scholarly journals The nucleus measures shape deformation for cellular proprioception and regulates adaptive morphodynamics

2019 ◽  
Author(s):  
Valeria Venturini ◽  
Fabio Pezzano ◽  
Frederic Català Castro ◽  
Hanna-Maria Häkkinen ◽  
Senda Jiménez-Delgado ◽  
...  
Keyword(s):  
Functional Module ◽  
Single Cells ◽  
Physical Space ◽  
Local Environment ◽  
Shape Deformation ◽  
Geometrical Shape ◽  
Active Deformation ◽  
Calcium Dependent ◽  
And Migration ◽  
Cellular Behaviour

AbstractThe physical microenvironment regulates cell behavior during tissue development and homeostasis. How single cells decode information about their geometrical shape under mechanical stress and physical space constraints within their local environment remains largely unknown. Here we show that the nucleus, the biggest cellular organelle, functions as a non-dissipative cellular shape deformation gauge that enables cells to continuously measure shape variations on the time scale of seconds. Inner nuclear membrane unfolding together with the relative spatial intracellular positioning of the nucleus provides physical information on the amplitude and type of cellular shape deformation. This adaptively activates a calcium-dependent mechano-transduction pathway, controlling the level of actomyosin contractility and migration plasticity. Our data support that the nucleus establishes a functional module for cellular proprioception that enables cells to sense shape variations for adapting cellular behaviour to their microenvironment.One Sentence SummaryThe nucleus functions as an active deformation sensor that enables cells to adapt their behavior to the tissue microenvironment.

scholarly journals The nucleus measures shape changes for cellular proprioception to control dynamic cell behavior

Science ◽  
2020 ◽  
Vol 370 (6514) ◽  
pp. eaba2644 ◽  
Author(s):  
Valeria Venturini ◽  
Fabio Pezzano ◽  
Frederic Català Castro ◽  
Hanna-Maria Häkkinen ◽  
Senda Jiménez-Delgado ◽  
...  
Keyword(s):  
Functional Module ◽  
Single Cells ◽  
Physical Space ◽  
Cell Behavior ◽  
Geometrical Shape ◽  
Zebrafish Model ◽  
Calcium Dependent ◽  
Dynamic Cell ◽  
And Migration ◽  
Shape Changes

The physical microenvironment regulates cell behavior during tissue development and homeostasis. How single cells decode information about their geometrical shape under mechanical stress and physical space constraints within tissues remains largely unknown. Here, using a zebrafish model, we show that the nucleus, the biggest cellular organelle, functions as an elastic deformation gauge that enables cells to measure cell shape deformations. Inner nuclear membrane unfolding upon nucleus stretching provides physical information on cellular shape changes and adaptively activates a calcium-dependent mechanotransduction pathway, controlling actomyosin contractility and migration plasticity. Our data support that the nucleus establishes a functional module for cellular proprioception that enables cells to sense shape variations for adapting cellular behavior to their microenvironment.

Ovarian Cancer Cell Invasiveness Correlates With Increased Cell Deformability

2012 ◽  
Author(s):  
Wenwei Xu ◽  
Roman Mezencev ◽  
Byungkyu Kim ◽  
Lijuan Wang ◽  
John McDonald ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Single Cells ◽  
Metastatic Cancer ◽  
Ovarian Surface Epithelium ◽  
Surface Epithelium ◽  
Ovarian Cancer Cells ◽  
Cell Deformability ◽  
Ovarian Cells ◽  
And Migration

Cancer cells undergo a variety of biochemical and biophysical transformations when compared to identical cells displaying a healthy phenotypic state, cancer cells show a drastic reduction of stiffness upon malignancy[1, 2] and change of stiffness of single cells can indicate the presence of disease [3–6]. Besides, metastatic cancer has a higher deformability than their benign counterparts[7, 8]. Using atomic force microscopy, we demonstrated that cancerous ovarian cells (OVCAR3, OVCAR4, HEY and HEYA8) are substantially softer than the healthy immortalized ovarian surface epithelium (IOSE) cells. In addition, within the different types of cancerous ovarian cells, increased invasiveness and migration are directly correlated with increased cell deformability. These results indicate that stiffness of individual cells can distinguish not only ovarian cancer cells from healthy cells types, but also invasive cancer types from less invasive types. Stiffness may provide an alternative and convenient biomarker to grade the metastasis potential of cancer cells.

