Biological cells embedded in fibrous matrices have been observed to form inter-cellular bands of dense and aligned fibers, through which they mechanically interact over long distances. Such matrix-mediated cellular interactions have been shown to regulate a variety of biological processes. The current study was aimed at exploring the effects of elastic nonlinearity of the fibers contained in the extracellular matrix (ECM) on the transmission of mechanical loads between contracting cells. Based on our biological experiments, we developed a finite-element model of two contracting cells embedded within a fibrous network. The individual fibers were modeled as showing either linear elasticity, compression-microbuckling, tension-stiffening or both of the latter. Compression-buckling resulted in smaller loads occurring in the ECM, but these were more directed toward the neighboring cell. The latter decreased with increasing cell-to-cell distance; when cells were >15 cell-diameters apart, no such inter-cellular interaction was observed. Tension-stiffening further contributed to directing the loads toward the neighboring cell, though to a smaller extent. The contraction of two neighboring cells resulted in mutual attraction forces, which were considerably increased by tension-stiffening, and decayed with increasing cell-to-cell distances. Nonlinear elasticity contributed also to the onset of force polarity on the cell boundary. The density and alignment of the fibers within the inter-cellular band were considerably greater when fibers buckled under compression, with tension-stiffening further contributing to this structural remodeling. Our model demonstrates the contribution of nonlinear elasticity of biological gels to directionality and efficiency of mechanical-signal transfer between distant cells.
We report an acoustic approach to measure the elastic properties of an extracellular matrix (ECM). This approach uses a short range evanescent waves to inject sound into the test material over a short distance using an electroded quartz crystal, also known as a quartz crystal microbalance (QCM). These measurements are applied with a press-to-contact approach to determine the elastic properties reliably and rapidly. The elasticity of ECM is connected to material chemistry which is linked to the tissue type and history. Measuring the minimum relative amplitude of the signal from the QCM shows th…
Protrusions at the leading-edge of a cell play an important role in sensing the extracellular cues, during cellular spreading and motility. Recent studies provided indications that these protrusions wrap (coil) around the extra-cellular fibers. The details of this coiling process, and the mechanisms that drive it, are not well understood. We present a combined theoretical and experimental study of the coiling of cellular protrusions on fibers of different geometry. Our theoretical model describes membrane protrusions that are produced by curved membrane proteins that recruit the protrusive for…
To computationally investigate the recent experimental finding such that extracellular ATP release caused by exogeneous mechanical forces promote wound closure, we introduce a mathematical model, the Cellular Pots Model (CPM), which is a popular discretized model on a lattice, where the movement of a "cell" is determined by a Monte Carlo procedure. In the experiment, it was observed that there is mechanosensitive ATP release from the leading cells facing the wound gap and the subsequent intracellular Ca$^{2+}$ influx. To model these phenomena, the Reaction-Diffusion equations for ATP and Ca$^{…
Cell migration is an indispensable physiological and pathological process for normal tissue development and cancer metastasis, which is greatly regulated by intracellular signal pathways and extracellular microenvironment (ECM). However, there is a lack of adequate tools to analyze the time-varying cell migration characteristics because of the effects of some factors, i.e., the ECM including the time-dependent local stiffness due to microstructural remodeling by migrating cells. Here, we develop an approach to derive the time-dependent motility parameters from cellular trajectories, based on t…
Nanoparticles, such as viruses, can enter cells via endocytosis. During endocytosis, the cell surface wraps around the nanoparticle to effectively eat it. Prior focus has been on how nanoparticle size and shape impacts endocytosis. However, inspired by the noted presence of extracellular vimentin affecting viral and bacteria uptake, as well as the structure of coronaviruses, we construct a computational model in which both the cell-like construct and the virus-like construct contain filamentous protein structures protruding from their surfaces. We then study the impact of these additional degr…
Using a mean field approach and simulation, we study the non-linear mechanical response of the vertex model (VM) of biological tissue under compression and dilation. The VM is known to exhibit a transition between rigid and fluid-like, or floppy, states driven by geometric incompatibility. Target perimeter and area set a target shape which may not be geometrically achievable, thereby engendering frustration. Previously, an asymmetry in the linear elastic response was identified at the rigidity transition between compression and dilation. Here we show and characterize how the asymmetry extends …
Bistability of cellular traction on strain-stiffening substrates
Universitat de Barcelona（巴塞罗那大学）；Institució Catalana de Recerca i Estudis Avançats (ICREA)（加泰罗尼亚研究与高等学院）；Max Planck Institute for the Physics of Complex Systems（马克斯·普朗克复杂系统物理研究所）；TU Dresden（德累斯顿工业大学）
