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Tissue Engineering. Part C, Methods Nov 2019Cell-cell adhesion complexes are macromolecular adhesive organelles that integrate cells into tissues. This mechanochemical coupling in cell-cell adhesion is required... (Review)
Review
Cell-cell adhesion complexes are macromolecular adhesive organelles that integrate cells into tissues. This mechanochemical coupling in cell-cell adhesion is required for a large number of cell behaviors, and perturbations of the cell-cell adhesion structure or related mechanotransduction pathways can lead to critical pathological conditions such as skin and heart diseases, arthritis, and cancer. Mechanical stretching has been a widely used method to stimulate the mechanotransduction process originating from the cell-cell adhesion and cell-extracellular matrix (ECM) complexes. These studies aimed to reveal the biophysical processes governing cell proliferation, wound healing, gene expression regulation, and cell differentiation in various tissues, including cardiac, muscle, vascular, and bone. This review explores techniques in mechanical stretching in two-dimensional settings with different stretching regimens on different cell types. The mechanotransduction responses from these different cell types will be discussed with an emphasis on their biophysical transformations during mechanical stretching and the cross talk between the cell-cell and cell-ECM adhesion complexes. Therapeutic aspects of mechanical stretching are reviewed considering these cellular responses after the application of mechanical forces, with a focus on wound healing and tissue regeneration. Impact Statement Mechanical stretching has been proposed as a therapeutic option for tissue regeneration and wound healing. It has been accepted that mechanotransduction processes elicited by mechanical stretching govern cellular response and behavior, and these studies have predominantly focused on the cell-extracellular matrix (ECM) sites. This review serves the mechanobiology community by shifting the focus of mechanical stretching effects from cell-ECM adhesions to the less examined cell-cell adhesions, which we believe play an equally important role in orchestrating the response pathways.
Topics: Adherens Junctions; Animals; Cell Adhesion; Desmosomes; Disease; Humans; Regeneration; Stress, Mechanical
PubMed: 31407627
DOI: 10.1089/ten.TEC.2019.0098 -
Allergology International : Official... Jan 2018The skin is continuously exposed to external pathogens, and its barrier function is critical for skin homeostasis. Previous studies have shown that the barrier... (Review)
Review
The skin is continuously exposed to external pathogens, and its barrier function is critical for skin homeostasis. Previous studies have shown that the barrier dysfunction is one of the most predisposing factors for the development of skin allergic diseases such as atopic dermatitis. In this article, we summarize how the physical barrier of the skin is organized and review its link to the pathomechanism of skin allergic diseases. We describe the formation of the SC barrier in terms of the following five categories: 1) filaggrin metabolism; 2) cornified envelope; 3) intercellular lipids; 4) corneodesmosome; and 5) corneocyte desquamation. New approaches to restoring the skin barrier function are also discussed.
Topics: Animals; Dermatitis, Atopic; Desmosomes; Filaggrin Proteins; Humans; Intermediate Filament Proteins; Lipid Metabolism; Skin
PubMed: 29153780
DOI: 10.1016/j.alit.2017.10.002 -
Frontiers in Immunology 2018Pemphigus is a severe autoimmune-blistering disease of the skin and mucous membranes caused by autoantibodies reducing desmosomal adhesion between epithelial cells.... (Review)
Review
Pemphigus is a severe autoimmune-blistering disease of the skin and mucous membranes caused by autoantibodies reducing desmosomal adhesion between epithelial cells. Autoantibodies against the desmosomal cadherins desmogleins (Dsgs) 1 and 3 as well as desmocollin 3 were shown to be pathogenic, whereas the role of other antibodies is unclear. Dsg3 interactions can be directly reduced by specific autoantibodies. Autoantibodies also alter the activity of signaling pathways, some of which regulate cell cohesion under baseline conditions and alter the turnover of desmosomal components. These pathways include Ca, p38MAPK, PKC, Src, EGFR/Erk, and several others. In this review, we delineate the mechanisms relevant for pemphigus pathogenesis based on the histology and the ultrastructure of patients' lesions. We then dissect the mechanisms which can explain the ultrastructural hallmarks detectable in pemphigus patient skin. Finally, we reevaluate the concept that the spectrum of mechanisms, which induce desmosome dysfunction upon binding of pemphigus autoantibodies, finally defines the clinical phenotype.
