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Cells
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Cellular Integrity under Mechanical Stress
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Cellular Integrity under Mechanical Stress

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Biophysics".

Deadline for manuscript submissions: closed (2 December 2022) | Viewed by 21125

Special Issue Editor

Prof. Dr. Annette Müller-Taubenberger

E-Mail Website
Guest Editor
Biomedical Center Munich, Cell Biology (Anatomy III), Ludwig Maximilian University, 82152 Planegg-Martinsried, Germany
Interests: actin cytoskeleton dynamics; cell migration; cytoskeletal proteins; live-cell imaging; reproductive medicine
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In multicellular organisms, cells and tissues are exposed in different situations to a variety of mechanical cues. Mechanical force can either be a physiological stimulus or cause a stress situation, but while responses of cells to metabolic changes, oxidative stress, or heat are well investigated, much less is known about the mechanosensitive properties of cells.

Cytoskeletal systems, cell–cell as well as cell–matrix contacts, and mechanosensitive channels are among the primary sensors to detect changes in cell tension and to trigger a variety of responses. In order to maintain cellular homeostasis when cells and tissues are exposed to mechanical forces in different situations, physiological responses and stress protection include a variety of reactions, such as adaption of cell tension, force-induced protein unfolding, or the activation of signaling cascades.

With this Special Issue, we aim to bring together a collection of research articles, reviews and communications that address the subject of how cells or tissues respond to mechanical changes in their microenvironment, including molecular studies that analyze the physiological and pathophysiological parameters that help to maintain cellular integrity.

Prof. Dr. Annette Müller-Taubenberger
Guest Editor

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Keywords

  • actin cytoskeleton
  • mechanobiology
  • mechanotransduction
  • shear stress

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Published Papers (7 papers)

