge. In conclusion, TGFβ1-induced airway remodeling is partially mediated through the hedgehog signaling pathway via the PTCH1-SMO-GLI axis. The Hedgehog signaling pathway is a promising new potential therapeutic target to alleviate airway tissue remodeling in patients with allergic airways disease. Full article
(This article belongs to the Special Issue Modeling Extracellular Matrix-Cell Interactions in Lung Repair and Chronic Disease)
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12 pages, 4804 KiB  
Article
MicroRNAs Associated with Chronic Mucus Hypersecretion in COPD Are Involved in Fibroblast–Epithelium Crosstalk
by Hataitip Tasena, Wim Timens, Maarten van den Berge, Joy van Broekhuizen, Brian K. Kennedy, Machteld N. Hylkema, Corry-Anke Brandsma and Irene H. Heijink
Cells 2022, 11(3), 526; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11030526 - 02 Feb 2022
Cited by 2 | Viewed by 2200
Abstract
We recently identified microRNAs (miRNAs) associated with chronic mucus hypersecretion (CMH) in chronic obstructive pulmonary disease (COPD), which were expressed in both airway epithelial cells and fibroblasts. We hypothesized that these miRNAs are involved in communication between fibroblasts and epithelium, contributing to airway [...] Read more.
We recently identified microRNAs (miRNAs) associated with chronic mucus hypersecretion (CMH) in chronic obstructive pulmonary disease (COPD), which were expressed in both airway epithelial cells and fibroblasts. We hypothesized that these miRNAs are involved in communication between fibroblasts and epithelium, contributing to airway remodeling and CMH in COPD. Primary bronchial epithelial cells (PBECs) differentiated at the air–liquid interface, and airway fibroblasts (PAFs) from severe COPD patients with CMH were cultured alone or together. RNA was isolated and miRNA expression assessed. miRNAs differentially expressed after co-culturing were studied functionally using overexpression with mimics in mucus-expressing human lung A549 epithelial cells or normal human lung fibroblasts. In PBECs, we observed higher miR-708-5pexpression upon co-culture with fibroblasts, and miR-708-5p expression decreased upon mucociliary differentiation. In PAFs, let-7a-5p, miR-31-5p and miR-146a-5p expression was significantly increased upon co-culture. miR-708-5p overexpression suppressed mucin 5AC (MUC5AC) secretion in A549, while let-7a-5poverexpression suppressed its target gene COL4A1 in lung fibroblasts. Our findings suggest that let-7a-5p, miR-31-5p and miR-146a-5p may be involved in CMH via fibroblasts–epithelium crosstalk, including extracellular matrix gene regulation, while airway epithelial expression of miR-708-5p may be involved directly, regulating mucin production. These findings shed light on miRNA-mediated mechanisms underlying CMH, an important symptom in COPD. Full article
(This article belongs to the Special Issue Modeling Extracellular Matrix-Cell Interactions in Lung Repair and Chronic Disease)
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13 pages, 1668 KiB  
Article
Mechanical Compression of Human Airway Epithelial Cells Induces Release of Extracellular Vesicles Containing Tenascin C
by Chimwemwe Mwase, Thien-Khoi N. Phung, Michael J. O’Sullivan, Jennifer A. Mitchel, Margherita De Marzio, Ayşe Kılıç, Scott T. Weiss, Jeffrey J. Fredberg and Jin-Ah Park
Cells 2022, 11(2), 256; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11020256 - 13 Jan 2022
Cited by 8 | Viewed by 2923
Abstract
Aberrant remodeling of the asthmatic airway is not well understood but is thought to be attributable in part to mechanical compression of airway epithelial cells. Here, we examine compression-induced expression and secretion of the extracellular matrix protein tenascin C (TNC) from well-differentiated primary [...] Read more.