Topics: Animals; Autoantibodies; Desmosomes; Humans; Pemphigus; Phenotype
PubMed: 29449846
DOI: 10.3389/fimmu.2018.00136 -
Apremilast prevents blistering in human epidermis and stabilizes keratinocyte adhesion in pemphigus.Nature Communications Jan 2023Pemphigus vulgaris is a life-threatening blistering skin disease caused by autoantibodies destabilizing desmosomal adhesion. Current therapies focus on suppression of...
Pemphigus vulgaris is a life-threatening blistering skin disease caused by autoantibodies destabilizing desmosomal adhesion. Current therapies focus on suppression of autoantibody formation and thus treatments directly stabilizing keratinocyte adhesion would fulfill an unmet medical need. We here demonstrate that apremilast, a phosphodiesterase 4 inhibitor used in psoriasis, prevents skin blistering in pemphigus vulgaris. Apremilast abrogates pemphigus autoantibody-induced loss of keratinocyte cohesion in ex-vivo human epidermis, cultured keratinocytes in vitro and in vivo in mice. In parallel, apremilast inhibits keratin retraction as well as desmosome splitting, induces phosphorylation of plakoglobin at serine 665 and desmoplakin assembly into desmosomal plaques. We established a plakoglobin phospho-deficient mouse model that reveals fragile epidermis with altered organization of keratin filaments and desmosomal cadherins. In keratinocytes derived from these mice, intercellular adhesion is impaired and not rescued by apremilast. These data identify an unreported mechanism of desmosome regulation and propose that apremilast stabilizes keratinocyte adhesion and is protective in pemphigus.
Topics: Humans; Mice; Animals; Pemphigus; gamma Catenin; Cell Adhesion; Keratinocytes; Epidermis; Blister; Autoantibodies; Keratins; Desmosomes
PubMed: 36624106
DOI: 10.1038/s41467-022-35741-0 -
Tissue Barriers Oct 2022Desmosomes are macromolecular cell-cell junctions critical for maintaining adhesion and resisting mechanical stress in epithelial tissue. Desmosome assembly and the...
Desmosomes are macromolecular cell-cell junctions critical for maintaining adhesion and resisting mechanical stress in epithelial tissue. Desmosome assembly and the relationship between maturity and molecular architecture are not well understood. To address this, we employed a calcium switch assay to synchronize assembly followed by quantification of desmosome nanoscale organization using direct Stochastic Optical Reconstruction Microscopy (dSTORM). We found that the organization of the desmoplakin rod/C-terminal junction changed over the course of maturation, as indicated by a decrease in the plaque-to-plaque distance, while the plaque length increased. In contrast, the desmoplakin N-terminal domain and plakoglobin organization (plaque-to-plaque distance) were constant throughout maturation. This structural rearrangement of desmoplakin was concurrent with desmosome maturation measured by E-cadherin exclusion and increased adhesive strength. Using two-color dSTORM, we showed that while the number of individual E-cadherin containing junctions went down with the increasing time in high Ca, they maintained a wider desmoplakin rod/C-terminal plaque-to-plaque distance. This indicates that the maturation state of individual desmosomes can be identified by their architectural organization. We confirmed these architectural changes in another model of desmosome assembly, cell migration. Desmosomes in migrating cells, closest to the scratch where they are assembling, were shorter, E-cadherin enriched, and had wider desmoplakin rod/C-terminal plaque-to-plaque distances compared to desmosomes away from the wound edge. Key results were demonstrated in three cell lines representing simple, transitional, and stratified epithelia. Together, these data suggest that there is a set of architectural programs for desmosome maturation, and we hypothesize that desmoplakin architecture may be a contributing mechanism to regulating adhesive strength.