Targeted inhibition of calcineurin signaling blocks calcium-dependent reactivation of Kaposi sarcoma–associated herpesvirus

Blood ◽  
2001 ◽  
Vol 97 (8) ◽  
pp. 2374-2380 ◽  
Author(s):  
J. Paul Zoeteweij ◽  
Ashlee V. Moses ◽  
Andrea S. Rinderknecht ◽  
David A. Davis ◽  
Willem W. Overwijk ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Intracellular Signaling ◽  
Primary Effusion Lymphoma ◽  
Single Cells ◽  
Kaposi Sarcoma ◽  
Lytic Cycle ◽  
Virus Reactivation ◽  
Calcium Dependent ◽  
Latently Infected ◽  
Dependent Signal

Abstract Kaposi sarcoma–associated herpesvirus (KSHV) is associated with KS, primary effusion lymphoma (PEL), and multicentric Castleman disease. Reactivation of KSHV in latently infected cells and subsequent plasma viremia occur before the development of KS. Intracellular signaling pathways involved in KSHV reactivation were studied. In latently infected PEL cells (BCBL-1), KSHV reactivation in single cells was determined by quantitative flow cytometry. Viral particle production was determined by electron microscope analyses and detection of minor capsid protein in culture supernatants. Agents that mobilized intracellular calcium (ionomycin, thapsigargin) induced expression of KSHV lytic cycle-associated proteins and led to increased virus production. Calcium-mediated virus reactivation was blocked by specific inhibitors of calcineurin-dependent signal transduction (cyclosporine, FK506). Similarly, calcium-mediated virus reactivation in KSHV-infected dermal microvascular endothelial cells was blocked by cyclosporine. Furthermore, retroviral transduction with plasmid DNA encoding VIVIT, a peptide specifically blocking calcineurin-NFAT interactions, inhibited calcium-dependent KSHV reactivation. By contrast, chemical induction of lytic-phase infection by the phorbol ester 12-O-tetradecanoyl-phorbol-13-acetate was blocked by protein kinase C inhibitors, but not by calcineurin inhibitors. In summary, calcineurin-dependent signal transduction, an important signaling cascade in vivo, induces calcium-dependent KSHV replication, providing a possible target for the design of antiherpesvirus strategies in KSHV-infected patients.

scholarly journals Arrhythmia Mechanisms and Spontaneous Calcium Release: II - From Calcium Spark to Re-entry and Back

2018 ◽  
Author(s):  
Michael A. Colman
Keyword(s):  
Calcium Release ◽  
Single Cells ◽  
Computational Cost ◽  
Conduction Block ◽  
Spiral Wave ◽  
Positive Role ◽  
Pharmacological Management ◽  
Calcium Dependent ◽  
Tissue Models

AbstractMotivationThe role of sub-cellular spontaneous calcium release events (SCRE) in the development of arrhythmia associated with atrial and ventricular tachycardia and fibrillation has yet to be investigated in detail. SCRE may underlie the emergence of spontaneous excitation in single cells, resulting in arrhythmic triggers in tissue. Furthermore, they can promote the substrate for conduction abnormalities. However, the potential interactions with re-entrant excitation have yet to be explored. The primary aim of this study was therefore to apply a novel computational approach to understand the multi-scale coupling between re-entrant excitation and SCRE.MethodsA general implementation of Spontaneous Release Functions - which reproduce the calcium dependent SCRE dynamics of detailed cell models at a significantly reduced computational cost - was used to reproduce SCRE in tissue models. Arrhythmic dynamics, such as rapid pacing and re-entry, were induced in the tissue models and the resulting interactions with SCRE were analysed.ResultsIn homogeneous tissue, the emergence of a spontaneous beat from a single source was observed and the positive role of coupling was demonstrated. Conduction block could be promoted by SCRE by both inactivation of the fast sodium channel as well as focal pacing heterogeneity interactions. Sustained re-entrant excitation promoted calcium overload, and led to the emergence of focal excitations both after termination of re-entry and also during re-entrant excitation. These results demonstrated a purely functional mechanism of re-entry and focal activity localisation, related to the unexcited spiral wave core.ConclusionsSCRE may interact with tissue excitation to promote and perpetuate arrhythmia through multiple mechanisms, including functional localisation and mechanism switching. These insights may be particularly relevant for successful pharmacological management of arrhythmia.