Aberrant remodeling of the asthmatic airway is not well understood but is thought to be attributable in part to mechanical compression of airway epithelial cells. Here, we examine compression-induced expression and secretion of the extracellular matrix protein tenascin C (TNC) from well-differentiated primary human bronchial epithelial (HBE) cells grown in an air–liquid interface culture. We measured TNC mRNA expression using RT-qPCR and secreted TNC protein using Western blotting and ELISA. To determine intracellular signaling pathways, we used specific inhibitors for either ERK or TGF-β receptor, and to assess the release of extracellular vesicles (EVs) we used a commercially available kit and Western blotting. At baseline, secreted TNC protein was significantly higher in asthmatic compared to non-asthmatic cells. In response to mechanical compression, both TNC mRNA expression and secreted TNC protein was significantly increased in both non-asthmatic and asthmatic cells. TNC production depended on both the ERK and TGF-β receptor pathways. Moreover, mechanically compressed HBE cells released EVs that contain TNC. These data reveal a novel mechanism by which mechanical compression, as is caused by bronchospasm, is sufficient to induce the production of ECM protein in the airway and potentially contribute to airway remodeling. Full article
(This article belongs to the Special Issue Modeling Extracellular Matrix-Cell Interactions in Lung Repair and Chronic Disease)
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14 pages, 2243 KiB  
Article
The Role of the Dynamic Lung Extracellular Matrix Environment on Fibroblast Morphology and Inflammation
by Tillie-Louise Hackett, Noamie R. T. F. Vriesde, May AL-Fouadi, Leila Mostaco-Guidolin, Delaram Maftoun, Aileen Hsieh, Nicole Coxson, Kauna Usman, Don D. Sin, Steve Booth and Emmanuel T. Osei
Cells 2022, 11(2), 185; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11020185 - 06 Jan 2022
Cited by 9 | Viewed by 3313
Abstract
The extracellular matrix (ECM) supports lung tissue architecture and physiology by providing mechanical stability and elastic recoil. Over the last several decades, it has become increasingly clear that the stiffness of the ECM governs many cellular processes, including cell-phenotype and functions during development, [...] Read more.
The extracellular matrix (ECM) supports lung tissue architecture and physiology by providing mechanical stability and elastic recoil. Over the last several decades, it has become increasingly clear that the stiffness of the ECM governs many cellular processes, including cell-phenotype and functions during development, healing, and disease. Of all the lung ECM proteins, collagen-I is the most abundant and provides tensile strength. In many fibrotic lung diseases, the expression of collagen is increased which affects the stiffness of the surrounding environment. The goal of this study was to assess the effect on fibroblast morphology, cell death, and inflammation when exposed to 2D and 3D low (0.4 mg/mL) versus high (2.0 mg/mL) collagen-I-matrix environments that model the mechanics of the breathing lung. This study demonstrates that human fetal lung fibroblasts (HFL1), grown in a 3D collagen type-I environment compared to a 2D one, do not form cells with a myofibroblast morphology, express less F-actin stress fibers, exhibit less cell death, and significantly produce less pro-inflammatory IL-6 and IL-8 cytokines. Exposure to mechanical strain to mimic breathing (0.2 Hz) led to the loss of HFL1 fibroblast dendritic extensions as well as F-actin stress fibers within the cell cytoskeleton, but did not influence cytokine production or cell death. This dynamic assay gives researchers the ability to consider the assessment of the mechanodynamic nature of the lung ECM environment in disease-relevant models and the potential of mechano-pharmacology to identify therapeutic targets for treatment. Full article
(This article belongs to the Special Issue Modeling Extracellular Matrix-Cell Interactions in Lung Repair and Chronic Disease)
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13 pages, 3853 KiB  
Article
Extracellular Matrix Oxidised by the Granulocyte Oxidants Hypochlorous and Hypobromous Acid Reduces Lung Fibroblast Adhesion and Proliferation In Vitro
by Michael Papanicolaou, Patrick He, Sandra Rutting, Alaina Ammit, Dikaia Xenaki, David van Reyk and Brian G. Oliver
Cells 2021, 10(12), 3351; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10123351 - 29 Nov 2021
Cited by 1 | Viewed by 1712
Abstract
Chronic airway inflammation and oxidative stress play crucial roles in the pathogenesis of chronic inflammatory lung diseases, with airway inflammation being a key driving mechanism of oxidative stress in the lungs. Inflammatory responses in the lungs activate neutrophils and/or eosinophils, leading to the [...] Read more.
