Bulletin of the American Physical Society
APS March Meeting 2022
Volume 67, Number 3
Monday–Friday, March 14–18, 2022; Chicago
Session Q07: Mechanobiology of Cell-Medium Interactions IFocus Recordings Available
|
Hide Abstracts |
Sponsoring Units: DBIO Chair: C. Nadir Kaplan, Virginia Tech Room: McCormick Place W-179A |
Wednesday, March 16, 2022 3:00PM - 3:12PM |
Q07.00001: Elastic interactions in confinement direct cell motility Subhaya Bose, Arvind Gopinath, Kinjal Dasbiswas Animal cells adhered to elastic substrates crawl and sense stiffness by exerting mechanical forces and actively deforming the underlying substrate. Many such cells exhibit durotaxis or preferential migration towards stiffer regions in the substrate. We present a physical model of durotaxis where cells are described as motile agents that exert contractile, traction forces on the underlying substrate. We combine agent-based Brownian dynamics simulations with linear elastic cell-substrate interactions to show how cell dynamics is influenced by mechanical interactions with clamped and free boundaries that represent interfaces with stiffer and softer regions, respectively. This is therefore a realization of elastic interaction-driven active matter in complex media. The speed of the motile cell determines the probability of it reaching the interface, which is either enhanced or reduced by the elastic forces and torques generated at the interface which in turn depend on the elastic boundary condition and stiffness gradient. We then analyze the density and orientation profiles of the model cells close to the interface to quantitatively predict the extent of durotaxis and its dependence on cell motility and traction forces. |
Wednesday, March 16, 2022 3:12PM - 3:24PM |
Q07.00002: Matrix-mediated symmetry breaking of single cells in a three-dimensional space Ik Sung Cho, Sing-Wan Wong, Stephen Lenzini, Jae-Won Shin Cells often undergo symmetry breaking in various physiological and developmental processes. While symmetry breaking of cells can occur spontaneously, spatial distribution of external signals from microenvironments, such as adhesion ligands from the extracellular matrix can also direct this process. While micropatterning was previously used to show cellular symmetry breaking on two-dimensional substrates, it remains unclear how this process occurs in a three-dimensional (3D) environment. To address this question, we developed a droplet-based microfluidic approach to encapsulate single cells between two different hydrogel compartments where ligand composition of each compartment can be independently controlled. We show that asymmetric presentation of an integrin adhesion ligand accelerates cell volume expansion with slightly decreased sphericity than symmetric presentation, while overall cell geometry is still symmetric. In contrast, membrane tension remains higher on the side of single cells interacting with the adhesion ligand than the side without the ligand. This suggests that there exists a mechanism to consolidate symmetry breaking of membrane tension despite that cell volume expansion occurs symmetrically. At a longer timescale, asymmetric distribution of the adhesion ligand enhances osteogenic differentiation of mesenchymal stem cells. This study highlights the utility of our approach in understanding biophysical mechanisms of cellular symmetry breaking in a 3D space with potential implications in directing cell fate decision. |
Wednesday, March 16, 2022 3:24PM - 3:36PM |
Q07.00003: Brittle-to-ductile cell escape from a two-dimensional spheroid Tara M Finegan, M. Lisa Manning, J. M Schwarz For cancer to metastasize, i.e. spread to other parts of the body, cancer cells must first escape from a localized tumor and invade their surroundings. Cancer cells exhibit many invasion strategies that are challenging to predict in vivo. Therefore, this phenomenon is studied in vitro using tumor spheroids, multi-cellular aggregates embedded in a collagen matrix. To determine how the geometry and the rheology of the spheroid affects how cells escape a tumor, we construct and study a minimal computational model in two dimensions for the outer edge of a spheroid that allows us to connect larger-scale geometric and rheological properties of the spheroid to the shapes of individual cells. More specifically, we implement a two-dimensional vertex model with mechanosensitive activity and impose a local pulling force, simulating a leader cell escaping from the spheroid. We test the hypothesis that rigid spheroids undergo brittle, single cell break-out, whereas more fluid spheroids exhibit more ductile, multi-cell break-out to allow us to formulate experimentally-testable predictions for the metastatic potential of spheroids and, ultimately, cancerous tumors. |
Wednesday, March 16, 2022 3:36PM - 4:12PM |
Q07.00004: Multidimensional mechano-tomography of biological cells: novel modes and machine learning data analysis Invited Speaker: Igor Y Sokolov New multidimensional AFM modalities, RingingMode and FT-NanoDMA allow collecting images of physical properties of cell surfaces and dynamical mechanical properties of the cell body for multiple frequencies simultaneously. These images show the distributions of nonspecific adhesion, energy losses due to the probe disconnection, size of the molecules covering the cell surface, viscoelastic properties of the cell membrane, storage, loss, and static elastic moduli of the cell body, etc. Repeating imaging at different load force/depth, it is possible to build “mechano-tomography” of the cell body. FT-NanoDMA allows simultaneous recording of more than 20 dynamical mechanical parameters, whereas RingingMode gives eight additional channels of information presenting the physical properties of the cell surface. |
