scholarly journals Cell cycle–dependent active stress drives epithelia remodeling

2021 ◽  
Vol 118 (10) ◽  
pp. e1917853118
Author(s):  
John Devany ◽  
Daniel M. Sussman ◽  
Takaki Yamamoto ◽  
M. Lisa Manning ◽  
Margaret L. Gardel
Keyword(s):  
Cell Cycle ◽  
Cell Shape ◽  
Epithelial Tissue ◽  
Experimental Conditions ◽  
Active Stress ◽  
Cell Cycle Inhibition ◽  
Cell Shapes ◽  
Cycle Dependent ◽  
Cell Cycle Dynamics ◽  
Shape Changes

Epithelia have distinct cellular architectures which are established in development, reestablished after wounding, and maintained during tissue homeostasis despite cell turnover and mechanical perturbations. In turn, cell shape also controls tissue function as a regulator of cell differentiation, proliferation, and motility. Here, we investigate cell shape changes in a model epithelial monolayer. After the onset of confluence, cells continue to proliferate and change shape over time, eventually leading to a final architecture characterized by arrested motion and more regular cell shapes. Such monolayer remodeling is robust, with qualitatively similar evolution in cell shape and dynamics observed across disparate perturbations. Here, we quantify differences in monolayer remodeling guided by the active vertex model to identify underlying order parameters controlling epithelial architecture. When monolayers are formed atop an extracellular matrix with varied stiffness, we find the cell density at which motion arrests varies significantly, but the cell shape remains constant, consistent with the onset of tissue rigidity. In contrast, pharmacological perturbations can significantly alter the cell shape at which tissue dynamics are arrested, consistent with varied amounts of active stress within the tissue. Across all experimental conditions, the final cell shape is well correlated to the cell proliferation rate, and cell cycle inhibition immediately arrests cell motility. Finally, we demonstrate cell cycle variation in junctional tension as a source of active stress within the monolayer. Thus, the architecture and mechanics of epithelial tissue can arise from an interplay between cell mechanics and stresses arising from cell cycle dynamics.

scholarly journals Cell cycle-dependent active stress drives epithelia remodeling

2019 ◽  
Author(s):  
John Devany ◽  
Daniel M. Sussman ◽  
M. Lisa Manning ◽  
Margaret L. Gardel
Keyword(s):  
Cell Cycle ◽  
Cell Shape ◽  
Shape Change ◽  
Epithelial Tissue ◽  
Experimental Conditions ◽  
Active Stress ◽  
Cell Shapes ◽  
Cycle Dependent ◽  
Cell Cycle Dynamics ◽  
Dependent Processes

AbstractEpithelia have distinct cellular architectures, which are established in development, re-established after wounding, and maintained during tissue homeostasis despite cell turnover and mechanical perturbations. In turn, cell shape also controls tissue function as a regulator of cell differentiation, proliferation, and motility. Here we investigate cell shape changes in a model epithelial monolayer. After the onset of confluence, cells continue to proliferate and change shape over time, eventually leading to a final architecture characterized by arrested motion and more regular cell shapes. Such monolayer remodeling is robust, with qualitatively similar changes in cell shape and dynamics observed across disparate perturbations. Here we quantify differences in monolayer remodeling guided by the active vertex model to identify underlying order parameters controlling epithelial architecture. For instance, for monolayers formed atop extracellular matrix with varied stiffness, we find the cell density at which motion arrests varies significantly but the cell shape remains constant. In contrast, pharmacological perturbations can significantly alter the cell shape at which tissue dynamics is arrested. Remarkably, we find across all experimental conditions the final cell shape is well correlated to the cell proliferation rate. Furthermore, inhibition of the cell cycle immediately arrests both cell motility and shape change, demonstrating that active stress from cell cycle-dependent processes contributes significantly to monolayer remodeling. Thus, the architecture and mechanics of epithelial tissue can arise from an interplay between cell mechanics and stresses arising from cell cycle dynamics.

scholarly journals Cell cycle-dependent phosphorylation and regulation of cellular differentiation

2018 ◽  
Vol 46 (5) ◽  
pp. 1083-1091 ◽  
Author(s):  
Laura J.A. Hardwick ◽  
Roberta Azzarelli ◽  
Anna Philpott
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Diverse Range ◽  
Cyclin Dependent Kinases ◽  
Cell Proliferation And Differentiation ◽  
Proliferation And Differentiation ◽  
Stem And Progenitor Cells ◽  
Cycle Dependent ◽  
Cell Cycle Dynamics ◽  
Bidirectional Interactions