Chronic airway inflammation and oxidative stress play crucial roles in the pathogenesis of chronic inflammatory lung diseases, with airway inflammation being a key driving mechanism of oxidative stress in the lungs. Inflammatory responses in the lungs activate neutrophils and/or eosinophils, leading to the generation of hypohalous acids (HOX). These HOX oxidants can damage the extracellular matrix (ECM) structure and may influence cell–ECM interactions. The ECM of the lung provides structural, mechanical, and biochemical support for cells and determines the airway structure. One of the critical cells in chronic respiratory disease is the fibroblast. Thus, we hypothesised that primary human lung fibroblasts (PHLF) exposed to an oxidised cell-derived ECM will result in functional changes to the PHLF. Here, we show that PHLF adhesion, proliferation, and inflammatory cytokine secretion is affected by exposure to HOX-induced oxidisation of the cell-derived ECM. Furthermore, we investigated the impact on fibroblast function from the presence of haloamines in the ECM. Haloamines are chemical by-products of HOX and, like the HOX, haloamines can also modify the ECM. In conclusion, this study revealed that oxidising the cell-derived ECM might contribute to functional changes in PHLF, a key mechanism behind the pathogenesis of inflammatory lung diseases. Full article
(This article belongs to the Special Issue Modeling Extracellular Matrix-Cell Interactions in Lung Repair and Chronic Disease)
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18 pages, 3069 KiB  
Article
Regulation of Cellular Senescence Is Independent from Profibrotic Fibroblast-Deposited ECM
by Kaj E. C. Blokland, Habibie Habibie, Theo Borghuis, Greta J. Teitsma, Michael Schuliga, Barbro N. Melgert, Darryl A. Knight, Corry-Anke Brandsma, Simon D. Pouwels and Janette K. Burgess
Cells 2021, 10(7), 1628; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10071628 - 29 Jun 2021
Cited by 9 | Viewed by 5065
Abstract
Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease with poor survival. Age is a major risk factor, and both alveolar epithelial cells and lung fibroblasts in this disease exhibit features of cellular senescence, a hallmark of ageing. Accumulation of fibrotic extracellular matrix [...] Read more.
Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease with poor survival. Age is a major risk factor, and both alveolar epithelial cells and lung fibroblasts in this disease exhibit features of cellular senescence, a hallmark of ageing. Accumulation of fibrotic extracellular matrix (ECM) is a core feature of IPF and is likely to affect cell function. We hypothesize that aberrant ECM deposition augments fibroblast senescence, creating a perpetuating cycle favouring disease progression. In this study, primary lung fibroblasts were cultured on control and IPF-derived ECM from fibroblasts pretreated with or without profibrotic and prosenescent stimuli, and markers of senescence, fibrosis-associated gene expression and secretion of cytokines were measured. Untreated ECM derived from control or IPF fibroblasts had no effect on the main marker of senescence p16Ink4a and p21Waf1/Cip1. However, the expression of alpha smooth muscle actin (ACTA2) and proteoglycan decorin (DCN) increased in response to IPF-derived ECM. Production of the proinflammatory cytokines C-X-C Motif Chemokine Ligand 8 (CXCL8) by lung fibroblasts was upregulated in response to senescent and profibrotic-derived ECM. Finally, the profibrotic cytokines transforming growth factor β1 (TGF-β1) and connective tissue growth factor (CTGF) were upregulated in response to both senescent- and profibrotic-derived ECM. In summary, ECM deposited by IPF fibroblasts does not induce cellular senescence, while there is upregulation of proinflammatory and profibrotic cytokines and differentiation into a myofibroblast phenotype in response to senescent- and profibrotic-derived ECM, which may contribute to progression of fibrosis in IPF. Full article
(This article belongs to the Special Issue Modeling Extracellular Matrix-Cell Interactions in Lung Repair and Chronic Disease)
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23 pages, 5229 KiB  
Article
A Robust Protocol for Decellularized Human Lung Bioink Generation Amenable to 2D and 3D Lung Cell Culture
by Mohammadhossein Dabaghi, Neda Saraei, Mabel Barreiro Carpio, Vibudha Nanduri, Julia Ungureanu, Mouhanad Babi, Abiram Chandiramohan, Alexander Noble, Spencer D. Revill, Boyang Zhang, Kjetil Ask, Martin Kolb, Yaron Shargall, Jose Moran-Mirabal and Jeremy Alexander Hirota
Cells 2021, 10(6), 1538; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10061538 - 18 Jun 2021
Cited by 22 | Viewed by 4490
Abstract
Decellularization efforts must balance the preservation of the extracellular matrix (ECM) components while eliminating the nucleic acid and cellular components. Following effective removal of nucleic acid and cell components, decellularized ECM (dECM) can be solubilized in an acidic environment with the assistance of [...] Read more.