Liquid-liquid phase separation has emerged as a fundamental mechanism underlying intracellular organization, with evidence for it being reported in numerous different systems. However, there is a growing concern regarding the lack of quantitative rigor in the techniques employed to study phase separation, and their ability to account for the complex nature of the cellular milieu, which affects key experimentally observable measures, such as the shape, size and transport dynamics of liquid droplets. Here we bridge this gap by combining recent experimental data with theoretical predictions that …
Cold atmospheric plasma (CAP) has shown its promising application in cancer treatment both in vitro and in vivo. However, the anti-cancer mechanism is still largely unknown. CAP may kill cancer cells via triggering the rise of intracellular ROS, DNA damage, mitochondrial damage, or cellular membrane damage. While, the specific vulnerability of cancer cells to CAP has been observed, the underlying mechanism of such cell-based specific vulnerability to CAP is completely unknown. Here, through the comparison of CAP treatment and H2O2 treatment on 10 different cancer cell lines in vitro, we observ…
A quantitative understanding of how cells interact with their extracellular matrix via molecular bonds is fundamental for many important processes in cell biology and engineering. In these interactions, the deformability of cells and matrix are usually comparable with that of the bonds, making their rebinding events globally coupled with the deformation states of whole systems. Unfortunately, this important principle is not realized or adopted in most conventional theoretical models for analyzing cellular adhesions. In this study, we considered a new theoretical model of a cluster of ligand-re…
Collective cell migration is crucial to many physiological and pathological processes. Recent experimental studies have indicated that the active traction forces generated by migrating cells in fibrous extracellular matrix (ECM) can mechanically remodel the ECM, enabling long-range propagation of cellular forces and leading to correlated migration dynamics regulated by the mechanical communication among the cells. Motivated by these experimental discoveries, we develop an active-particle model with polarized effective attractions (APPA) for modeling emergent multi-cellular migration dynamics r…
The internal and external mechanical environment plays an important role in tumorogenesis. As a proxy of an avascular early state tumor, we use multicellular spheroids, a composite material made of cells, extracellular matrix and permeating fluid. We characterize its effective rheology at the timescale of minutes to hours by compressing the aggregates with osmotic shocks and modeling the experimental results with an active poroelastic material that reproduces the stress and strain distributions in the aggregate. The model also predicts how the emergent bulk modulus of the aggregate as well as …
Eukaryotic cells adhere to extracellular matrix during the normal development of the organism, forming static adhesion as well as during cell motility. We study this process by considering a simplified coarse-grained model of a vesicle that has uniform adhesion energy with a flat substrate, mobile curved membrane proteins and active forces. We find that a high concentration of curved proteins alone increases the spreading of the vesicle, by the self-organization of the curved proteins at the high curvature vesicle-substrate contact line, thereby reducing the bending energy penalty at the vesic…
Tissues are characterized by layers of functional units such as cells and extracellular matrix (ECM). Nevertheless, how dynamics at interlayer interfaces help transmit cellular forces in tissues remains overlooked. Here, we investigate a multi-layer system where a layer of epithelial cells is seeded upon an elastic substrate in contact with a hard surface. Our experiments show that, upon a cell extrusion event in the cellular layer, long-range wave propagation emerges in the substrate only when the two substrate layers were weakly attached to each other. We then derive a theoretical model whic…
Electric pulses in biological cells (action potentials) have been reported to be accompanied by a propagating cell-surface deformation with a nano-scale amplitude. Typically, this cell surface is covered by external layers of polymer material (extracellular matrix, cell wall material etc.). It was recently demonstrated in excitable plant cells (Chara Braunii) that the rigid external layer (cell wall) hinders the underlying deformation. When the cell membrane was separated from the cell wall by osmosis, a mechanical deformation, in the micrometer range, was observed upon excitation of the cell.…
Angiogenesis is the formation of new blood vessels from the existing vessels. During tumour angiogenesis, tumour cells secret a number of chemical substrates called tumour angiogenic factors (TAFs). These factors diffuse through the extracellular matrix (ECM) and degrade the basement membrane of nearby vasculature. The TAFs also disrupt the corresponding endothelial cell receptors and form finger like capillary sprouts. These factors also create a chemical gradient (chemotaxis) between the tumour and the surrounding blood vessels. Due to the chemotactic force, the capillary sprouts migrate tow…
The development of traction-force microscopy, in the past two decades, has created the unprecedented opportunity of performing direct mechanical measurements on living cells as they adhere or crawl on uniform or micro-patterned substrates. Simultaneously, this has created the demand for a theoretical framework able to decipher the experimental observations, shed light on the complex biomechanical processes that govern the interaction between the cell and the extracellular matrix and offer testable predictions. Contour models of cellular adhesion, represent one of the simplest and yet most insi…