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Research

Jump to: Review, Other

20 pages, 8979 KiB  
Article
Elastomeric Pillar Cages Modulate Actomyosin Contractility of Epithelial Microtissues by Substrate Stiffness and Topography
by Lisann Esser, Ronald Springer, Georg Dreissen, Lukas Lövenich, Jens Konrad, Nico Hampe, Rudolf Merkel, Bernd Hoffmann and Erik Noetzel
Cells 2023, 12(9), 1256; https://doi.org/10.3390/cells12091256 - 26 Apr 2023
Cited by 1 | Viewed by 1611
Abstract
Cell contractility regulates epithelial tissue geometry development and homeostasis. The underlying mechanobiological regulation circuits are poorly understood and experimentally challenging. We developed an elastomeric pillar cage (EPC) array to quantify cell contractility as a mechanoresponse of epithelial microtissues to substrate stiffness and topography. [...] Read more.
Cell contractility regulates epithelial tissue geometry development and homeostasis. The underlying mechanobiological regulation circuits are poorly understood and experimentally challenging. We developed an elastomeric pillar cage (EPC) array to quantify cell contractility as a mechanoresponse of epithelial microtissues to substrate stiffness and topography. The spatially confined EPC geometry consisted of 24 circularly arranged slender pillars (1.2 MPa, height: 50 µm; diameter: 10 µm, distance: 5 µm). These high-aspect-ratio pillars were confined at both ends by planar substrates with different stiffness (0.15–1.2 MPa). Analytical modeling and finite elements simulation retrieved cell forces from pillar displacements. For evaluation, highly contractile myofibroblasts and cardiomyocytes were assessed to demonstrate that the EPC device can resolve static and dynamic cellular force modes. Human breast (MCF10A) and skin (HaCaT) cells grew as adherence junction-stabilized 3D microtissues within the EPC geometry. Planar substrate areas triggered the spread of monolayered clusters with substrate stiffness-dependent actin stress fiber (SF)-formation and substantial single-cell actomyosin contractility (150–200 nN). Within the same continuous microtissues, the pillar-ring topography induced the growth of bilayered cell tubes. The low effective pillar stiffness overwrote cellular sensing of the high substrate stiffness and induced SF-lacking roundish cell shapes with extremely low cortical actin tension (11–15 nN). This work introduced a versatile biophysical tool to explore mechanobiological regulation circuits driving low- and high-tensional states during microtissue development and homeostasis. EPC arrays facilitate simultaneously analyzing the impact of planar substrate stiffness and topography on microtissue contractility, hence microtissue geometry and function. Full article
(This article belongs to the Special Issue Cellular Integrity under Mechanical Stress)
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25 pages, 11112 KiB  
Article
Unleashed Actin Assembly in Capping Protein-Deficient B16-F1 Cells Enables Identification of Multiple Factors Contributing to Filopodium Formation
by Jens Ingo Hein, Jonas Scholz, Sarah Körber, Thomas Kaufmann and Jan Faix
Cells 2023, 12(6), 890; https://doi.org/10.3390/cells12060890 - 14 Mar 2023
Cited by 4 | Viewed by 3025
Abstract
Background: Filopodia are dynamic, finger-like actin-filament bundles that overcome membrane tension by forces generated through actin polymerization at their tips to allow extension of these structures a few microns beyond the cell periphery. Actin assembly of these protrusions is regulated by accessory proteins [...] Read more.
Background: Filopodia are dynamic, finger-like actin-filament bundles that overcome membrane tension by forces generated through actin polymerization at their tips to allow extension of these structures a few microns beyond the cell periphery. Actin assembly of these protrusions is regulated by accessory proteins including heterodimeric capping protein (CP) or Ena/VASP actin polymerases to either terminate or promote filament growth. Accordingly, the depletion of CP in B16-F1 melanoma cells was previously shown to cause an explosive formation of filopodia. In Ena/VASP-deficient cells, CP depletion appeared to result in ruffling instead of inducing filopodia, implying that Ena/VASP proteins are absolutely essential for filopodia formation. However, this hypothesis was not yet experimentally confirmed. Methods: Here, we used B16-F1 cells and CRISPR/Cas9 technology to eliminate CP either alone or in combination with Ena/VASP or other factors residing at filopodia tips, followed by quantifications of filopodia length and number. Results: Unexpectedly, we find massive formations of filopodia even in the absence of CP and Ena/VASP proteins. Notably, combined inactivation of Ena/VASP, unconventional myosin-X and the formin FMNL3 was required to markedly impair filopodia formation in CP-deficient cells. Conclusions: Taken together, our results reveal that, besides Ena/VASP proteins, numerous other factors contribute to filopodia formation. Full article
(This article belongs to the Special Issue Cellular Integrity under Mechanical Stress)
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12 pages, 1461 KiB  
Article
Biomechanical Assessment of Macro-Calcification in Human Carotid Atherosclerosis and Its Impact on Smooth Muscle Cell Phenotype
by Till Seime, Max van Wanrooij, Eva Karlöf, Malin Kronqvist, Staffan Johansson, Ljubica Matic, T. Christian Gasser and Ulf Hedin
Cells 2022, 11(20), 3279; https://doi.org/10.3390/cells11203279 - 18 Oct 2022
Cited by 9 | Viewed by 2329
Abstract
Intimal calcification and vascular stiffening are predominant features of end-stage atherosclerosis. However, their role in atherosclerotic plaque instability and how the extent and spatial distribution of calcification influence plaque biology remain unclear. We recently showed that extensive macro calcification can be a stabilizing [...] Read more.
Intimal calcification and vascular stiffening are predominant features of end-stage atherosclerosis. However, their role in atherosclerotic plaque instability and how the extent and spatial distribution of calcification influence plaque biology remain unclear. We recently showed that extensive macro calcification can be a stabilizing feature of late-stage human lesions, associated with a reacquisition of more differentiated properties of plaque smooth muscle cells (SMCs) and extracellular matrix (ECM) remodeling. Here, we hypothesized that biomechanical forces related to macro-calcification within plaques influence SMC phenotype and contribute to plaque stabilization. We generated a finite element modeling (FEM) pipeline to assess plaque tissue stretch based on image analysis of preoperative computed tomography angiography (CTA) of carotid atherosclerotic plaques to visualize calcification and soft tissues (lipids and extracellular matrix) within the lesions. Biomechanical stretch was significantly reduced in tissues in close proximity to macro calcification, while increased levels were observed within distant soft tissues. Applying this data to an in vitro stretch model on primary vascular SMCs revealed upregulation of typical markers for differentiated SMCs and contractility under low stretch conditions but also impeded SMC alignment. In contrast, high stretch conditions in combination with calcifying conditions induced SMC apoptosis. Our findings suggest that the load bearing capacities of macro calcifications influence SMC differentiation and survival and contribute to atherosclerotic plaque stabilization. Full article
(This article belongs to the Special Issue Cellular Integrity under Mechanical Stress)
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18 pages, 1917 KiB  
Article
Network-Based Analysis to Identify Hub Genes Involved in Spatial Root Response to Mechanical Constrains
by Anastazija Dimitrova, Gabriella Sferra, Gabriella Stefania Scippa and Dalila Trupiano
Cells 2022, 11(19), 3121; https://doi.org/10.3390/cells11193121 - 4 Oct 2022
Cited by 2 | Viewed by 1597
Abstract
Previous studies report that the asymmetric response, observed along the main poplar woody bent root axis, was strongly related to both the type of mechanical forces (compression or tension) and the intensity of force displacement. Despite a large number of targets that have [...] Read more.
Previous studies report that the asymmetric response, observed along the main poplar woody bent root axis, was strongly related to both the type of mechanical forces (compression or tension) and the intensity of force displacement. Despite a large number of targets that have been proposed to trigger this asymmetry, an understanding of the comprehensive and synergistic effect of the antistress spatially related pathways is still lacking. Recent progress in the bioinformatics area has the potential to fill these gaps through the use of in silico studies, able to investigate biological functions and pathway overlaps, and to identify promising targets in plant responses. Presently, for the first time, a comprehensive network-based analysis of proteomic signatures was used to identify functions and pivotal genes involved in the coordinated signalling pathways and molecular activities that asymmetrically modulate the response of different bent poplar root sectors and sides. To accomplish this aim, 66 candidate proteins, differentially represented across the poplar bent root sides and sectors, were grouped according to their abundance profile patterns and mapped, together with their first neighbours, on a high-confidence set of interactions from STRING to compose specific cluster-related subnetworks (I–VI). Successively, all subnetworks were explored by a functional gene set enrichment analysis to identify enriched gene ontology terms. Subnetworks were then analysed to identify the genes that are strongly interconnected with other genes (hub gene) and, thus, those that have a pivotal role in the bent root asymmetric response. The analysis revealed novel information regarding the response coordination, communication, and potential signalling pathways asymmetrically activated along the main root axis, delegated mainly to Ca2+ (for new lateral root formation) and ROS (for gravitropic response and lignin accumulation) signatures. Furthermore, some of the data indicate that the concave side of the bent sector, where the mechanical forces are most intense, communicates to the other (neighbour and distant) sectors, inducing spatially related strategies to ensure water uptake and accompanying cell modification. This information could be critical for understanding how plants maintain and improve their structural integrity—whenever and wherever it is necessary—in natural mechanical stress conditions. Full article
(This article belongs to the Special Issue Cellular Integrity under Mechanical Stress)
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17 pages, 9743 KiB  
Article
Optimization of Mechanosensitive Cross-Talk between Matrix Stiffness and Protein Density: Independent Matrix Properties Regulate Spreading Dynamics of Myocytes
by Judith Brock, Julia Erhardt, Stephan A. Eisler and Marcel Hörning
Cells 2022, 11(13), 2122; https://doi.org/10.3390/cells11132122 - 5 Jul 2022
Cited by 2 | Viewed by 2638
Abstract
Cells actively sense differences in topology, matrix elasticity and protein composition of the extracellular microenvironment and adapt their function and morphology. In this study, we focus on the cross-talk between matrix stiffness and protein coating density that regulates morphology and proliferation dynamics of [...] Read more.
Cells actively sense differences in topology, matrix elasticity and protein composition of the extracellular microenvironment and adapt their function and morphology. In this study, we focus on the cross-talk between matrix stiffness and protein coating density that regulates morphology and proliferation dynamics of single myocytes. For this, C2C12 myocytes were monitored on L-DOPA functionalized hydrogels of 22 different elasticity and fibronectin density compositions. Static images were recorded and statistically analyzed to determine morphological differences and to identify the optimized extracellular matrix (ECM). Using that information, selected ECMs were used to study the dynamics before and after cell proliferation by statistical comparison of distinct cell states. We observed a fibronectin-density-independent increase of the projected cell area until 12 kPa. Additionally, changes in fibronectin density led to an area that was optimum at about 2.6 μg/cm2, which was confirmed by independent F-actin analysis, revealing a maximum actin-filament-to-cell-area ratio of 7.5%. Proliferation evaluation showed an opposite correlation between cell spreading duration and speed to matrix elasticity and protein density, which did not affect cell-cycle duration. In summary, we identified an optimized ECM composition and found that independent matrix properties regulate distinct cell characteristics. Full article
(This article belongs to the Special Issue Cellular Integrity under Mechanical Stress)
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Review