Embryogenesis requires an exquisite regulation of cell proliferation, cell cycle withdrawal and differentiation into a massively diverse range of cells at the correct time and place. Stem cells also remain to varying extents in different adult tissues, acting in tissue homeostasis and repair. Therefore, regulated proliferation and subsequent differentiation of stem and progenitor cells remains pivotal throughout life. Recent advances have characterised the cell cycle dynamics, epigenetics, transcriptome and proteome accompanying the transition from proliferation to differentiation, revealing multiple bidirectional interactions between the cell cycle machinery and factors driving differentiation. Here, we focus on a direct mechanistic link involving phosphorylation of differentiation-associated transcription factors by cell cycle-associated Cyclin-dependent kinases. We discuss examples from the three embryonic germ layers to illustrate this regulatory mechanism that co-ordinates the balance between cell proliferation and differentiation.

scholarly journals Integrin binding and cell spreading on extracellular matrix act at different points in the cell cycle to promote hepatocyte growth.

1994 ◽  
Vol 5 (9) ◽  
pp. 967-975 ◽  
Author(s):  
L K Hansen ◽  
D J Mooney ◽  
J P Vacanti ◽  
D E Ingber
Keyword(s):  
Cell Cycle ◽  
Extracellular Matrix ◽  
Cell Shape ◽  
Time Course ◽  
Cell Spreading ◽  
S Phase ◽  
Similar Time ◽  
Cell Shape Changes ◽  
Hepatocyte Growth ◽  
Shape Changes

This study was undertaken to determine the importance of integrin binding and cell shape changes in the control of cell-cycle progression by extracellular matrix (ECM). Primary rat hepatocytes were cultured on ECM-coated dishes in serum-free medium with saturating amounts of growth factors (epidermal growth factor and insulin). Integrin binding and cell spreading were promoted in parallel by plating cells on dishes coated with fibronectin (FN). Integrin binding was separated from cell shape changes by culturing cells on dishes coated with a synthetic arg-gly-asp (RGD)-peptide that acts as an integrin ligand but does not support hepatocyte extension. Expression of early (junB) and late (ras) growth response genes and DNA synthesis were measured to determine whether these substrata induce G0-synchronized hepatocytes to reenter the growth cycle. Cells plated on FN exhibited transient increases in junB and ras gene expression (within 2 and 8 h after plating, respectively) and synchronous entry into S phase. Induction of junB and ras was observed over a similar time course in cells on RGD-coated dishes, however, these round cells did not enter S phase. The possibility that round cells on RGD were blocked in mid to late G1 was confirmed by the finding that when trypsinized and replated onto FN-coated dishes after 30 h of culture, they required a similar time (12-15 h) to reenter S phase as cells that had been spread and allowed to progress through G1 on FN. We have previously shown that hepatocytes remain viable and maintain high levels of liver-specific functions when cultured on these RGD-coated dishes. Thus, these results suggest that ECM acts at two different points in the cell cycle to regulate hepatocyte growth: first, by activating the G0/G1 transition via integrin binding and second, by promoting the G1/S phase transition and switching off the default differentiation program through mechanisms related to cell spreading.

scholarly journals Mathematical modelling in cell migration: tackling biochemistry in changing geometries

2020 ◽  
Vol 48 (2) ◽  
pp. 419-428
Author(s):  
Björn Stinner ◽  
Till Bretschneider
Keyword(s):  
Cell Migration ◽  
Molecular Motors ◽  
Cell Shape ◽  
Reaction Diffusion ◽  
Level Line ◽  
External Signal ◽  
Interface Capturing ◽  
Cell Shapes ◽  
Cell Shape Changes ◽  
Shape Changes

Directed cell migration poses a rich set of theoretical challenges. Broadly, these are concerned with (1) how cells sense external signal gradients and adapt; (2) how actin polymerisation is localised to drive the leading cell edge and Myosin-II molecular motors retract the cell rear; and (3) how the combined action of cellular forces and cell adhesion results in cell shape changes and net migration. Reaction–diffusion models for biological pattern formation going back to Turing have long been used to explain generic principles of gradient sensing and cell polarisation in simple, static geometries like a circle. In this minireview, we focus on recent research which aims at coupling the biochemistry with cellular mechanics and modelling cell shape changes. In particular, we want to contrast two principal modelling approaches: (1) interface tracking where the cell membrane, interfacing cell interior and exterior, is explicitly represented by a set of moving points in 2D or 3D space and (2) interface capturing. In interface capturing, the membrane is implicitly modelled analogously to a level line in a hilly landscape whose topology changes according to forces acting on the membrane. With the increased availability of high-quality 3D microscopy data of complex cell shapes, such methods will become increasingly important in data-driven, image-based modelling to better understand the mechanochemistry underpinning cell motion.