Decellularization efforts must balance the preservation of the extracellular matrix (ECM) components while eliminating the nucleic acid and cellular components. Following effective removal of nucleic acid and cell components, decellularized ECM (dECM) can be solubilized in an acidic environment with the assistance of various enzymes to develop biological scaffolds in different forms, such as sheets, tubular constructs, or three-dimensional (3D) hydrogels. Each organ or tissue that undergoes decellularization requires a distinct and optimized protocol to ensure that nucleic acids are removed, and the ECM components are preserved. The objective of this study was to optimize the decellularization process for dECM isolation from human lung tissues for downstream 2D and 3D cell culture systems. Following protocol optimization and dECM isolation, we performed experiments with a wide range of dECM concentrations to form human lung dECM hydrogels that were physically stable and biologically responsive. The dECM based-hydrogels supported the growth and proliferation of primary human lung fibroblast cells in 3D cultures. The dECM is also amenable to the coating of polyester membranes in Transwell™ Inserts to improve the cell adhesion, proliferation, and barrier function of primary human bronchial epithelial cells in 2D. In conclusion, we present a robust protocol for human lung decellularization, generation of dECM substrate material, and creation of hydrogels that support primary lung cell viability in 2D and 3D culture systems Full article
(This article belongs to the Special Issue Modeling Extracellular Matrix-Cell Interactions in Lung Repair and Chronic Disease)
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Review

Jump to: Editorial, Research

16 pages, 1150 KiB  
Review
DNA Methylation of Fibroblast Phenotypes and Contributions to Lung Fibrosis
by Poojitha Rajasekar, Jamie Patel and Rachel L. Clifford
Cells 2021, 10(8), 1977; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10081977 - 03 Aug 2021
Cited by 3 | Viewed by 3703
Abstract
Fibroblasts are an integral part of connective tissue and play a crucial role in developing and modulating the structural framework of tissues by acting as the primary source of extracellular matrix (ECM). A precise definition of the fibroblast remains elusive. Lung fibroblasts orchestrate [...] Read more.
Fibroblasts are an integral part of connective tissue and play a crucial role in developing and modulating the structural framework of tissues by acting as the primary source of extracellular matrix (ECM). A precise definition of the fibroblast remains elusive. Lung fibroblasts orchestrate the assembly and turnover of ECM to facilitate gas exchange alongside performing immune functions including the secretion of bioactive molecules and antigen presentation. DNA methylation is the covalent attachment of a methyl group to primarily cytosines within DNA. DNA methylation contributes to diverse cellular phenotypes from the same underlying genetic sequence, with DNA methylation profiles providing a memory of cellular origin. The lung fibroblast population is increasingly viewed as heterogeneous with between 6 and 11 mesenchymal populations identified across health and lung disease to date. DNA methylation has been associated with different lung fibroblast populations in health and with alterations in lung disease, but to varying extents. In this review, we will discuss lung fibroblast heterogeneity and the evidence for a contribution from DNA methylation to defining cell populations and alterations in disease. Full article
(This article belongs to the Special Issue Modeling Extracellular Matrix-Cell Interactions in Lung Repair and Chronic Disease)
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30 pages, 4467 KiB  
Review
Optical Microscopy and the Extracellular Matrix Structure: A Review
by Joshua J. A. Poole and Leila B. Mostaço-Guidolin
Cells 2021, 10(7), 1760; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10071760 - 12 Jul 2021
Cited by 32 | Viewed by 12205
Abstract
Biological tissues are not uniquely composed of cells. A substantial part of their volume is extracellular space, which is primarily filled by an intricate network of macromolecules constituting the extracellular matrix (ECM). The ECM serves as the scaffolding for tissues and organs throughout [...] Read more.
