Collective cell migration is a key driver of embryonic development, wound healing, and some types of cancer invasion. Here, we provide a physical perspective of the mechanisms underlying collective ...cell migration. We begin with a catalog of the cell-cell and cell-substrate interactions that govern cell migration, which we classify into positional and orientational interactions. We then review the physical models that have been developed to explain how these interactions give rise to collective cellular movement. These models span the subcellular to the supracellular scales, and they include lattice models, phase-field models, active network models, particle models, and continuum models. For each type of model, we discuss its formulation, its limitations, and the main emergent phenomena that it has successfully explained. These phenomena include flocking and fluid-solid transitions, as well as wetting, fingering, and mechanical waves in spreading epithelial monolayers. We close by outlining remaining challenges and future directions in the physics of collective cell migration.
The linkage of cells to their microenvironment is mediated by a series of bonds that dynamically engage and disengage, in what has been conceptualized as the molecular clutch model. Whereas this ...model has long been employed to describe actin cytoskeleton and cell migration dynamics, it has recently been proposed to also explain mechanotransduction (i.e., the process by which cells convert mechanical signals from their environment into biochemical signals). Here we review the current understanding on how cell dynamics and mechanotransduction are driven by molecular clutch dynamics and its master regulator, the force loading rate. Throughout this Review, we place a specific emphasis on the quantitative prediction of cell response enabled by combined experimental and theoretical approaches.
By considering the molecular and mechanical properties of actin filaments, myosin motors, adaptor proteins, and integrins/cadherins, the molecular clutch model can quantitatively predict cell response to internal and external mechanical factors.
These factors include cell contractility, matrix rigidity, and the density, nature, and distribution of matrix ligands, and affect cell response largely by controlling the rate of force loading in specific molecules.
Due to its dynamic nature, clutch-mediated mechanosensing requires force application to at least two molecular mechanosensors in series, with differential response to force.
The type of cell responses involved so far in clutch-mediated mechanosensing include cytoskeletal dynamics, the growth of cell adhesions, the nuclear localization of transcriptional regulators, and cell migration.
Collective cell chemotaxis, the directed migration of cell groups along gradients of soluble chemical cues, underlies various developmental and pathological processes. We use neural crest cells, a ...migratory embryonic stem cell population whose behavior has been likened to malignant invasion, to study collective chemotaxis in vivo. Studying
and zebrafish, we have shown that the neural crest exhibits a tensile actomyosin ring at the edge of the migratory cell group that contracts in a supracellular fashion. This contractility is polarized during collective cell chemotaxis: It is inhibited at the front but persists at the rear of the cell cluster. The differential contractility drives directed collective cell migration ex vivo and in vivo through the intercalation of rear cells. Thus, in neural crest cells, collective chemotaxis works by rear-wheel drive.
In recent years considerable progress has been made in the development of faithful procedures for the differentiation of human pluripotent stem cells (hPSCs). An important step in this direction has ...also been the derivation of organoids. This technology generally relies on traditional three-dimensional culture techniques that exploit cell-autonomous self-organization responses of hPSCs with minimal control over the external inputs supplied to the system. The convergence of stem cell biology and bioengineering offers the possibility to provide these stimuli in a controlled fashion, resulting in the development of naturally inspired approaches to overcome major limitations of this nascent technology. Based on the current developments, we emphasize the achievements and ongoing challenges of bringing together hPSC organoid differentiation, bioengineering and ethics. This Review underlines the need for providing engineering solutions to gain control of self-organization and functionality of hPSC-derived organoids. We expect that this knowledge will guide the community to generate higher-grade hPSC-derived organoids for further applications in developmental biology, drug screening, disease modelling and personalized medicine.
Cancer-associated fibroblasts (CAFs) promote tumour invasion and metastasis. We show that CAFs exert a physical force on cancer cells that enables their collective invasion. Force transmission is ...mediated by a heterophilic adhesion involving N-cadherin at the CAF membrane and E-cadherin at the cancer cell membrane. This adhesion is mechanically active; when subjected to force it triggers β-catenin recruitment and adhesion reinforcement dependent on α-catenin/vinculin interaction. Impairment of E-cadherin/N-cadherin adhesion abrogates the ability of CAFs to guide collective cell migration and blocks cancer cell invasion. N-cadherin also mediates repolarization of the CAFs away from the cancer cells. In parallel, nectins and afadin are recruited to the cancer cell/CAF interface and CAF repolarization is afadin dependent. Heterotypic junctions between CAFs and cancer cells are observed in patient-derived material. Together, our findings show that a mechanically active heterophilic adhesion between CAFs and cancer cells enables cooperative tumour invasion.
The mechanical properties of the extracellular matrix (ECM)-a complex, 3D, fibrillar scaffold of cells in physiological environments-modulate cell behavior and can drive tissue morphogenesis, ...regeneration, and disease progression. For simplicity, it is often convenient to assume these properties to be time-invariant. In living systems, however, cells dynamically remodel the ECM and create time-dependent local microenvironments. Here, we show how cell-generated contractile forces produce substantial irreversible changes to the density and architecture of physiologically relevant ECMs-collagen I and fibrin-in a matter of minutes. We measure the 3D deformation profiles of the ECM surrounding cancer and endothelial cells during stages when force generation is active or inactive. We further correlate these ECM measurements to both discrete fiber simulations that incorporate fiber crosslink unbinding kinetics and continuum-scale simulations that account for viscoplastic and damage features. Our findings further confirm that plasticity, as a mechanical law to capture remodeling in these networks, is fundamentally tied to material damage via force-driven unbinding of fiber crosslinks. These results characterize in a multiscale manner the dynamic nature of the mechanical environment of physiologically mimicking cell-in-gel systems.
Contractile forces are the end effectors of cell migration, division, morphogenesis, wound healing and cancer invasion. Here we report optogenetic tools to upregulate and downregulate such forces ...with high spatiotemporal accuracy. The technology relies on controlling the subcellular activation of RhoA using the CRY2/CIBN light-gated dimerizer system. We fused the catalytic domain (DHPH domain) of the RhoA activator ARHGEF11 to CRY2-mCherry (optoGEF-RhoA) and engineered its binding partner CIBN to bind either to the plasma membrane or to the mitochondrial membrane. Translocation of optoGEF-RhoA to the plasma membrane causes a rapid and local increase in cellular traction, intercellular tension and tissue compaction. By contrast, translocation of optoGEF-RhoA to mitochondria results in opposite changes in these physical properties. Cellular changes in contractility are paralleled by modifications in the nuclear localization of the transcriptional regulator YAP, thus showing the ability of our approach to control mechanotransductory signalling pathways in time and space.
The isotropic or anisotropic organization of biological extracellular matrices has important consequences for tissue function. We study emergent anisotropy using fibroblasts that generate varying ...degrees of matrix alignment from uniform starting conditions. This reveals that the early migratory paths of fibroblasts are correlated with subsequent matrix organization. Combined experimentation and adaptation of Vicsek modelling demonstrates that the reorientation of cells relative to each other following collision plays a role in generating matrix anisotropy. We term this behaviour 'cell collision guidance'. The transcription factor TFAP2C regulates cell collision guidance in part by controlling the expression of RND3. RND3 localizes to cell-cell collision zones where it downregulates actomyosin activity. Cell collision guidance fails without this mechanism in place, leading to isotropic matrix generation. The cross-referencing of alignment and TFAP2C gene expression signatures against existing datasets enables the identification and validation of several classes of pharmacological agents that disrupt matrix anisotropy.
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