scholarly journals Control of tissue development by cell cycle dependent transcriptional filtering

2020 ◽  
Author(s):  
Maria Abou Chakra ◽  
Ruth Isserlin ◽  
Thinh Tran ◽  
Gary D. Bader
Keyword(s):  
Cell Cycle ◽  
Cell Fate ◽  
Control Cell ◽  
Cell Types ◽  
Cycle Duration ◽  
Cell Diversity ◽  
Cycle Dependent ◽  
Cell Cycle Dynamics ◽  
Different Cell Types ◽  
Long Genes

AbstractCell cycle duration changes dramatically during development, starting out fast to generate cells quickly and slowing down over time as the organism matures. The cell cycle can also act as a transcriptional filter to control the expression of long genes which are partially transcribed in short cycles. Using mathematical simulations of cell proliferation, we identify an emergent property, that this filter can act as a tuning knob to control cell fate, cell diversity and the number and proportion of different cell types in a tissue. Our predictions are supported by comparison to single-cell RNA-seq data captured over embryonic development. Evolutionary genome analysis shows that fast developing organisms have a narrow genomic distribution of gene lengths while slower developers have an expanded number of long genes. Our results support the idea that cell cycle dynamics may be important across multicellular animals for controlling gene expression and cell fate.

scholarly journals 3D viscoelastic drag forces drive changes to cell shapes during organogenesis in the zebrafish embryo

2021 ◽  
Author(s):  
Paula C. Sanematsu ◽  
Gonca Erdemci-Tandogan ◽  
Himani Patel ◽  
Emma M. Retzlaff ◽  
Jeffrey D. Amack ◽  
...  
Keyword(s):  
Cell Shape ◽  
Shape Change ◽  
New Physics ◽  
Tissue Mechanics ◽  
List Type ◽  
Drag Forces ◽  
Velocity Gradients ◽  
Cell Shapes ◽  
Cell Shape Changes ◽  
Shape Changes

AbstractThe left-right organizer in zebrafish embryos, Kupffer’s Vesicle (KV), is a simple organ that undergoes programmed asymmetric cell shape changes that are necessary to establish the left-right axis of the embryo. We use simulations and experiments to investigate whether 3D mechanical drag forces generated by the posteriorly-directed motion of the KV through the tailbud tissue are sufficient to drive such shape changes. We develop a fully 3D vertex-like (Voronoi) model for the tissue architecture, and demonstrate that the tissue can generate drag forces and drive cell shape changes. Furthermore, we find that tailbud tissue presents a shear-thinning, viscoelastic behavior consistent with those observed in published experiments. We then perform live imaging experiments and particle image velocimetry analysis to quantify the precise tissue velocity gradients around KV as a function of developmental time. We observe robust velocity gradients around the KV, indicating that mechanical drag forces must be exerted on the KV by the tailbud tissue. We demonstrate that experimentally observed velocity fields are consistent with the viscoelastic response seen in simulations. This work also suggests that 3D viscoelastic drag forces could be a generic mechanism for cell shape change in other biological processes.Highlightsnew physics-based simulation method allows study of dynamic tissue structures in 3Dmovement of an organ through tissue generates viscoelastic drag forces on the organthese drag forces can generate precisely the cell shape changes seen in experimentPIV analysis of experimental data matches simulations and probes tissue mechanicsGraphical abstract

scholarly journals Cellular structure image classification with small targeted training samples

2019 ◽  
Author(s):  
Dali Wang ◽  
Zheng Lu ◽  
Yichi Xu ◽  
Zi Wang ◽  
Chengcheng Li ◽  
...  
Keyword(s):  
Deep Learning ◽  
Image Classification ◽  
Cell Shape ◽  
Time Lapse ◽  
Training Dataset ◽  
Generative Adversarial Networks ◽  
Training Samples ◽  
Cell Shapes ◽  
Cell Shape Changes ◽  
Shape Changes

