Synthetic Notch Activation Patterns in a Proliferating Tissue.

Cell-cell communication through direct contact is essential during fundamental biological processes such as tissue repair and morphogenesis. Synthetic forms of contact-mediated cell-cell communication can generate custom gene expression outputs, making them valuable for tissue engineering and regenerative medicine. To precisely control the location and timing of synthetic signal outputs in growing tissues, it is necessary to understand the mechanisms underlying its spatiotemporal patterns. Towards this goal, we combine theory and experiments to study patterns of synthetic Notch (synNotch) activation - a custom synthetic gene circuit that we implement within Drosophila wing imaginal discs. We show that output synthesis and degradation rates together with cell division are the key minimal parameters that predict the heterogeneous spatiotemporal patterns of synNotch activation. Notably, synNotch output forms a graded exponential spatial profile that extends several cell diameters from the signal source, establishing evidence for signal propagation without diffusion or long range cell-cell communication. Furthermore, we discover that the shape of the interface between ligand and receptor cells is important in determining the synNotch output. Overall, we elucidate key biophysical principles that underlie complex emergent spatiotemporal patterns of synNotch output in a growing tissue.

Cell clusters softening triggers collective cell migration in vivo.

Embryogenesis, tissue repair and cancer metastasis rely on collective cell migration. In vitro studies propose that cells are stiffer while migrating in stiff substrates, but softer when plated in compliant surfaces which are typically considered as non-permissive for migration. Here we show that cells within clusters from embryonic tissue dynamically decrease their stiffness in response to the temporal stiffening of their native substrate to initiate collective cell migration. Molecular and mechanical perturbations of embryonic tissues reveal that this unexpected mechanical response involves a mechanosensitive pathway relying on Piezo1-mediated microtubule deacetylation. We further show that decreasing microtubule acetylation and consequently cluster stiffness is sufficient to trigger collective cell migration in soft non-permissive substrates. This suggests that reaching an optimal cluster-to-substrate stiffness ratio is essential to trigger the onset of this collective process. Overall, these in vivo findings challenge the current understanding of collective cell migration and its physiological and pathological roles.

Adhesion strength between cells regulate nonmonotonic growth by a biomechanical feedback mechanism.

We determine how intercellular interactions and mechanical pressure experienced by single cells regulate cell proliferation using a minimal computational model for three-dimensional multicellular spheroid (MCS) growth. We discover that emergent spatial variations in the cell division rate, depending on the location of the cells either at the core or periphery within the MCS, is regulated by intercellular adhesion strength (fad). Varying fad results in nonmonotonic proliferation of cells in the MCS. A biomechanical feedback mechanism coupling the fad and microenvironment-dependent pressure fluctuations relative to a threshold value (pc) determines the onset of a dormant phase, and explains the nonmonotonic proliferation response. Increasing fad from low values enhances cell proliferation because pressure on individual cells is smaller compared with pc. However, at high fad, cells readily become dormant and cannot rearrange effectively in spacetime, leading to arrested cell proliferation. Utilizing our theoretical predictions, we explain experimental data on the impact of adhesion strength on cell proliferation and find good agreement. Our work, which shows that proliferation is regulated by pressure-adhesion feedback mechanism, may be a general feature of multicellular growth.

Interparticle Adhesion Regulates the Surface Roughness of Growing Dense Three-Dimensional Active Particle Aggregates.

Activity and self-generated motion are fundamental features observed in many living and nonliving systems. Given that interparticle adhesive forces can regulate particle dynamics, we investigate how interparticle adhesion strength controls the boundary growth and roughness of active particle aggregates. Using particle based simulations incorporating both activity (birth, death, and growth) and systematic physical interactions (elasticity and adhesion), we establish that interparticle adhesion strength (fad) controls the surface roughness of a densely packed three-dimensional(3D) active particle aggregate expanding into a highly viscous medium. We discover that the surface roughness of a 3D active particle aggregate increases in proportion to the interparticle adhesion strength (fad) and show that asymmetry in the radial and transverse active particle mean-squared displacement (MSD) suppresses 3D surface roughness at lower adhesion strengths. By analyzing the statistical properties of particle displacements at the aggregate periphery, we determine that the 3D surface roughness is driven by the movement of active particle toward the core at high interparticle adhesion strengths. Our results elucidate the physics controlling the expansion of adhesive 3D active particle collectives into a highly viscous medium, with implications into understanding stochastic interface growth in active matter systems characterized by self-generation of particles.

Correction: Spatially heterogeneous dynamics of cells in a growing tumor spheroid: comparison between theory and experiments.

Correction for 'Spatially heterogeneous dynamics of cells in a growing tumor spheroid: comparison between theory and experiments' by Sumit Sinha et al., Soft Matter, 2020, 16, 5294-5304, DOI: .

Spatially heterogeneous dynamics of cells in a growing tumor spheroid: comparison between theory and experiments.

Collective cell movement, characterized by multiple cells that are in contact for substantial periods of time and undergo correlated motion, plays a central role in cancer and embryogenesis. Recent imaging experiments have provided time-dependent traces of individual cells, thus providing an unprecedented picture of tumor spheroid growth. By using simulations of a minimal cell model, we analyze the experimental data that map the movement of cells in a fibrosarcoma tumor spheroid embedded in a collagen matrix. Both simulations and experiments show that cells in the core of the spheroid exhibit subdiffusive glassy dynamics (mean square displacement, Δ(t) ≈ tα with α < 1), whereas cells in the periphery exhibit superdiffusive motion, Δ(t) ≈ tα with α > 1. The motion of most of the cells near the periphery is highly persistent and correlated directional motion due to cell doubling and apoptosis rates, thus explaining the observed superdiffusive behavior. The α values for cells in the core and periphery, extracted from simulations and experiments, are in near quantitative agreement with each other, which is surprising given that no parameter in the model was used to fit the measurements. The qualitatively different dynamics of cells in the core and periphery is captured by the fourth order susceptibility, introduced to characterize metastable states in glass forming systems. Analyses of the velocity autocorrelation of individual cells show remarkable spatial heterogeneity with no two cells exhibiting similar behavior. The prediction that α should depend on the location of the cells in the tumor is amenable to experimental testing. The highly heterogeneous dynamics of cells in the tumor spheroid provides a plausible mechanism for the origin of intratumor heterogeneity.