Bulletin of the American Physical Society
APS March Meeting 2022
Volume 67, Number 3
Monday–Friday, March 14–18, 2022; Chicago
Session Y07: Mechanics of Cells and Tissues: The Role of Heterogeneity IIFocus Recordings Available
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Sponsoring Units: DBIO GSNP DSOFT Chair: Jonathan Michel, Rochester Institute of Technology Room: McCormick Place W-179A |
Friday, March 18, 2022 8:00AM - 8:12AM |
Y07.00001: Microtubule deacetylation enables in vivo collective cell migration by tuning cell stiffness in relation to substrate stiffness Abdul N Malmi Kakkada, Christian Marchant, Jaime Espina, Elias Barriga Cells in multicellular organisms migrate during tissue formation, regeneration, and immune defense. Cells migrate in vivo by exerting forces on surrounding tissue structures with cell-substrate mechanical interaction shown to be important in cell migration. By combining computational modeling and in vivo experimental data from Xenopus laevis embryos we show that neural crest cell stiffness is dynamically reduced in response to the temporal stiffening of the mesoderm - the substrate upon which neural crest cells move in vivo. We discover that the reduction in neural crest cell stiffness and consequently its migration is triggered by microtubule deacetylation mediated by Piezo1. We show that the effect of microtubule deacetylation on cell movement is well characterized by the stiffness ratio between the substrate(sub) and the cell (E_sub/E_cell). As lowering microtubule acetylation and consequently cell stiffness rescues cell migration in soft substrates, we provide evidence that an optimal cell-to-substrate stiffness ratio is important in allowing for collective cell migration rather than a fixed value of substrate stiffness. |
Friday, March 18, 2022 8:12AM - 8:24AM |
Y07.00002: Modulation of cell signals with nanotopography through cytoskeleton actuation Qixin Yang, Yuchuan Miao, Matt Hourwitz, Minxi Hu, Quan Qing, Peter N Devreotes, John T Fourkas, Wolfgang Losert Nanotopography is a powerful tool for modulating cell migration. However, the underlying molecular mechanisms of this guidance remain elusive. Here we explore how aligned nanoridges guide cell migration by modulating the regulatory signal-transduction excitable network (STEN) coupled with the cytoskeleton excitable network (CEN). We demonstrate that nanoridges guide waves of coordinated signaling molecules and filamentous actin. By applying systematic perturbations to affect the key components in STEN and CEN, we show that STEN is essential for wave formation, whereas CEN act as the primary sensing system for nanotopography. |
Friday, March 18, 2022 8:24AM - 8:36AM |
Y07.00003: In the blink of an eye: Modeling structural transformations during the ultrafast contraction of a single-celled organism Carlos S Floyd, Xiangting Lei, Jerry E Honts, Suriyanarayanan Vaikuntanathan, Aaron Dinner, Saad Bhamla Spriostomum ambiguum is a ciliated protist that has one of the fastest contraction rates observed in all of biology, reaching speeds around 200 body lengths per second. This rapid contraction is mediated by an influx of Ca2+, which binds to protein filaments called myonemes that comprise a mesh-like structure near the plasma membrane. The binding of Ca2+ causes the individual filaments in the mesh to suddenly shorten, so that the entire organism contracts. An exciting possibility is that this Ca2+-powered contractile machinery can serve as a controllable artificial cytoskeletal structure for sub-cellular force generation. However, the mechanical forces that control the changes in the microstructure of the myoneme mesh during contraction are not well understood. In this talk, we will discuss light microscopy measurements that allow for detailed quantification of the myoneme mesh structure. These measurements guided the development of a computational model for the mechanics of the mesh, in which myoneme filaments are spatially resolved and the relevant constraints on the mesh are included. The computational model reproduces the observed configurations before and after contraction, and it reveals the competing mechanical forces that balance in the equilibrated states. |
Friday, March 18, 2022 8:36AM - 9:12AM |
Y07.00004: How rigid is a microtubule? Invited Speaker: Taviare L Hawkins Microtubules are cytoskeletal filaments responsible for the intracellular organization and cell morphology. Their mechanical properties are regulated through the nucleotide state of the tubulin dimers, the binding of drugs, posttranslational modifications, and microtubule-associated proteins. Interestingly, microtubule-stabilizing factors have differential effects on microtubule mechanics, but whether stabilizers have cumulative effects on mechanics, or one effect dominates another is unclear. |
Friday, March 18, 2022 9:12AM - 9:24AM |