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23 pages, 1360 KiB  
Review
Caveolae Mechanotransduction at the Interface between Cytoskeleton and Extracellular Matrix
by Laura Sotodosos-Alonso, Marta Pulgarín-Alfaro and Miguel A. del Pozo
Cells 2023, 12(6), 942; https://doi.org/10.3390/cells12060942 - 20 Mar 2023
Cited by 16 | Viewed by 5563
Abstract
The plasma membrane (PM) is subjected to multiple mechanical forces, and it must adapt and respond to them. PM invaginations named caveolae, with a specific protein and lipid composition, play a crucial role in this mechanosensing and mechanotransduction process. They respond to PM [...] Read more.
The plasma membrane (PM) is subjected to multiple mechanical forces, and it must adapt and respond to them. PM invaginations named caveolae, with a specific protein and lipid composition, play a crucial role in this mechanosensing and mechanotransduction process. They respond to PM tension changes by flattening, contributing to the buffering of high-range increases in mechanical tension, while novel structures termed dolines, sharing Caveolin1 as the main component, gradually respond to low and medium forces. Caveolae are associated with different types of cytoskeletal filaments, which regulate membrane tension and also initiate multiple mechanotransduction pathways. Caveolar components sense the mechanical properties of the substrate and orchestrate responses that modify the extracellular matrix (ECM) according to these stimuli. They perform this function through both physical remodeling of ECM, where the actin cytoskeleton is a central player, and via the chemical alteration of the ECM composition by exosome deposition. Here, we review mechanotransduction regulation mediated by caveolae and caveolar components, focusing on how mechanical cues are transmitted through the cellular cytoskeleton and how caveolae respond and remodel the ECM. Full article
(This article belongs to the Special Issue Cellular Integrity under Mechanical Stress)
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Other