Wednesday, March 16, 2022 4:12PM - 4:24PM |
Q07.00005: Chemo-mechanical Diffusion Waves Orchestrate Collective Oscillations of Immune Cell Podosomes Ze Gong, Koen van den Dries, Alessandra Cambi, Vivek b Shenoy Dendritic cells utilize podosomes, actin-rich protrusions, to migrate in tissues and patrol for foreign antigens. Individual podosomes show protrusion and retraction cycles (vertical oscillations) to probe underlying matrices, while multiple podosomes arranged in clusters exhibit coordinated wave-like spatiotemporal dynamics. However, the mechanism linking vertical oscillations and wave-like dynamics remains unclear. Here we develop a chemo-mechanical model for both oscillatory growth of individual podosomes and wave-like dynamics in podosome clusters. We found that podosomes oscillate when actin polymerization-associated protrusion and signaling-associated myosin contraction occur at similar rates; actin diffusion within clusters drives wave-like dynamics. By quantifying and comparing the wavelength, frequency, and speed of wave dynamics in experiments and simulations, we validated our model by predicting the impact of different drug treatments and substrate stiffness on podosome dynamics. The integrated theoretical and experimental approach reveals the mechanism of podosome dynamics and sheds light on podosomes' roles in immune cell mechanosensing and mechanotransduction. |
Wednesday, March 16, 2022 4:24PM - 4:36PM |
Q07.00006: Vimentin intermediate filaments increases collective cell migration through extracellular matrix network Minh-Tri Ho Thanh, Alison E Patteson The intermediate filament (IF) protein vimentin (V) is associated with many diseases with phenotypes of enhanced cellular migration and aggressive invasion through the extracellular matrix (ECM) of tissues, but vimentin's role in in vivo cell migration is still largely unclear. Vimentin is important for proper cellular adhesion and force generation, which are critical to cell migration; yet, the vimentin cytoskeleton also hinders the ability of cells to squeeze through small pores in ECM, resisting migration. To identify the role of vimentin in collective cell migration, we generate spheroids of wide-type and vimentin-null mouse embryonic fibroblast (mEF) and embed them in a 3D collagen matrix. We find that loss of vimentin significantly impairs the ability of the spheroid to collectively expand through collagen networks and remodel the collagen network. In addition, coculture of vimentin-null and wild-type mEFs leads to a persistent sorting pattern: wild-type cells enveloping vimentin-null cells, suggesting differential adhesion between these two cell lines. Taken together, these results signify that VIF play a critical role in enhancing migratory persistence in 3D environments, a hallmark feature of diseases such as fibrosis and cancer. |
Wednesday, March 16, 2022 4:36PM - 4:48PM |
Q07.00007: Cell-Induced Dynamic Remodeling of an Extracellular Matrix Taeyoon Kim, Brandon M Slater It has been known that cells are able to structurally remodel a surrounding extracellular matrix (ECM) by exerting contractile forces. We recently demonstrated how forces generated from a contracting cell are transmitted to and remodel ECM using a computational model. However, we did not consider cell protrusion and dynamic focal adhesion (FA) formation in the former model. In this study, we significantly improved the model to simulate dynamic remodeling of ECM driven by cells under more physiologically relevant conditions. In the new model, cells keep protruding and contracting with dynamic formation and turnover of FA sites. In addition, force-dependent redistribution of myosin motors was considered. We found that substantial ECM remodeling observed in experiments is reproducible only with consistent cell protrusion and contraction, which is why former models only with cell contraction failed to reproduce large ECM deformations. In addition, we demonstrated that dynamic FAs and force-induced myosin redistribution can further enhance the ECM deformation. Our results provide insights into understanding the mechanisms of cell-induced ECM remodeling. |
Wednesday, March 16, 2022 4:48PM - 5:24PM |
Q07.00008: A multiscale theory for opposing durotactic regimes in mesenchymal cell migration Invited Speaker: C. Nadir Kaplan Increasing experimental evidence validates that both the elastic stiffness and viscosity of the extracellular matrix (ECM) significantly affect cell motility. As a function of stiffness and viscosity, malignant cells rationally switch between durotaxis (migration to stiffer regions) and negative durotaxis (migration to softer regions) in biological tissues. To discern the underlying parameters of this rich behavior we developed a multiscale single-cell model for mesenchymal migration: At the sub-cellular scale, our framework translates the coupling between the viscoelastic substrate, chemical signaling pathways involving Rac and Rho GTPases, the intracellular dynamics of actomyosin complexes and microtubules to the emergent chemo-mechanical forces. At the cellular scale, the model integrates the gradients of the sub-cellular information from different parts of the cell to determine the polarity, which in turn drives the migration by concerted localized protrusions and contractions at opposite ends of the cell, a hallmark of mesenchymal mode. Through the dynamical feedback across these two scales, our simulated cell (i) yields a biphasic migration speed profile in response to the ECM stiffness; (ii) can exhibit both durotaxis and negative durotaxis, in either case migrating toward the region with an optimal stiffness from softer and stiffer regions, respectively; (iii) reveals that high actomyosin contractions driven by steep RhoA GTPase gradients can steer cells against stiffness gradients. Our simulations further predict that viscosity gradients along a substrate can induce migration toward softer regions, preempting stiffness-induced durotaxis. Overall, our multiscale model demonstrates that opposing durotactic behaviors can emerge from predominantly mechanical interactions between the cell and the external medium in quantitative agreement with experiments, thereby elucidating complex mechano-sensing at a single-cell level. |
