The Impact of Mechanical Forces in Heart Morphogenesis

Our understanding of the function and development of the lymphatic system is expanding rapidly due to the identification of specific molecular markers and the availability of novel genetic approaches. In connection, it has been demonstrated that mechanical forces contribute to the endothelial cell fate commitment and play a critical role in influencing lymphatic endothelial cell shape and alignment by promoting sprouting, development, maturation of the lymphatic network, and coordinating lymphatic valve morphogenesis and the stabilization of lymphatic valves. However, the mechanosignaling and mechanotransduction pathways involved in these processes are poorly understood. Here, we provide an overview of the impact of mechanical forces on lymphatics and summarize the current understanding of the molecular mechanisms involved in the mechanosensation and mechanotransduction by lymphatic endothelial cells. We also discuss how these mechanosensitive pathways affect endothelial cell fate and regulate lymphatic development and function. A better understanding of these mechanisms may provide a deeper insight into the pathophysiology of various diseases associated with impaired lymphatic function, such as lymphedema and may eventually lead to the discovery of novel therapeutic targets for these conditions.

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Evidence for the Desmosomal Cadherin Desmoglein-3 in Regulating YAP and Phospho-YAP in Keratinocyte Responses to Mechanical Forces

International Journal of Molecular Sciences ◽

10.3390/ijms20246221 ◽

2019 ◽

Vol 20 (24) ◽

pp. 6221 ◽

Cited By ~ 4

Author(s):

Jutamas Uttagomol ◽

Usama Sharif Ahmad ◽

Ambreen Rehman ◽

Yunying Huang ◽

Ana C. Laly ◽

...

Keyword(s):

Target Genes ◽

Hippo Pathway ◽

Cyclic Strain ◽

Cell Periphery ◽

Mechanical Forces ◽

Force Transmission ◽

Direct Role ◽

The Impact ◽

Desmoglein 3 ◽

E Cadherin

Desmoglein 3 (Dsg3) plays a crucial role in cell-cell adhesion and tissue integrity. Increasing evidence suggests that Dsg3 acts as a regulator of cellular mechanotransduction, but little is known about its direct role in mechanical force transmission. The present study investigated the impact of cyclic strain and substrate stiffness on Dsg3 expression and its role in mechanotransduction in keratinocytes. A direct comparison was made with E-cadherin, a well-characterized mechanosensor. Exposure of oral and skin keratinocytes to equiaxial cyclic strain promoted changes in the expression and localization of junction assembly proteins. The knockdown of Dsg3 by siRNA blocked strain-induced junctional remodeling of E-cadherin and Myosin IIa. Importantly, the study demonstrated that Dsg3 regulates the expression and localization of yes-associated protein (YAP), a mechanosensory, and an effector of the Hippo pathway. Furthermore, we showed that Dsg3 formed a complex with phospho-YAP and sequestered it to the plasma membrane, while Dsg3 depletion had an impact on both YAP and phospho-YAP in their response to mechanical forces, increasing the sensitivity of keratinocytes to the strain or substrate rigidity-induced nuclear relocation of YAP and phospho-YAP. Plakophilin 1 (PKP1) seemed to be crucial in recruiting the complex containing Dsg3/phospho-YAP to the cell surface since its silencing affected Dsg3 junctional assembly with concomitant loss of phospho-YAP at the cell periphery. Finally, we demonstrated that this Dsg3/YAP pathway has an influence on the expression of YAP1 target genes and cell proliferation. Together, these findings provide evidence of a novel role for Dsg3 in keratinocyte mechanotransduction.

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METHOD OF PAINT COAT DURABILITY ASSESSMENT EXPOSED TO MINERAL MASS

Tribologia ◽

10.5604/01.3001.0012.6985 ◽

2018 ◽

Vol 278 (2) ◽

pp. 123-131

Author(s):

Piotr SZCZYGLAK

Keyword(s):

Original Method ◽

Mechanical Forces ◽

Rotating Drum ◽

Testing Method ◽

Wear And Tear ◽

Durability Assessment ◽

Testing Stand ◽

Mechanical Factors ◽

The Impact ◽

Mineral Mass

This study analyses issues concerning defects of passive paint coats. Four reasons of their occurrence have been identified: constructional, technological, operational, and caused by wear and tear. Standardized methods of paint coat assessment are discussed based on the impact of mechanical factors (PN-EN ISO 2409:2013-06, ASTM D3359-17, PN-EN ISO 1522:2008, PN-EN ISO 4624:2016-05, PN-EN ISO 1518-1:2011, PN-EN ISO 16276-2:2008, PN-EN ISO 6272:2011, PN-EN ISO 6860:2006, PN-EN ISO 2815:2004, PN-EN ISO 1519:2000). The original method of paint coat durability evaluation is presented with the consideration of synergetic impact of mechanical forces. This method permits carrying out testing in conditions close to those during normal service. The testing stand equipped with a rotating drum filled with mineral mass has been described as well as the optical method of assessing paint coat quality using original software developed by authors. Tests for three coating systems were carried out in order to present the possibilities of the developed method. In summary, the conclusions relating to the presented testing method are presented.

