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Register a new userA mechano-chemical feedback underlies co-existence of qualitatively distinct cell polarity patterns within diverse cell populations
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Cell polarization and directional cell migration can display random, persistent and oscillatory dynamic patterns. However, it is not clear if these polarity patterns can be explained by the same underlying regulatory mechanism. Here, we show that random, persistent and oscillatory migration accompanied by polarization can simultaneously occur in populations of melanoma cells derived from tumors with different degrees of aggressiveness. We demonstrate that all these patterns and the probabilities of their occurrence are quantitatively accounted for by a simple mechanism involving a spatially distributed, mechano-chemical feedback coupling the dynamically changing extracellular matrix (ECM)-cell contacts to the activation of signaling downstream of the Rho-family small GTPases. This mechanism is supported by a predictive mathematical model and extensive experimental validation, and can explain previously reported results for diverse cell types. In melanoma, this mechanism also accounts for the effects of genetic and environmental perturbations, including mutations linked to invasive cell spread. The resulting mechanistic understanding of cell polarity quantitatively captures the relationship between population variability and phenotypic plasticity, with the potential to account for a wide variety of cell migration states in diverse pathological and physiological conditions.
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Cells crawling through tissues migrate inside a complex fibrous environment called the extracellular matrix (ECM), which provides signals regulating motility. Here we investigate one such well-known pathway, involving mutually antagonistic signalling molecules (small GTPases Rac and Rho) that control the protrusion and contraction of the cell edges (lamellipodia). Invasive melanoma cells were observed migrating on surfaces with topography (array of posts), coated with adhesive molecules (fibronectin, FN) by Park et al., 2016. Several distinct qualitative behaviors they observed included persistent polarity, oscillation between the cell front and back, and random dynamics. To gain insight into the link between intracellular and ECM signaling, we compared experimental observations to a sequence of mathematical models encoding distinct hypotheses. The successful model required several critical factors. (1) Competition of lamellipodia for limited pools of GTPases. (2) Protrusion / contraction of lamellipodia influence ECM signaling. (3) ECM-mediated activation of Rho. A model combining these elements explains all three cellular behaviors and correctly predicts the results of experimental perturbations. This study yields new insight into how the dynamic interactions between intracellular signaling and the cells environment influence cell behavior.
The polarisation of cells and tissues is fundamental for tissue morphogenesis during biological development and regeneration. A deeper understanding of biological polarity pattern formation can be gained from the consideration of pattern reorganisation in response to an opposing instructive cue, which we here consider by example of experimentally inducible body axis
Various molecules exclusively accumulate at the front or back of migrating eukaryotic cells in response to a shallow gradient of extracellular signals. Directional sensing and signal amplification highlight the essential properties in the migrating cells, known as cell polarity. In addition to these, such properties of cell polarity involve unique determination of migrating direction (uniqueness of axis) and localized gradient sensing at the front edge (localization of sensitivity), both of which may be required for smooth migration. Here we provide the mass conservation system based on the reaction-diffusion system with two components, where the mass of the two components is always conserved. Using two models belonging to this mass conservation system, we demonstrate through both numerical simulation and analytical approximations that the spatial pattern with a single peak (uniqueness of axis) can be generally observed and that the existent peak senses a gradient of parameters at the peak position, which guides the movement of the peak. We extended this system with multiple components, and we developed a multiple-component model in which cross-talk between members of the Rho family of small GTPases is involved. This model also exhibits the essential properties of the two models with two components. Thus, the mass conservation system shows properties similar to those of cell polarity, such as uniqueness of axis and localization of sensitivity, in addition to directional sensing and signal amplification.
Cyanobacteria forming one-dimensional filaments are paradigmatic model organisms of the transition between unicellular and multicellular living forms. Under nitrogen limiting conditions, in filaments of the genus Anabaena, some cells differentiate into heterocysts, which lose the possibility to divide but are able to fix environmental nitrogen for the colony. These heterocysts form a quasi-regular pattern in the filament, representing a prototype of patterning and morphogenesis in prokaryotes. Recent years have seen advances in the identification of the molecular mechanism regulating this pattern. We use this data to build a theory on heterocyst pattern formation, for which both genetic regulation and the effects of cell division and filament growth are key components. The theory is based on the interplay of three generic mechanisms: local autoactivation, early long range inhibition, and late long range inhibition. These mechanisms can be identified with the dynamics of hetR, patS and hetN expression. Our theory reproduces quantitatively the experimental dynamics of pattern formation and maintenance for wild type and mutants. We find that hetN alone is not enough to play the role as the late inhibitory mechanism: a second mechanism, hypothetically the products of nitrogen fixation supplied by heterocysts, must also play a role in late long range inhibition. The preponderance of even intervals between heterocysts arises naturally as a result of the interplay between the timescales of genetic regulation and cell division. We also find that a purely stochastic initiation of the pattern, without a two-stage process, is enough to reproduce experimental observations.
Massive single-cell profiling efforts have accelerated our discovery of the cellular composition of the human body, while at the same time raising the need to formalise this new knowledge. Here, we review current cell ontology efforts to harmonise and integrate different sources of annotations of cell types and states. We illustrate with examples how a unified ontology can consolidate and advance our understanding of cell types across scientific communities and biological domains.
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