scholarly journals Reorganisation of complex ciliary flows around regenerating Stentor coeruleus

2019 ◽  
Author(s):  
Kirsty Y. Wan ◽  
Sylvia K. Hürlimann ◽  
Aidan M. Fenix ◽  
Rebecca M. McGillivary ◽  
Tatyana Makushok ◽  
...  
Keyword(s):  
Anterior Part ◽  
Single Cells ◽  
Ring Structure ◽  
The Body ◽  
Band Formation ◽  
Environmental Perturbations ◽  
Biophysical Studies ◽  
Stentor Coeruleus ◽  
And Migration ◽  
Anterior Ring

SummaryThe phenomenon of ciliary coordination has garnered increasing attention in recent decades, with multiple theories accounting for its emergence in different contexts. The heterotrich ciliate Stentor coeruleus is a unicellular organism which boasts a number of features which present unrivalled opportunities for biophysical studies of cilia coordination. With their cerulean colour and distinctive morphology, these large protists possess a characteristic differentiation between cortical rows of short body cilia used for swimming, and an anterior ring structure of fused oral cilia forming a membranellar band. The oral cilia beat metachronously to produce strong feeding currents. In addition to this complex body plan, Stentor have remarkable regenerative capabilities. Minute fragments of single cells can over the period of hours or days, regenerate independently into new, proportional individuals. Certain environmental perturbations elicit a unique programmed response known as oral regeneration wherein only the membranellar band is shed and a new, ciliated oral primordium formed on the side of the body. Here, we target oral regeneration induced by sucrose-shock to reveal the complex interplay between ciliary restructuring and hydrodynamics in Stentor, which accompanies the complete developmental sequence from band formation, elongation, curling, and migration toward the cell anterior.“When the anterior part is open, one may perceive about its Edges a very lively Motion; and when the Polyps presents itself in a certain manner, it discovers, on either side of these edges of its anterior part, somewhat very much resembling the wheels of a little Mill, that move with great velocity.”A. Trembley F.R.S describing the membranellar band of Stentor, Phil. Soc. Trans. Royal Society (London), 1744.

scholarly journals Regulation of C-cadherin function during activin induced morphogenesis of Xenopus animal caps.

1994 ◽  
Vol 126 (2) ◽  
pp. 519-527 ◽  
Author(s):  
W M Brieher ◽  
B M Gumbiner
Keyword(s):  
Cell Adhesion ◽  
Single Cells ◽  
Cell Types ◽  
Aggregation Assay ◽  
Animal Pole ◽  
Mesodermal Cell ◽  
Calcium Dependent ◽  
L Cells ◽  
Steady State Levels ◽  
Cell Cell

Treatment of Xenopus animal pole tissue with activin results in the induction of mesodermal cell types and a dramatic elongation of the tissue. The morphogenetic movements involved in the elongation appear similar to those in normal gastrulation, which is driven by cell rearrangement and cell intercalations. We have used this system to explore the potential regulation of cell-cell adhesion and cadherin function during morphogenesis. Quantitative blastomere aggregation assays revealed that activin induction reduced the calcium-dependent adhesion between blastomeres. Activin-induced blastomeres formed smaller aggregates, and a greater proportion of the population remained as single cells compared to uninduced blastomeres. The aggregation was mediated by C-cadherin because C-cadherin was present in the blastomeres during the aggregation assay, and monoclonal antibodies against C-cadherin inhibited the calcium-dependent aggregation of blastomeres. E-cadherin was not detectable until after the completion of the assay and, therefore, does not explain the adhesive differences between induced and uninduced blastomeres. L cells stably expressing C-cadherin (LC cells) were used to demonstrate that C-cadherin activity was specifically altered after activin induction. Blastomeres induced with activin bound fewer LC cells than uninduced blastomers. L cells not expressing C-cadherin did not adhere to blastomeres. The changes in C-cadherin-mediated adhesion occurred without detectable changes in the steady-state levels of C-cadherin or the amount of C-cadherin present on the surface of the cell. Immunoprecipitation of C-cadherin and its associated catenins revealed that the ratio of C-cadherin and the catenins was not altered by activin induction. These results demonstrate that activin decreases the adhesive function of existing C-cadherin molecules on the surface of blastomeres and suggest that decreased cadherin mediated cell-cell adhesion is associated with increased morphogenetic movement.