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Digital twinning of Cellular Capsule Technology: Emerging outcomes from the perspective of porous media mechanics

PLoS ONE ◽

10.1371/journal.pone.0254512 ◽

2021 ◽

Vol 16 (7) ◽

pp. e0254512

Author(s):

Stéphane Urcun ◽

Pierre-Yves Rohan ◽

Wafa Skalli ◽

Pierre Nassoy ◽

Stéphane P. A. Bordas ◽

...

Keyword(s):

Tumor Cells ◽

Mechanical Model ◽

Interstitial Fluid ◽

Sensitivity Analyses ◽

Mechanical Forces ◽

Alginate Capsules ◽

Phenotype Switch ◽

New Perspective ◽

The Impact

Spheroids encapsulated within alginate capsules are emerging as suitable in vitro tools to investigate the impact of mechanical forces on tumor growth since the internal tumor pressure can be retrieved from the deformation of the capsule. Here we focus on the particular case of Cellular Capsule Technology (CCT). We show in this contribution that a modeling approach accounting for the triphasic nature of the spheroid (extracellular matrix, tumor cells and interstitial fluid) offers a new perspective of analysis revealing that the pressure retrieved experimentally cannot be interpreted as a direct picture of the pressure sustained by the tumor cells and, as such, cannot therefore be used to quantify the critical pressure which induces stress-induced phenotype switch in tumor cells. The proposed multiphase reactive poro-mechanical model was cross-validated. Parameter sensitivity analyses on the digital twin revealed that the main parameters determining the encapsulated growth configuration are different from those driving growth in free condition, confirming that radically different phenomena are at play. Results reported in this contribution support the idea that multiphase reactive poro-mechanics is an exceptional theoretical framework to attain an in-depth understanding of CCT experiments, to confirm their hypotheses and to further improve their design.

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Shear flow-driven actin re-organization induces ICAM-1 nanoclustering on endothelial cells that impact T-cell migration

10.1101/2020.06.29.177816 ◽

2020 ◽

Author(s):

Izabela K. Piechocka ◽

Sarah Keary ◽

Alberto Sosa-Costa ◽

Lukas Lau ◽

Nitin Mohan ◽

...

Keyword(s):

T Cells ◽

Endothelial Cells ◽

Cell Migration ◽

T Cell ◽

Shear Flow ◽

Membrane Receptors ◽

Mechanical Forces ◽

Shear Forces ◽

T Cell Migration ◽

The Impact

ABSTRACTThe leukocyte specific β2-integrin LFA-1, and its ligand ICAM-1 expressed on endothelial cells (ECs), are involved in the arrest, adhesion and transendothelial migration of leukocytes. Although the role of mechanical forces on LFA-1 activation is well established, the impact of forces on its major ligand ICAM-1, has received less attention. Using a parallel-plate flow chamber combined with confocal and super-resolution microscopy, we show that prolonged shear-flow induces a global translocation of ICAM-1 on ECs upstream of flow direction. Interestingly, shear-forces promoted ICAM-1 nanoclustering prior to LFA-1 engagement. This spatial nanoscale organization was driven by actin cytoskeleton re-arrangements induced by shear-force. We further assessed the impact of prolonged shear-stress EC stimulation on T cell migration. T cells adhered to mechanically pre-stimulated ECs developed a more pro-migratory phenotype, migrated faster and exhibited shorter EC interactions than when adhered to non-mechanically stimulated ECs. Together, our results indicate that shear-forces increase the number of ICAM-1/LFA-1 bonds due to ICAM-1 nanoclustering, strengthening adhesion and thereby reducing actin retrograde flow of T-cells, leading to their increased migration speed. Our data also underscores the importance of mechanical forces regulating the spatial organization of cell membrane receptors and their contribution to adhesion regulation, regardless of integrin activation.Summary statementWe show that shear forces promote ICAM-1 spatial re-arrangement and actin-dependent nanoclustering on ECs prior to integrin engagement. This mechanism might be important for firm leukocyte adhesion and migration during the immune response.