In-vivo, cells are frequently exposed to multiple mechanical stimuli arising from the extracellular microenvironment, with deep impact on many biological functions. On the other hand, current methods for mechanobiology do not allow to easily replicate in-vitro the complex spatio-temporal behavior of such mechanical signals. Here, we introduce a new platform for studying the mechanical coupling between the extracellular environment and the nucleus in living cells, based on active substrates for cell culture made of Fe-coated polymeric micropillars. Under the action of quasi-static external magn…
Elasticity is a fundamental cellular property that is related to the anatomy, functionality and pathological state of cells and tissues. However, current techniques based on cell deformation, atomic force microscopy or Brillouin scattering are rather slow and do not always accurately represent cell elasticity. Here, we have developed an alternative technique by applying shear wave elastography to the micrometer scale. Elastic waves were mechanically induced in live mammalian oocytes using a vibrating micropipette. These audible frequency waves were observed optically at 200,000 frames per seco…
The functioning of double-stranded (ds) nucleic acids (NAs) in cellular processes is strongly mediated by their elastic response. These processes involve proteins that interact with dsDNA or dsRNA and distort their structures. The perturbation of the elasticity of NAs arising from these deformations is not properly considered by most theoretical frameworks. In this work, we introduce a novel method to assess the impact of mechanical stress on the elastic response of dsDNA and dsRNA through the analysis of the fluctuations of the double helix. Application of this approach to atomistic simulatio…
The question of what guides lineage segregation is central to development, where cellular differentiation leads to segregated cell populations destined for specialized functions. Here, using optical tweezers measurements of mouse embryonic stem cells (mESCs), we reveal a mechanical mechanism based on differential elasticity in the second lineage segregation of the embryonic inner cell mass into epiblast (EPI) cells - that will develop into the fetus - and primitive endoderm (PrE) - which will form extraembryonic structures such as the yolk sac. Remarkably, we find that these mechanical differe…
The cells and tissues that make up our body juggle contradictory mechanical demands. It is crucial for their survival to be able to withstand large mechanical loads, but it is equally crucial for them to produce forces and actively change shape during biological processes such as tissue growth and repair. The mechanics of cell and tissues is determined by scaffolds of protein polymers known as the cytoskeleton and the extracellular matrix, respectively. Experiments on model systems reconstituted from purified components combined with polymer physics concepts have already successfully uncovered…
Collagen fibers, an important component of the extracellular matrix (ECM), can both inhibit and promote cellular migration. {\it In-vitro} studies have revealed that the fibers' orientations are crucial to cellular invasion, while {\it in-vivo} investigations have led to the development of tumor-associated collagen signatures (TACS) as an important prognostic factor. Studying biophysical regulation of cell invasion and the effect of the fibers' oritentation not only deepens our understanding of the phenomenon, but also helps classifying the TACSs precisely, which is currently lacking. We prese…
Focal adhesions are the loci of cellular adhesion to the extracellular matrix. At these sites, various integrins forge connections between the intracellular cytoskeleton and the outside world: large patches of multiple types of integrins together grip hold of collagen, fibronectin and other extracellular matrix components. The mixture of integrins composing the FA will, in general, contain both slip bond integrins and catch bond integrins---bonds whose lifetime increases with applied load and bonds for whom it decreases when forced. Prior work suggests that catch bonds are essential for proper…
Bacterial biofilms, surface-attached communities of cells, are in some respects similar to colloidal solids; both are densely packed with non-zero yield stresses. However, unlike non-living materials, bacteria reproduce and die, breaking mechanical equilibrium and inducing collective dynamic responses. We report experiments and theory investigating the motion of immotile Vibrio cholerae, which can kill each other and reproduce in biofilms. We vary viscosity by using bacterial variants that secrete different amounts of extracellular matrix polymers, but are otherwise identical. Unlike thermally…
Cell migration in fibreous extracellular matrix (ECM) is crucial to many physiological and pathological processes such as tissue regeneration, immune response and cancer progression. During migration, individual cells can generate active pulling forces via actin filament contraction, which are transmitted to the ECM fibers through focal adhesion complexes, remodel the ECM, and eventually propagate to and can be sensed by other cells in the system. The microstructure and physical properties of the ECM can also significantly influence cell migration, e.g., via durotaxis and contact guidance. Her…
SERS study of single-live-cell electrical permeabilization dynamics via plasmonic nanotubes
University of Oulu（奥卢大学）；Institute of Modern Physics Chinese Academy of Sciences（中国科学院近代物理研究所）；Advanced Energy Science and Technology Guangdong Laboratory（先进能源科学技术广东省实验室）；Istituto Italiano di Tecnologia（意大利理工学院）
Princeton University（普林斯顿大学）；Max Planck Institute for the Physics of Complex Systems（马克斯·普朗克复杂系统物理研究所）；Max Planck Institute of Molecular Cell Biology and Genetics（马克斯·普朗克分子细胞生物学与遗传学研究所）；Center for Systems Biology Dresden（德累斯顿系统生物学中心）；University of California, Santa Barbara（加州大学圣塔芭芭拉分校）