scholarly journals Cell explosions: single cell death triggers an avoidance response in local populations of the ecologically prominent phytoplankton genus Micromonas

2019 ◽  
Author(s):  
Richard Henshaw ◽  
Jonathan Roberts ◽  
Marco Polin
Keyword(s):  
Cell Death ◽  
Avoidance Response ◽  
Single Cell ◽  
Single Cells ◽  
Local Environment ◽  
Warning Signal ◽  
Predator Prey ◽  
A Cell ◽  
Observed Behaviour ◽  
Micromonas Pusilla

The global phytoplankton community, comprised of aquatic photosynthetic organisms, is acknowledged for being responsible for half of the global oxygen production Prominent among these is the pico-eukaryote Micromonas commoda (formally Micromonas pusilla of the genus Micromonas), which can be found in marine and coastal environments across the globe. Cell death of phytoplankton has been identified as contributing to the largest carbon transfers on the planet moving 109 tonnes of carbon in the oceans every day. During a cell death organic matter is released into the local environment which can act as both a food source and a warning signal for nearby organisms. Here we present a novel motility response to single cell death in populations of Micromonas sp., where the death of a single cell releases a chemical patch triggers surrounding cells to escape the immediate affected area. These so-called “burst events” are then modelled and compared with a spherically symmetric diffusing patch which is found to faithfully reproduce the observed behaviour. Finally, laser ablation of single cells reproduces the observed avoidance response, confirming that Micromonas sp. has evolved a specific motility response in order to escape harmful environments for example nearby predator-prey interactions or virus lysis induced cell death.

scholarly journals Lack of IRF6 Disrupts Human Epithelial Homeostasis by Altering Colony Morphology, Migration Pattern, and Differentiation Potential of Keratinocytes

2021 ◽  
Vol 9 ◽  
Author(s):  
Eleftheria Girousi ◽  
Lukas Muerner ◽  
Ludovica Parisi ◽  
Silvia Rihs ◽  
Stephan von Gunten ◽  
...  
Keyword(s):  
Wound Healing ◽  
Cleft Lip ◽  
Single Cells ◽  
Vital Role ◽  
Keratinocyte Differentiation ◽  
Gene Encoding ◽  
Differentiation Potential ◽  
Model Cell ◽  
Cleft Lip Palate ◽  
And Migration

Variants within the gene encoding for the transcription factor Interferon Regulatory Factor 6 (IRF6) are associated with syndromic and non-syndromic Cleft Lip/Palate (CLP) cases. IRF6 plays a vital role in the regulation of the proliferation/differentiation balance in keratinocytes and is involved in wound healing and migration. Since a fraction of CLP patients undergoing corrective cleft surgery experience wound healing complications, IRF6 represents an interesting candidate gene linking the two processes. However, Irf6 function has been mainly studied in mice and knowledge on IRF6 in human cells remains sparse. Here, we aimed to elucidate the role of IRF6 in human postnatal skin- and oral mucosa-derived keratinocytes. To do so, we applied CRISPR/Cas9 to ablate IRF6 in two TERT-immortalized keratinocyte cultures, which we used as model cell lines. We show that IRF6 controls the appearance of single cells and colonies, with the latter being less cohesive in its absence. Consequently, IRF6 knockout keratinocytes often moved as single cells instead of a collective epithelial sheet migration but maintained their epithelial character. Lack of IRF6 triggered severe keratinocyte differentiation defects, which were already apparent in the stratum spinosum and extended to the stratum corneum in 3D organotypic skin cultures, while it did not alter their growth rate. Finally, proteomics revealed that most of the differentially expressed proteins in the absence of IRF6 could be associated with differentiation, cell-cell adhesion as well as immune response. Our data expand the knowledge on IRF6 in human postnatal keratinocytes, which will help to better understand IRF6-related pathologies.