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Functional states of kinetochores revealed by laser microsurgery and fluorescent speckle microscopy

Molecular Biology of the Cell ◽

10.1091/mbc.e11-06-0494 ◽

2011 ◽

Vol 22 (24) ◽

pp. 4801-4808 ◽

Cited By ~ 9

Author(s):

James R. LaFountain ◽

Christopher S. Cohan ◽

Rudolf Oldenbourg

Keyword(s):

Normal Velocity ◽

Mechanical Forces ◽

Laser Microsurgery ◽

Meiotic Chromosomes ◽

Late Anaphase ◽

Functional States ◽

And Control ◽

The Impact ◽

Meiosis I

The impact of mechanical forces on kinetochore motility was investigated using laser microsurgery to detach kinetochores with associated chromatin (K fragment) from meiotic chromosomes in spermatocytes from the crane fly Nephrotoma suturalis. In spermatocytes, elastic tethers connect telomeres of homologues during anaphase A of meiosis I, thus preventing complete disjunction until mid- to late anaphase A. K fragments liberated from tethered arms moved at twice the normal velocity toward their connected poles. To assess functional states of detached and control kinetochores, we loaded cells with fluorescently labeled tubulin for fluorescent speckle microscopy on kinetochore microtubules. Control kinetochores added fluorescent speckles at the kinetochore during anaphase A, whereas kinetochores of K fragments generally did not. In cases in which speckles reappeared in K-fragment K fibers, speckles and K fragments moved poleward at similar velocities. Thus detached kinetochores convert from their normal polymerization (reverse pac-man) state to a different state, in which polymerization is not evident. We suggest that the converted state is “park,” in which kinetochores are anchored to plus ends of kinetochore microtubules that shorten exclusively at their polar ends.

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Airway mechanical compression: its role in asthma pathogenesis and progression

European Respiratory Review ◽

10.1183/16000617.0123-2019 ◽

2020 ◽

Vol 29 (157) ◽

pp. 190123 ◽

Cited By ~ 2

Author(s):

Punnam Chander Veerati ◽

Jennifer A. Mitchel ◽

Andrew T. Reid ◽

Darryl A. Knight ◽

Nathan W. Bartlett ◽

...

Keyword(s):

Ex Vivo ◽

Experimental Models ◽

Normal Lung ◽

Mechanical Forces ◽

Mechanical Compression ◽

Cell Hyperplasia ◽

Airway Narrowing ◽

The Impact

The lung is a mechanically active organ, but uncontrolled or excessive mechanical forces disrupt normal lung function and can contribute to the development of disease. In asthma, bronchoconstriction leads to airway narrowing and airway wall buckling. A growing body of evidence suggests that pathological mechanical forces induced by airway buckling alone can perpetuate disease processes in asthma. Here, we review the data obtained from a variety of experimental models, including in vitro, ex vivo and in vivo approaches, which have been used to study the impact of mechanical forces in asthma pathogenesis. We review the evidence showing that mechanical compression alters the biological and biophysical properties of the airway epithelium, including activation of the epidermal growth factor receptor pathway, overproduction of asthma-associated mediators, goblet cell hyperplasia, and a phase transition of epithelium from a static jammed phase to a mobile unjammed phase. We also define questions regarding the impact of mechanical forces on the pathology of asthma, with a focus on known triggers of asthma exacerbations such as viral infection.

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Digital twinning of Cellular Capsule Technology: emerging outcomes from the perspective of porous media mechanics

10.1101/2020.06.09.142927 ◽

2020 ◽

Cited By ~ 1

Author(s):

Stéphane Urcun ◽

Pierre-Yves Rohan ◽

Wafa Skalli ◽

Pierre Nassoy ◽

Stéphane P.A. Bordas ◽

...

Keyword(s):

Tumor Cells ◽

Mechanical Model ◽

Interstitial Fluid ◽

Sensitivity Analyses ◽

Mechanical Forces ◽

Digital Twin ◽

Alginate Capsules ◽

New Perspective ◽

The Impact

AbstractSpheroids encapsulated within alginate capsules are emerging as suitable in vitro tools to investigate the impact of mechanical forces on tumor growth since the internal tumor pressure can be retrieved from the deformation of the capsule. Here we focus in particular on the Cellular Capsule Technology (CCT).We show that a modeling approach accounting for the triphasic nature of the spheroid (it consists of extracellular matrix, tumor cells and interstitial fluid) offers a new perspective of analysis revealing that the pressure retrieved experimentally is representative of the average stress state in the multiphase continuum, so it cannot be interpreted as a direct picture of the pressure sustained by the tumor cells.A multiphase reactive poro-mechanical model is cross-validated and proposed here as a suitable digital twin of the CCT experiment. Parameter sensitivity analyses on the digital twin allows us to show that the main parameters determining the encapsulated growth configuration are different from those which drive growth in free condition, confirming that radically different phenomena are at play. Multiphase reactive poro-mechanics emerges here as an exceptional theoretical framework to deeply understand CCT experiments, to confirm their hypotheses or further improve their design.

