From Molecular Signal Activation to Locomotion: An Integrated, Multiscale Analysis of Cell Motility on Defined Matrices

The adhesion, mechanics, and motility of eukaryotic cells are highly sensitive to the ligand density and stiffness of the extracellular matrix (ECM). This relationship bears profound implications for stem cell engineering, tumor invasion and metastasis. Yet, our quantitative understanding of how ECM biophysical properties, mechanotransductive signals, and assembly of contractile and adhesive structures collude to control these cell behaviors remains extremely limited. Here we present a novel multiscale model of cell migration on ECMs of defined biophysical properties that integrates local activation of biochemical signals with adhesion and force generation at the cell-ECM interface. We capture the mechanosensitivity of individual cellular components by dynamically coupling ECM properties to the activation of Rho and Rac GTPases in specific portions of the cell with actomyosin contractility, cell-ECM adhesion bond formation and rupture, and process extension and retraction. We show that our framework is capable of recreating key experimentally-observed features of the relationship between cell migration and ECM biophysical properties. In particular, our model predicts for the first time recently reported transitions from filopodial to “stick-slip” to gliding motility on ECMs of increasing stiffness, previously observed dependences of migration speed on ECM stiffness and ligand density, and high-resolution measurements of mechanosensitive protrusion dynamics during cell motility we newly obtained for this study. It also relates the biphasic dependence of cell migration speed on ECM stiffness to the tendency of the cell to polarize. By enabling the investigation of experimentally-inaccessible microscale relationships between mechanotransductive signaling, adhesion, and motility, our model offers new insight into how these factors interact with one another to produce complex migration patterns across a variety of ECM conditions

Nonlinear gap junctions enable long-distance propagation of pulsating calcium waves in astrocyte networks

A new paradigm has recently emerged in brain science whereby communications between glial cells and neuron-glia interactions should be considered together with neurons and their networks to understand higher brain functions. In particular, astrocytes, the main type of glial cells in the cortex, have been shown to communicate with neurons and with each other. They are thought to form a gap-junction-coupled syncytium supporting cell-cell communication via propagating Ca2+ waves. An identified mode of propagation is based on cytoplasm-to-cytoplasm transport of inositol trisphosphate (IP3) through gap junctions that locally trigger Ca2+ pulses via IP3-dependent Ca2+-induced Ca2+ release. It is, however, currently unknown whether this intracellular route is able to support the propagation of long-distance regenerative Ca2+ waves or is restricted to short-distance signaling. Furthermore, the influence of the intracellular signaling dynamics on intercellular propagation remains to be understood. In this work, we propose a model of the gap-junctional route for intercellular Ca2+ wave propagation in astrocytes showing that: (1) long-distance regenerative signaling requires nonlinear coupling in the gap junctions, and (2) even with nonlinear gap junctions, long-distance regenerative signaling is favored when the internal Ca2+ dynamics implements frequency modulation-encoding oscillations with pulsating dynamics, while amplitude modulation-encoding dynamics tends to restrict the propagation range. As a result, spatially heterogeneous molecular properties and/or weak couplings are shown to give rise to rich spatiotemporal dynamics that support complex propagation behaviors. These results shed new light on the mechanisms implicated in the propagation of Ca2+ waves across astrocytes and precise the conditions under which glial cells may participate in information processing in the brain.Comment: Article: 30 pages, 7 figures. Supplementary Material: 11 pages, 6 figure

Mechanochemical modeling of neutrophil migration based on four signaling layers, integrin dynamics, and substrate stiffness

Directional neutrophil migration during human immune responses is a highly coordinated process regulated by both biochemical and biomechanical environments. In this paper, we developed an integrative mathematical model of neutrophil migration using a lattice Boltzmann-particle method built in-house to solve the moving boundary problem with spatiotemporal regulation of biochemical components. The mechanical features of the cell cortex are modeled by a series of spring-connected nodes representing discrete cell-substrate adhesive sites. The intracellular signaling cascades responsible for cytoskeletal remodeling [e.g., small GTPases, phosphoinositide-3-kinase (PI3K), and phosphatase and tensin homolog] are built based on our previous four-layered signaling model centered on the bidirectional molecular transport mechanism and implemented as reaction-diffusion equations. Focal adhesion dynamics are determined by force-dependent integrin-ligand binding kinetics and integrin recycling and are thus integrated with cell motion. Using numerical simulations, the model reproduces the major features of cell migration in response to uniform and gradient biochemical stimuli based on the quantitative spatiotemporal regulation of signaling molecules, which agree with experimental observations. The existence of multiple types of integrins with different binding kinetics could act as an adaptation mechanism for substrate stiffness. Moreover, cells can perform reversal, U-turn, or lock-on behaviors depending on the steepness of the reversal biochemical signals received. Finally, this model is also applied to predict the responses of mutants in which PTEN is overexpressed or disrupted