Y07.00005: Deciphering the origins of heterogeneity in biological tissues Alexandra Bermudez, Junxiang Huang, Zachary Gonzalez, Dapeng Bi, Neil Lin Cell heterogeneity in biological tissues is ubiquitous and known to play an essential role in organ development and disease progression. While genotypic heterogeneity has been extensively studied, much remains unknown about the emergence of cell morphological and mechanical heterogeneity. Previous experimental and theoretical studies mainly attribute such heterogeneity to the effect of physical packing, ignoring essential biological contributions (e.g., random cell partitioning and epigenetics). To examine this paradigm, we experimentally disentangle the physical and biological contributions. To do so, we compare monolayers of randomly seeded cells to cloned cells, where both experience the same physical packing effect, but different genetic heterogeneity distributions. By analyzing the spatial correlation of morphological properties, we observe a preferential cell morphology that may be generationally inherited, suggesting that the biological contribution is significant. Using vertex-model based simulations, we further quantified the physical and biological contributions. Our results suggest that the interplay between both contributions is essential to understand collective organization and mechanics of epithelia. |
Friday, March 18, 2022 9:24AM - 9:36AM |
Y07.00006: Mechanical Basis for Epithelialization Christian Cammarota, Nicole Dawney, Mimi Jüng, Dan Bergstralh Epithelial tissues are comprised of sheets of cells that must establish and maintain proper architecture to function. The role cell mechanics in architecture development has been difficult to study in vivo since tissue development is predicated on the existence of cell-cell contacts. Our work addresses the question of how physical constraints such as the cellular density of a tissue, cell stiffness, and cell-cell or cell-substrate connections affect the development of a polarized tissue architecture. We made a 2D computational model of cells in a plane perpendicular to the tissue plane and found that a spatial constraint holding the cells in close proximity is required for cells to develop cell-cell borders. The model also predicts that cell-cell borders form in reduced adhesion simulations. These results were validated in culture using Madin Darby Canine Kidney cells. Our work suggests that cell density is the primary factor in cell-cell border development and that cell-cell adhesion is subordinate. We are currently working to address the question of how cell density affects the regulation of epithelial architecture. |
Friday, March 18, 2022 9:36AM - 9:48AM |
Y07.00007: No large-scale demixing due to differences in diffusivity at high densities Erin McCarthy, Ojan K Damavandi, M. Lisa Manning Spontaneous phase-separation, or demixing, is an emergent behavior important in biological phenomena such as cell sorting. In particulate matter, differences in size, shape and persistent motion have all been shown to cause large-scale demixing. An open question is whether differences in diffusivity, i.e. the magnitude of translational noise, between particle types can drive demixing. Recently, researchers found that in particle-based packings, higher densities drive differential-diffusivity-induced phase separation up to a packing fraction of 0.7. We investigate whether this demixing persists at higher densities. For particle packing fractions between 0.7 and 1.0, we find the system demixes for certain diffusivity ratios. However, we observe that the system remains mixed at packing fractions above unity, exposing re-entrant behavior in the phase diagram. These changes in phase are associated with specific features in the interaction and active contributions to the total pressure. Using a Voronoi model, we examine a confluent system with differential diffusivity and find no evidence of phase-separation, consistent with the highest-density particle-based simulations. |
Friday, March 18, 2022 9:48AM - 10:00AM |
Y07.00008: Measuring mechanical heterogeneities in live epithelia Zachary A Gonzalez, Alexandra Bermudez, Bao Zhao, Xuanqing Liu, Ethan Salter, Khalid Jawed, Cho-Jui Hsieh, Neil Lin The mechanical heterogeneity of biological tissues not only influences the tissue rigidity and cell migration, but also closely regulates essential biological processes such as organogenesis, homeostasis, and cancer invasion. However, experimentally measuring the modulus field in live epithelia has been challenging, as conventional tools (e.g., atomic force microscopy and rheometry) can be invasive, time-consuming, or lack cell-level resolution. In this work, we develop a method to visualize the heterogenous modulus distribution in live epithelial monolayers by integrating a cell stretcher, light microscopy, and artificial intelligence (AI)-based inference. Specifically, we capture the non-affine displacement of cells during extension and utilize AI models to translate such measurements into the modulus field. This experimental platform allows for a method to determine the correlation between cell modulus and morphological features including area and aspect ratio. Contrary to previous numerical studies, in which epithelial packing was suggested to be predominantly governed by geometric constraint, our results show that cell modulus variation plays an equally important role. |
Friday, March 18, 2022 10:00AM - 10:12AM |