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The desmosomal cadherin Desmoglein-3 regulates YAP and phospho-YAP in keratinocyte responses to mechanical forces

10.1101/827725 ◽

2019 ◽

Author(s):

Jutamas Uttagomol ◽

Usama Sharif Ahmad ◽

Ambreen Rehman ◽

Yunying Huang ◽

Ana C. Laly ◽

...

Keyword(s):

Target Genes ◽

Hippo Pathway ◽

Cyclic Strain ◽

Human Keratinocytes ◽

Mechanical Forces ◽

Force Transmission ◽

Direct Role ◽

The Impact ◽

Desmoglein 3 ◽

E Cadherin

ABSTRACTDesmoglein 3 (Dsg3), plays a crucial role in cell-cell adhesion and tissue integrity. Increasing evidence suggests that Dsg3 acts as a regulator of cellular mechanotransduction, but little is known about its direct role in mechanical force transmission. The present study investigated the impact of cyclic strain and substrate stiffness on Dsg3 expression and its role in mechanotransduction. A direct comparison was made with E-cadherin, a well-characterized mechanosensor, in human keratinocytes. Exposure of oral and skin keratinocytes to equiaxial cyclic strain promoted changes in expression and localization of junction assembly proteins. Knockdown of Dsg3 by siRNA blocked strain-induced junctional remodeling of E-cadherin and Myosin IIa. Importantly, the study demonstrated that Dsg3 regulates the expression and localization of YAP, a mechanosensor and an effector of the Hippo pathway. Furthermore, we showed that Dsg3 forms a complex with phospho-YAP and sequestered it to the plasma membrane, while Dsg3 depletion had an impact on both YAP and phospho-YAP in their response to mechanical forces, increasing the sensitivity of keratinocytes to both strain-or substrate rigidity-induced nuclear relocalization of YAP and phospho-YAP. We showed that PKP1 seemed to be the key in such a complex formation since its silencing resulted in Dsg3 disruption at the junctions with concomitant loss of pYAP in the peripheral cytoplasm. Finally, we demonstrated that this Dsg3/YAP pathway has an influence on the expression of YAP1 target genes as well as cell proliferation in keratinocytes. Together, these findings provide evidence of a novel role for Dsg3 in keratinocyte mechanotransduction.

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Transcriptomic analysis reveals dynamic molecular changes in skin induced by mechanical forces secondary to tissue expansion

Scientific Reports ◽

10.1038/s41598-020-71823-z ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Joanna K. Ledwon ◽

Lauren J. Kelsey ◽

Elbert E. Vaca ◽

Arun K. Gosain

Keyword(s):

Cell Biology ◽

Cell Metabolism ◽

Tissue Expander ◽

Tissue Expansion ◽

Mechanical Forces ◽

Biological Processes ◽

Molecular Changes ◽

Cytoskeleton Organization ◽

The Impact

Abstract Tissue expansion procedures (TE) utilize mechanical forces to induce skin growth and regeneration. While the impact of quick mechanical stimulation on molecular changes in cells has been studied extensively, there is a clear gap in knowledge about sequential biological processes activated during long-term stimulation of skin in vivo. Here, we present the first genome-wide study of transcriptional changes in skin during TE, starting from 1 h to 7 days of expansion. Our results indicate that mechanical forces from a tissue expander induce broad molecular changes in gene expression, and that these changes are time-dependent. We revealed hierarchical changes in skin cell biology, including activation of an immune response, a switch in cell metabolism and processes related to muscle contraction and cytoskeleton organization. In addition to known mechanoresponsive genes (TNC, MMPs), we have identified novel candidate genes (SFRP2, SPP1, CCR1, C2, MSR1, C4A, PLA2G2F, HBB), which might play crucial roles in stretched-induced skin growth. Understanding which biological processes are affected by mechanical forces in TE is important for the development of skin treatments to maximize the efficacy and minimize the risk of complications during expansion procedures.

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