Wednesday, March 16, 2022 5:24PM - 5:36PM |
Q07.00009: Active regulation of contractility and ion transport drives "nuclear piston" mechanism of 3D migration in tumor cells Zhaoqiang Song, Vivek b Shenoy, Ryan Petrie In the absence of protease activity, tumor cells can switch from the lamellipodia mode of migration to a lobopodial mode, characterized by the blunt, cylindrical protrusions. In this case, the nucleus acts as a piston and physically compartmentalizes the cytoplasm with a larger hydrostatic pressure in the anterior of the cell compared to the posterior. To quantitatively understand the biophysical mechanisms governing this pressure driven migration mode, we developed a model that considers the translocation of the nucleus driven by actomyosin contractility through Nesprin links. The movement of the nucleus leads to the exchange of ions and water with the microenvironment, driven by differences in electrostatic potential and osmotic and hydrostatic pressures. Our model predicts that actomyosin contractility, integrin-based cell adhesions, Nesprin links and the presence of intracellular negative charges associated with proteins and organic phosphates are essential for lobopodial migration. We also predict that influx of Calcium ions through mechano-sensitive channels plays a critical role in the active regulation of the pressure difference. The predictions of the model are in excellent quantitative agreement with experiments, and we propose new experiments to further test the model. |
Wednesday, March 16, 2022 5:36PM - 5:48PM |
Q07.00010: Mechanotransduction of matrix remodeling-directed lineage specification Sing-Wan Wong, Prerak Gupta, Ik Sung Cho, Jae-Won Shin Cells build their microenvironments by producing and depositing the extracellular matrix (ECM). Advances in biomaterial design have revealed profound roles of predefined matrix properties in directing various biological processes. However, the relationship between nascent matrix production and preexisting matrix properties in the microenvironment remains generally unclear. Fundamentally, it is unknown how cells make a decision to produce new matrix molecules, and how this process directs cellular functions. To address this question, we leveraged a droplet-based microfluidic approach to deposit a predefined amount of minimal soft hydrogel matrix with an integrin adhesion ligand around single cells. Remarkably, mesenchymal stem cells (MSCs) deposit more nascent proteins when they are surrounded by a smaller predefined amount of minimal matrix. This occurs due to increased cell volume expansion and membrane tension, followed by activation of a transcriptional program that leads to synthesis of matrix molecules. In contrast, this program is not activated with increased matrix rigidity where membrane tension is increased without cell volume expansion. This program is essential to promote osteogenic differentiation of MSCs over adipogenic lineage. Together, our work reveals a mechanism where stem cells sense the preexisting amount of their surrounding matrix, and build a new one to direct lineage specification. |
Wednesday, March 16, 2022 5:48PM - 6:00PM |
Q07.00011: Does cellular ability to adapt fast varying forces determine the biphasic vs monotonic behaviour of actin retrograde flow with substrate stiffness? Rumi De, Partho Sakha De Cell migration plays an important role in diverse biological processes, such as embryonic development, morphogenesis, wound healing, and tissue regeneration. During migration, focal adhesions arrest actin retrograde flow towards the cell interior, allowing actin polymerization and cell protrusion to advance at the cell front. Here, we present a theoretical model for cell-matrix adhesions at the leading edge of a crawling cell and address a puzzling observation of the biphasic versus monotonic relationship of the retrograde flow with increasing substrate rigidity. Two distinct phenomena have been observed - a biphasic behaviour of the retrograde flow and cell traction force with increasing substrate rigidity, with maximum traction force and minimum retrograde flow velocity present at an optimal substrate stiffness. In contrast, a monotonic relationship between them where the retrograde flow decreases and traction force increases with the substrate stiffness. Our study shows that the difference in the cellular behaviours could arise due to the cell's ability to sense the fast varying force and adapt to the growing force loading rate through adhesion reinforcement mechanisms. Our theory further elucidates how the substrate viscosity along with substrate elasticity alter these nonlinear cellular responses. |
Follow Us |
Engage
Become an APS Member |
My APS
Renew Membership |
Information for |
About APSThe American Physical Society (APS) is a non-profit membership organization working to advance the knowledge of physics. |
© 2024 American Physical Society
| All rights reserved | Terms of Use
| Contact Us
Headquarters
1 Physics Ellipse, College Park, MD 20740-3844
(301) 209-3200
Editorial Office
100 Motor Pkwy, Suite 110, Hauppauge, NY 11788
(631) 591-4000
Office of Public Affairs
529 14th St NW, Suite 1050, Washington, D.C. 20045-2001
(202) 662-8700