Topics: Desmosomes; gamma Catenin; Desmoplakins; Calcium; Cadherins
PubMed: 34983311
DOI: 10.1080/21688370.2021.2017225 -
The Journal of Investigative Dermatology Nov 2007Desmosomes are highly specialized anchoring junctions that link intermediate filaments to sites of intercellular adhesion, thus facilitating the formation of a... (Review)
Review
Desmosomes are highly specialized anchoring junctions that link intermediate filaments to sites of intercellular adhesion, thus facilitating the formation of a supracellular scaffolding that distributes mechanical forces throughout a tissue. These junctions are thus particularly important for maintaining the integrity of tissues that endure physical stress, such as the epidermis and myocardium. The importance of the classic mechanical functions of desmosomal constituents is underscored by pathologies reported in animal models and an ever-expanding list of human mutations that target both desmosomal cadherins and their associated cytoskeletal anchoring proteins. However, the notion that desmosomes are static structures that exist simply to glue cells together belies their susceptibility to remodeling in response to environmental cues and their important tissue-specific roles in cell behavior and signaling. Here, we review the molecular blueprint of the desmosome and models for assembling its protein components to form an adhesive interface and the desmosomal plaque. We also discuss emerging evidence of supra-adhesive roles for desmosomal proteins in regulating tissue morphogenesis and homeostasis. Finally, we highlight the dynamic nature of these adhesive organelles, examining mechanisms in health and disease for modulating adhesive strength and stability of desmosomes.
Topics: Animals; Cell Adhesion; Cytoskeletal Proteins; Desmosomal Cadherins; Desmosomes; Humans; Intermediate Filaments; Keratinocytes; Models, Animal
PubMed: 17934502
DOI: 10.1038/sj.jid.5701015 -
Stem Cell Reports Feb 2022Loss-of-function mutations in PKP2, which encodes plakophilin-2, cause arrhythmogenic cardiomyopathy (AC). Restoration of deficient molecules can serve as upstream...
Loss-of-function mutations in PKP2, which encodes plakophilin-2, cause arrhythmogenic cardiomyopathy (AC). Restoration of deficient molecules can serve as upstream therapy, thereby requiring a human model that recapitulates disease pathology and provides distinct readouts in phenotypic analysis for proof of concept for gene replacement therapy. Here, we generated isogenic induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) with precisely adjusted expression of plakophilin-2 from a patient with AC carrying a heterozygous frameshift PKP2 mutation. After monolayer differentiation, plakophilin-2 deficiency led to reduced contractility, disrupted intercalated disc structures, and impaired desmosome assembly in iPSC-CMs. Allele-specific fluorescent labeling of endogenous DSG2 encoding desmoglein-2 in the generated isogenic lines enabled real-time desmosome-imaging under an adjusted dose of plakophilin-2. Adeno-associated virus-mediated gene replacement of PKP2 recovered contractility and restored desmosome assembly, which was sequentially captured by desmosome-imaging in plakophilin-2-deficient iPSC-CMs. Our isogenic set of iPSC-CMs recapitulates AC pathology and provides a rapid and convenient cellular platform for therapeutic development.
Topics: Arrhythmias, Cardiac; CRISPR-Cas Systems; Cell Differentiation; Desmosomes; Female; Gene Editing; Genetic Vectors; Heterozygote; Humans; Induced Pluripotent Stem Cells; Male; Models, Biological; Myocardial Contraction; Myocytes, Cardiac; Pedigree; Plakophilins
PubMed: 35063130
DOI: 10.1016/j.stemcr.2021.12.016 -
European Journal of Human Genetics :... Feb 2013Inherited ichthyoses, defined as the generalized form of Mendelian disorders of cornification, are characterized by visible scaling and/or hyperkeratosis of most or all... (Review)
Review
Inherited ichthyoses, defined as the generalized form of Mendelian disorders of cornification, are characterized by visible scaling and/or hyperkeratosis of most or all of the skin. This etiologically and phenotypically heterogenous group of conditions is caused by mutations in various different genes important for keratinocyte differentiation and epidermal barrier function. Diagnosing a specific entity is a particular challenge for the nonspecialist presented with the common clinical scaling. For the clinician, this review outlines an algorithmic approach for utilizing diagnostic clues to narrow down the differential diagnosis and to guide further testing and treatment options.