Biological tissues are not uniquely composed of cells. A substantial part of their volume is extracellular space, which is primarily filled by an intricate network of macromolecules constituting the extracellular matrix (ECM). The ECM serves as the scaffolding for tissues and organs throughout the body, playing an essential role in their structural and functional integrity. Understanding the intimate interaction between the cells and their structural microenvironment is central to our understanding of the factors driving the formation of normal versus remodelled tissue, including the processes involved in chronic fibrotic diseases. The visualization of the ECM is a key factor to track such changes successfully. This review is focused on presenting several optical imaging microscopy modalities used to characterize different ECM components. In this review, we describe and provide examples of applications of a vast gamut of microscopy techniques, such as widefield fluorescence, total internal reflection fluorescence, laser scanning confocal microscopy, multipoint/slit confocal microscopy, two-photon excited fluorescence (TPEF), second and third harmonic generation (SHG, THG), coherent anti-Stokes Raman scattering (CARS), fluorescence lifetime imaging microscopy (FLIM), structured illumination microscopy (SIM), stimulated emission depletion microscopy (STED), ground-state depletion microscopy (GSD), and photoactivated localization microscopy (PALM/fPALM), as well as their main advantages, limitations. Full article
(This article belongs to the Special Issue Modeling Extracellular Matrix-Cell Interactions in Lung Repair and Chronic Disease)
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Graphical abstract

26 pages, 2121 KiB  
Review
The Role of miRNAs in Extracellular Matrix Repair and Chronic Fibrotic Lung Diseases
by Kauna Usman, Aileen Hsieh and Tillie-Louise Hackett
Cells 2021, 10(7), 1706; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10071706 - 06 Jul 2021
Cited by 13 | Viewed by 3876
Abstract
The lung extracellular matrix (ECM) plays a key role in the normal architecture of the lung, from embryonic lung development to mechanical stability and elastic recoil of the breathing adult lung. The lung ECM can modulate the biophysical environment of cells through ECM [...] Read more.
The lung extracellular matrix (ECM) plays a key role in the normal architecture of the lung, from embryonic lung development to mechanical stability and elastic recoil of the breathing adult lung. The lung ECM can modulate the biophysical environment of cells through ECM stiffness, porosity, topography and insolubility. In a reciprocal interaction, lung ECM dynamics result from the synthesis, degradation and organization of ECM components by the surrounding structural and immune cells. Repeated lung injury and repair can trigger a vicious cycle of aberrant ECM protein deposition, accompanied by elevated ECM stiffness, which has a lasting effect on cell and tissue function. The processes governing the resolution of injury repair are regulated by several pathways; however, in chronic lung diseases such as asthma, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary disease (IPF) these processes are compromised, resulting in impaired cell function and ECM remodeling. Current estimates show that more than 60% of the human coding transcripts are regulated by miRNAs. miRNAs are small non-coding RNAs that regulate gene expressions and modulate cellular functions. This review is focused on the current knowledge of miRNAs in regulating ECM synthesis, degradation and topography by cells and their dysregulation in asthma, COPD and IPF. Full article
(This article belongs to the Special Issue Modeling Extracellular Matrix-Cell Interactions in Lung Repair and Chronic Disease)
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51 pages, 3691 KiB  
Review
Airway-On-A-Chip: Designs and Applications for Lung Repair and Disease
by Tanya J. Bennet, Avineet Randhawa, Jessica Hua and Karen C. Cheung
Cells 2021, 10(7), 1602; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10071602 - 26 Jun 2021
Cited by 24 | Viewed by 12070
Abstract
The lungs are affected by illnesses including asthma, chronic obstructive pulmonary disease, and infections such as influenza and SARS-CoV-2. Physiologically relevant models for respiratory conditions will be essential for new drug development. The composition and structure of the lung extracellular matrix (ECM) plays [...] Read more.
The lungs are affected by illnesses including asthma, chronic obstructive pulmonary disease, and infections such as influenza and SARS-CoV-2. Physiologically relevant models for respiratory conditions will be essential for new drug development. The composition and structure of the lung extracellular matrix (ECM) plays a major role in the function of the lung tissue and cells. Lung-on-chip models have been developed to address some of the limitations of current two-dimensional in vitro models. In this review, we describe various ECM substitutes utilized for modeling the respiratory system. We explore the application of lung-on-chip models to the study of cigarette smoke and electronic cigarette vapor. We discuss the challenges and opportunities related to model characterization with an emphasis on in situ characterization methods, both established and emerging. We discuss how further advancements in the field, through the incorporation of interstitial cells and ECM, have the potential to provide an effective tool for interrogating lung biology and disease, especially the mechanisms that involve the interstitial elements. Full article
(This article belongs to the Special Issue Modeling Extracellular Matrix-Cell Interactions in Lung Repair and Chronic Disease)
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