Y07.00009: Alignment of tractions between neighboring cells in a monolayer causes more persistent migration and faster wound closure Kelly Vazquez, Jacob Notbohm Following a wound, cell-generated forces elicit a migratory response as epithelial cells migrate collectively from the wound borders into the free space. The persistence of migration is a critical parameter in this phenomenon as cells must direct their migration towards the free edge. Migration persistence can be perturbed by physical and pharmacologic cues, such as wound geometry or heparin binding epidermal growth factor (HB-EGF), as both have a promigratory role in wound healing and strongly increase directional persistence. However, the role of cellular forces in altering the migration persistence is still unclear. To address this gap in understanding, we use both wound geometry and HB-EGF to systematically perturb the persistence of migration. Using single-cell velocity measurements and single-cell traction force microscopy, we compute the velocity and traction magnitudes, correlation lengths, and persistence times. We find a consistent trend caused by both wound geometry and HB-EGF wherein increased traction correlation length, but not traction magnitude or persistence, leads to more persistent migration. Hence, we conclude that increased traction correlation length, indicating increased coordination between neighbors, can increase the rate of wound closure. |
Friday, March 18, 2022 10:12AM - 10:24AM |
Y07.00010: The mechanics of cephalic furrow formation in the Drosophila embryo investigated using anadvanced vertex model Redowan Ahmed Niloy, Michael C Holcomb, Jeffrey H Thomas, Jerzy Blawzdziewicz Cephalic furrow formation (CFF) in the Drosophila embryo is driven by a sequence of intricate cell-shape changes in the invagination region. Mechanical cell activity involves coordinated constrictions and expansions of the apical, lateral and basal cell membranes. Moreover, as evident from the membrane curvature, there is also pressure variation from cell to cell. To identify mechanical forces that drive CFF we have developed an advanced 2D vertex model that incorporates membrane curvature into the system description. Our simulations of the invagination process show that the pressure in the cells entering the invagination region from anterior and posterior directions initially decreases, which results in the enhancement of the cell flexibility. As the cells advance through the invagination region the pressure increases to produce a stiffer base of the invaginated domain. In coordination with these pressure changes, apical and lateral cell membranes first relax and then increase their tension to produce unidirectional motion towards the high-pressure base. Our simulations of a perturbed system show that precise mechanical coordination of cell activities is needed for a successful invagination. |
Friday, March 18, 2022 10:24AM - 10:36AM |
Y07.00011: Mechanical boundaries in 3D models for confluent tissue Elizabeth Lawson-Keister, Tao Zhang, Lisa Manning A stratified epithelium, such as human skin, consists of many different layers of tissue that each express unique combinations of signaling and adhesion proteins, with strong and sharp boundaries between each layer. To create this tissue structure during development, and maintain it over time in mature organisms, carefully regulated cell divisions and cell migration are required. Specifically, cell divisions occur only in the lowest layer, and new cells must differentiate and delaminate from the basement membrane and move to the upper layers without disrupting the boundaries. We investigate possible mechanisms for the creation and stabilization of these boundaries using an extended 3D Vertex model with features specific to stratified epithelia, such as additional heterotypic tension at interfaces between cells of different types. We then make predictions about how these features affect the geometric and dynamic behavioral signatures of cells in each layer. We explore how changes to individual cell mechanical properties might drive migration across a layer boundary, as well as how the surrounding heterogeneous tissue mechanically responds to a migrating cell. |
Friday, March 18, 2022 10:36AM - 10:48AM |
Y07.00012: Emergent order in athree-dimensional vertex model for organoids Tao Zhang, J. M Schwarz Organoids, or in vitro cellular collectives from which brain-like, or intestine-like structures, for example, emerge give us a high throughput glimpse into the window of organogenesis. To make quantitative predictions regarding the morphology and rheology of a developing organoid, we construct and study a three-dimensional vertex model. In such a model, the cells are represented as deformable polyhedrons with cells sharing faces such that there are no gaps between them. In a bulk model, we find a rigidity transition as a function of the target cell shape index. For a cellular collective with a finite boundary, we uncover emergent, cellular ordering near the boundary. We explore how this ordering affects the interior of the cellular collective in the presence of external stresses and internal, active stresses. Such emergent ordering might underline the pattern in organogenesis. |
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