An official website of the United States government
Cells interacting over an extracellular matrix (ECM) exhibit emergent behaviors, which are often observably different from single-cell dynamics. Fibroblasts embedded in a 3-D ECM, for example, compact the surrounding gel and generate an anisotropic strain field, which cannot be observed in single cellinduced gel compaction. This emergent matrix behavior results from collective intracellular mechanical interaction and is crucial to explain the large deformations and mechanical tensions that occur during embryogenesis, tissue development and wound healing. Prediction of multi-cellular interactions entails nonlinear dynamic simulation, which is prohibitively complex to compute using first principles especially as the number of cells increase. Here, we introduce a new methodology for predicting nonlinear behaviors of multiple cells interacting mechanically through a 3D ECM. In the proposed method, we first apply Dual- Faceted Linearization to nonlinear dynamic systems describing cell/matrix behavior. Using this unique linearization method, the original nonlinear state equations can be expressed with a pair of linear dynamic equations by augmenting the independent state variables with auxiliary variables which are nonlinearly dependent on the original states. Furthermore, we can find a reduced order latent space representation of the dynamic equations by orthogonal projection onto the basis of a lower dimensional linear manifold within the augmented variable space. Once converted to latent variable equations, we superpose multiple dynamic systems to predict their collective behaviors. The method is computationally efficient and accurate as demonstrated through its application for prediction of emergent cell induced ECM compaction.
more »
« less
Absorbing–active transition in a multi-cellular system regulated by a dynamic force network
Collective cell migration in 3D extracellular matrix (ECM) is crucial to many physiological and pathological processes. Migrating cells can generate active pulling forces via actin filament contraction, which are transmitted to the ECM fibers and lead to a dynamically evolving force network in the system. Here, we elucidate the role of this force network in regulating collective cell behaviors using a minimal active-particle-on-network (APN) model, in which active particles can pull the fibers and hop between neighboring nodes of the network following local durotaxis. Our model reveals a dynamic transition as the particle number density approaches a critical value, from an “absorbing” state containing isolated stationary small particle clusters, to an “active” state containing a single large cluster undergoing constant dynamic reorganization. This reorganization is dominated by a subset of highly dynamic “radical” particles in the cluster, whose number also exhibits a transition at the same critical density. The transition is underlaid by the percolation of “influence spheres” due to the particle pulling forces. Our results suggest a robust mechanism based on ECM-mediated mechanical coupling for collective cell behaviors in 3D ECM.
more »
« less
- Award ID(s):
- 1844627
- PAR ID:
- 10159346
- Date Published:
- Journal Name:
- Soft Matter
- Volume:
- 15
- Issue:
- 35
- ISSN:
- 1744-683X
- Page Range / eLocation ID:
- 6938 to 6945
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
-
Abstract Cells move in collective groups in biological processes such as wound healing, morphogenesis, and cancer metastasis. How active cell forces produce the motion in collective cell migration is still unclear. Many theoretical models have been introduced to elucidate the relationship between the cell’s active forces and different observations about the collective motion such as collective swirls, oscillations, and rearrangements. Though many models share the common feature of balancing forces in the cell layer, the specific relationships between force and motion vary among the different models, which can lead to different conclusions. Simultaneous experimental measurements of force and motion can aid in testing assumptions and predictions of the theoretical models. Here, we provide time-lapse images of cells in 1 mm circular islands, which are used to compute cell velocities, cell-substrate tractions, and monolayer stresses. Additional data are included from experiments that perturbed cell number density and actomyosin contractility. We expect this data set to be useful to researchers interested in force and motion in collective cell migration.more » « less
-
Capillary suspensions are three-phase mixtures containing a solid particulate phase, a continuous liquid phase, and a second immiscible liquid forming capillary bridges between particles. Capillary suspensions are encountered in a wide array of applications including 3D printing, porous materials, and food formulations, but despite recent progress, the micromechanics of particle clusters in flow is not fully understood. In this work, we study the dynamics of meniscus-bound particle clusters in planar extensional flow using a Stokes trap, which is an automated flow control technique that allows for precise manipulation of freely suspended particles or particle clusters in flow. Focusing on the case of a two-particle doublet, we use a combination of experiments and analytical modeling to understand how particle clusters rearrange, deform, and ultimately break up in extensional flow. The time required for cluster breakup is quantified as a function of capillary number Ca and meniscus volume V. Importantly, a critical capillary number Cacrit for cluster breakup is determined using a combination of experiments and modeling. Cluster relaxation experiments are also performed by deforming particle clusters in flow, followed by flow cessation prior to breakup and observing cluster relaxation dynamics under zero-flow conditions. In all cases, experiments are complemented by an analytical model that accounts for capillary forces, lubrication forces, hydrodynamic drag forces, and hydrodynamic interactions acting on the particles. Results from the analytical models are found to be in good agreement with experiments. Overall, this work provides a new quantitative understanding of the deformation dynamics of capillary clusters in extensional flow.more » « less
-
null (Ed.)Cells in vivo generate mechanical traction on the surrounding 3D extracellular matrix (ECM) and neighboring cells. Such traction and biochemical cues may remodel the matrix, e.g., increase stiffness, which, in turn, influences cell functions and forces. This dynamic reciprocity mediates development and tumorigenesis. Currently, there is no method available to directly quantify single-cell forces and matrix remodeling in 3D. Here, we introduce a method to fulfill this long-standing need. We developed a high-resolution microfabricated sensor that hosts a 3D cell-ECM tissue formed by self-assembly. This sensor measures cell forces and tissue stiffness and can apply mechanical stimulation to the tissue. We measured single and multicellular force dynamics of fibroblasts (3T3), human colon (FET) and lung (A549) cancer cells, and cancer-associated fibroblasts (CAF05) with 1-nN resolution. Single cells show notable force fluctuations in 3D. FET/CAF coculture system, mimicking cancer tumor microenvironment, increased tissue stiffness by three times within 24 hours.more » « less
-
Abstract The collagen-rich tumor microenvironment plays a critical role in directing the migration behavior of cancer cells. 3D collagen architectures with small pores have been shown to confine cells and induce aggressive collective migration, irrespective of matrix stiffness and density. However, it remains unclear how cells sense collagen architecture and transduce this information to initiate collective migration. Here, we tune collagen architecture and analyze its effect on four core cell-ECM interactions: cytoskeletal polymerization, adhesion, contractility, and matrix degradation. From this comprehensive analysis, we deduce that matrix architecture initially modulates cancer cell adhesion strength, and that this results from architecture-induced changes to matrix degradability. That is, architectures with smaller pores are less degradable, and degradability is required for cancer cell adhesion to 3D fibrilar collagen. The biochemical consequences of this 3D low-attachment state are similar to those induced by suspension culture, including metabolic and oxidative stress. One distinction from suspension culture is the induction of collagen catabolism that occurs in 3D low-attachment conditions. Cells also upregulate Snail1 and Notch signaling in response to 3D low-attachment, which suggests a mechanism for the emergence of collective behaviors.more » « less
- Free Publicly Accessible Full Text
-
Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1039/C9SM01244C