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10 pages, 630 KiB  
Perspective
Do Tumor Mechanical Stresses Promote Cancer Immune Escape?
by Killian Onwudiwe, Julian Najera, Saeed Siri and Meenal Datta
Cells 2022, 11(23), 3840; https://doi.org/10.3390/cells11233840 - 30 Nov 2022
Cited by 7 | Viewed by 2932
Abstract
Immune evasion—a well-established cancer hallmark—is a major barrier to immunotherapy efficacy. While the molecular mechanisms and biological consequences underpinning immune evasion are largely known, the role of tissue mechanical stresses in these processes warrants further investigation. The tumor microenvironment (TME) features physical abnormalities [...] Read more.
Immune evasion—a well-established cancer hallmark—is a major barrier to immunotherapy efficacy. While the molecular mechanisms and biological consequences underpinning immune evasion are largely known, the role of tissue mechanical stresses in these processes warrants further investigation. The tumor microenvironment (TME) features physical abnormalities (notably, increased fluid and solid pressures applied both inside and outside the TME) that drive cancer mechanopathologies. Strikingly, in response to these mechanical stresses, cancer cells upregulate canonical immune evasion mechanisms, including epithelial–mesenchymal transition (EMT) and autophagy. Consideration and characterization of the origins and consequences of tumor mechanical stresses in the TME may yield novel strategies to combat immunotherapy resistance. In this Perspective, we posit that tumor mechanical stresses—namely fluid shear and solid stresses—induce immune evasion by upregulating EMT and autophagy. In addition to exploring the basis for our hypothesis, we also identify explicit gaps in the field that need to be addressed in order to directly demonstrate the existence and importance of this biophysical relationship. Finally, we propose that reducing or neutralizing fluid shear stress and solid stress-induced cancer immune escape may improve immunotherapy outcomes. Full article
(This article belongs to the Special Issue Cellular Integrity under Mechanical Stress)
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