scholarly journals Filopodome mapping identifies p130Cas as a mechanosensitive regulator of filopodia stability

2018 ◽  
Author(s):  
Guillaume Jacquemet ◽  
Rafael Saup ◽  
Hellyeh Hamidi ◽  
Mitro Miihkinen ◽  
Johanna Ivaska
Keyword(s):  
Binding Sites ◽  
Focal Adhesions ◽  
Structure And Function ◽  
Structured Illumination ◽  
Structured Illumination Microscopy ◽  
Cell Adhesion And Migration ◽  
And Migration ◽  
Cellular Behaviour ◽  
And Function ◽  
Fine Tune

AbstractFilopodia are adhesive cellular protrusions specialised in the detection of extracellular matrix (ECM)-derived cues. While ECM engagement at focal adhesions is known to trigger the recruitment of hundreds of proteins (“adhesome”) to fine-tune cellular behaviour, the components of the filopodia adhesions remain undefined. Here, we performed a structured illumination microscopy-based screen to map the localisation of 80 target proteins, linked to cell adhesion and migration, within filopodia. We demonstrate preferential enrichment of several adhesion proteins to either filopodia tips, filopodia shafts, or shaft subdomains suggesting divergent, spatially restricted functions for these proteins. Moreover, proteins with phospho-inositide (PI) binding sites are particularly enriched in filopodia. This, together with the strong localisation of PI(3,4)P2 in filopodia tips, predicts critical roles for PIs in regulating filopodia ultra-structure and function. Our mapping further reveals that filopodia adhesions consist of a unique set of proteins, the filopodome, that are distinct from classical nascent adhesions, focal adhesions and fibrillar adhesions. Using live imaging, we observe that filopodia adhesions can give rise to nascent adhesions, which, in turn, form focal adhesions. Finally, we demonstrate that p130Cas (BCAR1) is recruited to filopodia tips via its CCHD domain and acts as a mechanosensitive regulator of filopodia stability.

scholarly journals Purinoreceptors and ectonucleotidases control ATP-induced calcium waveforms and calcium-dependent responses in microglia

2021 ◽  
Author(s):  
Byeong Jae Chun ◽  
Surya Aryal ◽  
Bin Sun ◽  
Josh Bruno ◽  
Chris Richards ◽  
...  
Keyword(s):  
Purinergic Receptors ◽  
Cytokine Production ◽  
Purinergic Receptor ◽  
Receptor Activation ◽  
Receptor Expression ◽  
Microglia Cell ◽  
Calcium Dependent ◽  
Murine Microglia ◽  
Bv2 Microglia ◽  
And Migration

Adenosine triphosphate (ATP) drives microglia motility and cytokine production by activating P2X- and P2Y- class purinergic receptors with extracellular ATP and its metabolites. Purinergic receptor activation gives rise to diverse intracellular Ca2+ signals, or waveforms, that differ in amplitude, duration, and frequency. Whether and how these diverse waveforms influence microglia function is not well established. We developed a computational model trained with published primary murine microglia studies. We simulate how purinoreceptors influence Ca2+ signaling and migration and how purinoreceptor expression modifies these processes. Our simulation confirmed that P2 receptors encode the amplitude and duration of the ATP-induced calcium waveforms. Our simulations also implicate CD39, an ectonucleotidase that rapidly degrades ATP, as a regulator of purinergic receptor-induced Ca2+ responses. We, therefore, next evaluated how purinoreceptors and ectonucleotidase work in tandem. Our modeling results indicate that small transients are sufficient to promote motility, while large and sustained transients are needed for cytokine responses. Lastly, we predict how these phenotypical responses vary in a BV2 microglia cell line using published P2 receptor mRNA data to illustrate how our computer model can be extrapolated to diverse microglia subtypes. These findings provide important insights into how differences in purinergic receptor expression influence the microglial responses to ATP.

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