Special Issue "Epithelial Cell Mechanics: From Physiology to Pathology"

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 June 2021).

Special Issue Editor

Dr. Rudolf E. Leube
E-Mail Website
Guest Editor
Institute of Molecular and Cellular Anatomy, RWTH Aachen University, 52074 Aachen, Germany
Interests: epithelia; cytoskeleton; junctions; mechanobiology
Special Issues and Collections in MDPI journals

Special Issue Information

Dear Colleagues,

Epithelia protect the body against external mechanical forces while maintaining a tight barrier to the underlying connective tissue. They have developed a particularly resilient cytoskeleton consisting of interconnected filament networks that are anchored to adhesion sites connecting cells to each other and the extracellular matrix. The resulting transcellular scaffold supports epithelial barrier functions, withstands extreme mechanical deformation, and responds to different mechanical environments through mechanosensing and re-organization. The precise contribution of the different cellular and extracellular matrix components to the overall mechanical properties of epithelial tissues is slowly emerging with the advent of novel tools, software, and image processing routines to study mechanical properties in a vital 3D tissue context.

This current volume aims to present new ideas and novel findings on how mechanical factors determine:

  • Epithelial tissue differentiation (e.g., stem cell differentiation, luminogenesis, stratification);
  • Epithelial physiology (e.g., ciliary function, single cell extrusion);
  • Epithelial wound healing;
  • Intraepithelial inflammatory responses;
  • Invasion of epithelial cells into the connective tissue compartment;

and how these insights can be exploited to improve epithelial tissue engineering (e.g., the production of functional organoids).

Dr. Rudolf Leube
Guest Editor

Manuscript Submission Information

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Keywords

  • Epithelial mechanobiology
  • Cytoskeleton
  • Adhesion
  • Extracellular matrix
  • Tissue engineering
  • Mechanical probing

Published Papers (8 papers)