AbstractMotivationCell shapes provide crucial biology information on complex tissues. Different cell types often have distinct cell shapes, and collective shape changes usually indicate morphogenetic events and mechanisms. The identification and detection of collective cell shape changes in an extensive collection of 3D time-lapse images of complex tissues is an important step in assaying such mechanisms but is a tedious and time-consuming task. Machine learning provides new opportunities to automatically detect cell shape changes. However, it is challenging to generate sufficient training samples for pattern identification through deep learning because of a limited amount of images and annotations.ResultWe present a deep learning approach with minimal well-annotated training samples and apply it to identify multicellular rosettes from 3D live images of the Caenorhabditis elegans embryo with fluorescently labelled cell membranes. Our strategy is to combine two approaches, namely, feature transfer and generative adversarial networks (GANs), to boost image classification with small training samples. Specifically, we use a GAN framework and conduct an unsupervised training to capture the general characteristics of cell membrane images with 11,250 unlabelled images. We then transfer the structure of the GAN discriminator into a new Alex-style neural network for further learning with several dozen labelled samples. Our experiments showed that with 10-15 well-labelled rosette images and 30-40 randomly selected non-rosette images our approach can identify rosettes with over 80% accuracy and capture over 90% of the model accuracy achieved with a training dataset that is five times larger. We also established a public benchmark dataset for rosette detection. This GAN-based transfer approach can be applied to study other cellular structures with minimal training [email protected], [email protected]

scholarly journals Unified quantitative characterization of epithelial tissue development

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Boris Guirao ◽  
Stéphane U Rigaud ◽  
Floris Bosveld ◽  
Anaïs Bailles ◽  
Jesús López-Gay ◽  
...  
Keyword(s):  
Cell Shape ◽  
Tissue Growth ◽  
Epithelial Tissue ◽  
Tissue Development ◽  
Tissue Morphogenesis ◽  
Quantitative Characterization ◽  
Cell Shape Changes ◽  
The Impact ◽  
Shape Changes

Understanding the mechanisms regulating development requires a quantitative characterization of cell divisions, rearrangements, cell size and shape changes, and apoptoses. We developed a multiscale formalism that relates the characterizations of each cell process to tissue growth and morphogenesis. Having validated the formalism on computer simulations, we quantified separately all morphogenetic events in the Drosophila dorsal thorax and wing pupal epithelia to obtain comprehensive statistical maps linking cell and tissue scale dynamics. While globally cell shape changes, rearrangements and divisions all significantly participate in tissue morphogenesis, locally, their relative participations display major variations in space and time. By blocking division we analyzed the impact of division on rearrangements, cell shape changes and tissue morphogenesis. Finally, by combining the formalism with mechanical stress measurement, we evidenced unexpected interplays between patterns of tissue elongation, cell division and stress. Our formalism provides a novel and rigorous approach to uncover mechanisms governing tissue development.

Regulation of cell shape in Euglena gracilis. II. The effects of altered extra- and intracellular Ca2+ concentrations and the effect of calmodulin antagonists

1984 ◽  
Vol 71 (1) ◽  
pp. 37-50
Author(s):  
T.A. Lonergan
Keyword(s):  
Euglena Gracilis ◽  
Cell Shape ◽  
Ionophore A23187 ◽  
Free Medium ◽  
Calmodulin Antagonists ◽  
Daily Cycle ◽  
Cell Shapes ◽  
Euglena Gracilis Z ◽  
Shape Changes ◽  
Synchronized Cultures

When cultures of Euglena gracilis Z., normally grown in medium containing 180 microM-Ca2+, are resuspended in Ca2+-free medium cells assume round shapes within 10 min, from which they recover slowly when Ca2+ is returned to the cultures. Cultures grown in 10 microM-Ca2+ do not display the typical circadian rhythm in cell shape even though the photosynthesis and cell division circadian rhythms are unaffected. Elevating intracellular Ca2+ levels by the addition of the Ca2+ ionophore A23187 prevents cells from undergoing the two daily shape changes characteristic of growth-synchronized cultures, but does not alter the ability to maintain the cell shapes found at the time of ionophore addition. When the calmodulin inhibitors trifluoperazine or chlorpromazine are added to cultures, the cells always respond by rounding. Cells are not able to maintain any cell shape other than spherical in the presence of these inhibitors and therefore cannot change shape throughout the daily cycle as is found in the control populations.

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