Topics: Apoptosis; Cell Differentiation; Cornea; Desmosomes; Diagnosis, Differential; Humans; Ichthyosis; Keratinocytes; Microscopy, Electron; Mutation; Skin
PubMed: 22739337
DOI: 10.1038/ejhg.2012.121 -
The Journal of Investigative Dermatology Jan 2016Expression and interaction of desmosomal components and keratins provide stable cell cohesion and protect the epidermis against various types of stress. The...
Expression and interaction of desmosomal components and keratins provide stable cell cohesion and protect the epidermis against various types of stress. The differentiation-specific isotype composition of the keratin cytoskeleton and desmosomes is regarded as a major determinant of adhesive strength. In support, wound healing is characterized by a transient decrease in desmosomal adhesion accompanied by increased expression of keratins K6/K16/K17 at the expense of K1/K10. The significance of altered keratin expression for desmosomal composition and adhesion remains incompletely understood at a mechanistic and functional level. Here, we investigated the respective contribution of K5/K14 or K6/K17 to desmosome adhesion, on their stable re-expression in keratinocytes lacking all keratins. This revealed that K5/K14 filaments support stable desmosomes, whereas "wound healing" keratins K6/K17 induce elevated protein kinase C alpha-mediated desmosome disassembly and subsequent destabilization of epithelial sheets. Moreover, our data suggest that K5/K14 sequester protein kinase C alpha in the cytoplasm, whereas K6/K17 or the absence of all keratins enables protein kinase C alpha translocation to the plasma membrane and induction of desmosome disassembly. Gain- and loss-of-function experiments support a major role of K5 in desmosome stability control via protein kinase C alpha. Our data show that keratin isotypes differently and specifically regulate wound healing and invasion by modulating intercellular adhesion.
Topics: Biotinylation; Blotting, Western; Cell Differentiation; Cell Fractionation; Cells, Cultured; Cytoskeleton; Desmosomes; Epidermal Cells; Epidermis; Gene Silencing; Humans; Keratinocytes; Microscopy, Fluorescence; Protein Kinase C-alpha; Real-Time Polymerase Chain Reaction; Sensitivity and Specificity; Wound Healing
PubMed: 26763440
DOI: 10.1038/JID.2015.403 -
Progress in Molecular Biology and... 2013Desmosomes are adhesive intercellular junctions that mechanically integrate adjacent cells by coupling adhesive interactions mediated by desmosomal cadherins to the... (Review)
Review
Desmosomes are adhesive intercellular junctions that mechanically integrate adjacent cells by coupling adhesive interactions mediated by desmosomal cadherins to the intermediate filament cytoskeletal network. Desmosomal cadherins are connected to intermediate filaments by densely clustered cytoplasmic plaque proteins comprising members of the armadillo gene family, including plakoglobin and plakophilins, and members of the plakin family of cytolinkers, such as desmoplakin. The importance of desmosomes in tissue integrity is highlighted by human diseases caused by mutations in desmosomal genes, autoantibody attack of desmosomal cadherins, and bacterial toxins that selectively target desmosomal cadherins. In addition to reviewing the well-known roles of desmosomal proteins in tissue integrity, this chapter also highlights the growing appreciation for how desmosomal proteins are integrated with cell signaling pathways to contribute to vertebrate tissue organization and differentiation.
Topics: Animals; Cytoskeleton; Desmosomal Cadherins; Desmosomes; Humans; Signal Transduction
PubMed: 23481192
DOI: 10.1016/B978-0-12-394311-8.00005-4