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Research

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Article
From Microspikes to Stress Fibers: Actin Remodeling in Breast Acini Drives Myosin II-Mediated Basement Membrane Invasion
Cells 2021, 10(8), 1979; https://doi.org/10.3390/cells10081979 - 04 Aug 2021
Viewed by 369
Abstract
The cellular mechanisms of basement membrane (BM) invasion remain poorly understood. We investigated the invasion-promoting mechanisms of actin cytoskeleton reorganization in BM-covered MCF10A breast acini. High-resolution confocal microscopy has characterized actin cell protrusion formation and function in response to tumor-resembling ECM stiffness and [...] Read more.
The cellular mechanisms of basement membrane (BM) invasion remain poorly understood. We investigated the invasion-promoting mechanisms of actin cytoskeleton reorganization in BM-covered MCF10A breast acini. High-resolution confocal microscopy has characterized actin cell protrusion formation and function in response to tumor-resembling ECM stiffness and soluble EGF stimulation. Traction force microscopy quantified the mechanical BM stresses that invasion-triggered acini exerted on the BM–ECM interface. We demonstrate that acini use non-proteolytic actin microspikes as functional precursors of elongated protrusions to initiate BM penetration and ECM probing. Further, these microspikes mechanically widened the collagen IV pores to anchor within the BM scaffold via force-transmitting focal adhesions. Pre-invasive basal cells located at the BM–ECM interface exhibited predominantly cortical actin networks and actin microspikes. In response to pro-invasive conditions, these microspikes accumulated and converted subsequently into highly contractile stress fibers. The phenotypical switch to stress fiber cells matched spatiotemporally with emerging high BM stresses that were driven by actomyosin II contractility. The activation of proteolytic invadopodia with MT1-MMP occurred at later BM invasion stages and only in cells already disseminating into the ECM. Our study demonstrates that BM pore-widening filopodia bridge mechanical ECM probing function and contractility-driven BM weakening. Finally, these EMT-related cytoskeletal adaptations are critical mechanisms inducing the invasive transition of benign breast acini. Full article
(This article belongs to the Special Issue Epithelial Cell Mechanics: From Physiology to Pathology)
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Article
Skin under Strain: From Epithelial Model Tissues to Adult Epithelia
Cells 2021, 10(7), 1834; https://doi.org/10.3390/cells10071834 - 20 Jul 2021
Viewed by 546
Abstract
Formation of a barrier capable of protecting tissue from external damage, chemical factors, and pathogens is one of the main functions of the epidermis. Furthermore, upon development and during aging, mechanoprotective epidermal functions change dramatically. However, comparative studies between embryonic and adult skin [...] Read more.
Formation of a barrier capable of protecting tissue from external damage, chemical factors, and pathogens is one of the main functions of the epidermis. Furthermore, upon development and during aging, mechanoprotective epidermal functions change dramatically. However, comparative studies between embryonic and adult skin in comparison to skin equivalents are still scarce which is especially due to the lack of appropriate measurement systems with sufficient accuracy and long-term tissue compatibility. Our studies fill this gap by developing a combined bioreactor and tensile testing machine for biomechanical analysis of living epithelia. Based on this tissue stretcher, our data clearly show that viscoelastic and plastic deformation behavior of embryonic and adult skin differ significantly. Tissue responses to static strain compared to cyclic strain also show a clear dependence on differentiation stage. Multilayered unkeratinized epidermis equivalents, on the other hand, respond very similar to mechanical stretch as adult tissue. This mechanical similarity is even more evident after a single cycle of mechanical preconditioning. Our studies therefore suggest that skin equivalents are well suited model systems to analyze cellular interactions of epidermal cells in natural tissues. Full article
(This article belongs to the Special Issue Epithelial Cell Mechanics: From Physiology to Pathology)
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Article
Mechanical Adaptations of Epithelial Cells on Various Protruded Convex Geometries
Cells 2020, 9(6), 1434; https://doi.org/10.3390/cells9061434 - 09 Jun 2020
Cited by 1 | Viewed by 1659
Abstract
The shape of epithelial tissue supports physiological functions of organs such as intestinal villi and corneal epithelium. Despite the mounting evidence showing the importance of geometry in tissue microenvironments, the current understanding on how it affects biophysical behaviors of cells is still elusive. [...] Read more.
The shape of epithelial tissue supports physiological functions of organs such as intestinal villi and corneal epithelium. Despite the mounting evidence showing the importance of geometry in tissue microenvironments, the current understanding on how it affects biophysical behaviors of cells is still elusive. Here, we cultured cells on various protruded convex structure such as triangle, square, and circle shape fabricated using two-photon laser lithography and quantitatively analyzed individual cells. Morphological data indicates that epithelial cells can sense the sharpness of the corner by showing the characteristic cell alignments, which was caused by actin contractility. Cell area was mainly influenced by surface convexity, and Rho-activation increased cell area on circle shape. Moreover, we found that intermediate filaments, vimentin, and cytokeratin 8/18, play important roles in growth and adaptation of epithelial cells by enhancing expression level on convex structure depending on the shape. In addition, microtubule building blocks, α-tubulin, was also responded on geometric structure, which indicates that intermediate filaments and microtubule can cooperatively secure mechanical stability of epithelial cells on convex surface. Altogether, the current study will expand our understanding of mechanical adaptations of cells on out-of-plane geometry. Full article
(This article belongs to the Special Issue Epithelial Cell Mechanics: From Physiology to Pathology)
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Article
Transcriptional and Ultrastructural Analyses Suggest Novel Insights into Epithelial Barrier Impairment in Celiac Disease
Cells 2020, 9(2), 516; https://doi.org/10.3390/cells9020516 - 24 Feb 2020
Cited by 1 | Viewed by 1411
Abstract
Disruption of epithelial junctional complex (EJC), especially tight junctions (TJ), resulting in increased intestinal permeability, is supposed to activate the enhanced immune response to gluten and to induce the development of celiac disease (CD). This study is aimed to present the role of [...] Read more.
Disruption of epithelial junctional complex (EJC), especially tight junctions (TJ), resulting in increased intestinal permeability, is supposed to activate the enhanced immune response to gluten and to induce the development of celiac disease (CD). This study is aimed to present the role of EJC in CD pathogenesis. To analyze differentially expressed genes the next-generation mRNA sequencing data from CD326+ epithelial cells isolated from non-celiac and celiac patients were involved. Ultrastructural studies with morphometry of EJC were done in potential CD, newly recognized active CD, and non-celiac controls. The transcriptional analysis suggested disturbances of epithelium and the most significant gene ontology enriched terms in epithelial cells from CD patients related to the plasma membrane, extracellular exome, extracellular region, and extracellular space. Ultrastructural analyses showed significantly tighter TJ, anomalies in desmosomes, dilatations of intercellular space, and shorter microvilli in potential and active CD compared to controls. Enterocytes of fetal-like type and significantly wider adherence junctions were observed only in active CD. In conclusion, the results do not support the hypothesis that an increased passage of gluten peptides by unsealing TJ precedes CD development. However, increased intestinal permeability due to abnormality of epithelium might play a role in CD onset. Full article
(This article belongs to the Special Issue Epithelial Cell Mechanics: From Physiology to Pathology)
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Review

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Review
How Mechanical Forces Change the Human Endometrium during the Menstrual Cycle in Preparation for Embryo Implantation
Cells 2021, 10(8), 2008; https://doi.org/10.3390/cells10082008 - 06 Aug 2021
Viewed by 459
Abstract
The human endometrium is characterized by exceptional plasticity, as evidenced by rapid growth and differentiation during the menstrual cycle and fast tissue remodeling during early pregnancy. Past work has rarely addressed the role of cellular mechanics in these processes. It is becoming increasingly [...] Read more.
The human endometrium is characterized by exceptional plasticity, as evidenced by rapid growth and differentiation during the menstrual cycle and fast tissue remodeling during early pregnancy. Past work has rarely addressed the role of cellular mechanics in these processes. It is becoming increasingly clear that sensing and responding to mechanical forces are as significant for cell behavior as biochemical signaling. Here, we provide an overview of experimental evidence and concepts that illustrate how mechanical forces influence endometrial cell behavior during the hormone-driven menstrual cycle and prepare the endometrium for embryo implantation. Given the fundamental species differences during implantation, we restrict the review to the human situation. Novel technologies and devices such as 3D multifrequency magnetic resonance elastography, atomic force microscopy, organ-on-a-chip microfluidic systems, stem-cell-derived organoid formation, and complex 3D co-culture systems have propelled the understanding how endometrial receptivity and blastocyst implantation are regulated in the human uterus. Accumulating evidence has shown that junctional adhesion, cytoskeletal rearrangement, and extracellular matrix stiffness affect the local force balance that regulates endometrial differentiation and blastocyst invasion. A focus of this review is on the hormonal regulation of endometrial epithelial cell mechanics. We discuss potential implications for embryo implantation. Full article
(This article belongs to the Special Issue Epithelial Cell Mechanics: From Physiology to Pathology)
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Review
Cell Mechanics in Embryoid Bodies
Cells 2020, 9(10), 2270; https://doi.org/10.3390/cells9102270 - 11 Oct 2020
Cited by 2 | Viewed by 1199
Abstract
Embryoid bodies (EBs) resemble self-organizing aggregates of pluripotent stem cells that recapitulate some aspects of early embryogenesis. Within few days, the cells undergo a transition from rather homogeneous epithelial-like pluripotent stem cell colonies into a three-dimensional organization of various cell types with multifaceted [...] Read more.
Embryoid bodies (EBs) resemble self-organizing aggregates of pluripotent stem cells that recapitulate some aspects of early embryogenesis. Within few days, the cells undergo a transition from rather homogeneous epithelial-like pluripotent stem cell colonies into a three-dimensional organization of various cell types with multifaceted cell–cell interactions and lumen formation—a process associated with repetitive epithelial-mesenchymal transitions. In the last few years, culture methods have further evolved to better control EB size, growth, cellular composition, and organization—e.g., by the addition of morphogens or different extracellular matrix molecules. There is a growing perception that the mechanical properties, cell mechanics, and cell signaling during EB development are also influenced by physical cues to better guide lineage specification; substrate elasticity and topography are relevant, as well as shear stress and mechanical strain. Epithelial structures outside and inside EBs support the integrity of the cell aggregates and counteract mechanical stress. Furthermore, hydrogels can be used to better control the organization and lineage-specific differentiation of EBs. In this review, we summarize how EB formation is accompanied by a variety of biomechanical parameters that need to be considered for the directed and reproducible self-organization of early cell fate decisions. Full article
(This article belongs to the Special Issue Epithelial Cell Mechanics: From Physiology to Pathology)
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Review
The Intestinal Barrier and Current Techniques for the Assessment of Gut Permeability
Cells 2020, 9(8), 1909; https://doi.org/10.3390/cells9081909 - 17 Aug 2020
Cited by 22 | Viewed by 2410
Abstract
The intestinal barrier is essential in human health and constitutes the interface between the outside and the internal milieu of the body. A functional intestinal barrier allows absorption of nutrients and fluids but simultaneously prevents harmful substances like toxins and bacteria from crossing [...] Read more.
The intestinal barrier is essential in human health and constitutes the interface between the outside and the internal milieu of the body. A functional intestinal barrier allows absorption of nutrients and fluids but simultaneously prevents harmful substances like toxins and bacteria from crossing the intestinal epithelium and reaching the body. An altered intestinal permeability, a sign of a perturbed barrier function, has during the last decade been associated with several chronic conditions, including diseases originating in the gastrointestinal tract but also diseases such as Alzheimer and Parkinson disease. This has led to an intensified interest from researchers with diverse backgrounds to perform functional studies of the intestinal barrier in different conditions. Intestinal permeability is defined as the passage of a solute through a simple membrane and can be measured by recording the passage of permeability markers over the epithelium via the paracellular or the transcellular route. The methodological tools to investigate the gut barrier function are rapidly expanding and new methodological approaches are being developed. Here we outline and discuss, in vivo, in vitro and ex vivo techniques and how these methods can be utilized for thorough investigation of the intestinal barrier. Full article
(This article belongs to the Special Issue Epithelial Cell Mechanics: From Physiology to Pathology)
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Review
Ciliary Genes in Renal Cystic Diseases
Cells 2020, 9(4), 907; https://doi.org/10.3390/cells9040907 - 08 Apr 2020
Cited by 8 | Viewed by 1725
Abstract
Cilia are microtubule-based organelles, protruding from the apical cell surface and anchoring to the cytoskeleton. Primary (nonmotile) cilia of the kidney act as mechanosensors of nephron cells, responding to fluid movements by triggering signal transduction. The impaired functioning of primary cilia leads to [...] Read more.
Cilia are microtubule-based organelles, protruding from the apical cell surface and anchoring to the cytoskeleton. Primary (nonmotile) cilia of the kidney act as mechanosensors of nephron cells, responding to fluid movements by triggering signal transduction. The impaired functioning of primary cilia leads to formation of cysts which in turn contribute to development of diverse renal diseases, including kidney ciliopathies and renal cancer. Here, we review current knowledge on the role of ciliary genes in kidney ciliopathies and renal cell carcinoma (RCC). Special focus is given on the impact of mutations and altered expression of ciliary genes (e.g., encoding polycystins, nephrocystins, Bardet-Biedl syndrome (BBS) proteins, ALS1, Oral-facial-digital syndrome 1 (OFD1) and others) in polycystic kidney disease and nephronophthisis, as well as rare genetic disorders, including syndromes of Joubert, Meckel-Gruber, Bardet-Biedl, Senior-Loken, Alström, Orofaciodigital syndrome type I and cranioectodermal dysplasia. We also show that RCC and classic kidney ciliopathies share commonly disturbed genes affecting cilia function, including VHL (von Hippel-Lindau tumor suppressor), PKD1 (polycystin 1, transient receptor potential channel interacting) and PKD2 (polycystin 2, transient receptor potential cation channel). Finally, we discuss the significance of ciliary genes as diagnostic and prognostic markers, as well as therapeutic targets in ciliopathies and cancer. Full article
(This article belongs to the Special Issue Epithelial Cell Mechanics: From Physiology to Pathology)
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