Collective Cell Motility Promotes Chemotactic Prowess and Resistance to Chemorepulsion

A long-standing question in collective cell migration has been what might be the relative advantage of forming a cluster over migrating individually. Does an increase in the size of a collectively migrating group of cells enable them to sample the chemical gradient over a greater distance because the difference between front and rear of a cluster would be greater than for single cells? We combined theoretical modeling with experiments to study collective migration of the border cells in-between nurse cells in the Drosophila egg chamber. We discovered that cluster size is positively correlated with migration speed, up to a particular point above which speed plummets. This may be due to the effect of viscous drag from surrounding nurse cells together with confinement of all of the cells within a stiff extracellular matrix. The model predicts no relationship between cluster size and velocity for cells moving on a flat surface, in contrast to movement within a 3D environment. Our analyses also suggest that the overall chemoattractant profile in the egg chamber is likely to be exponential, with the highest concentration in the oocyte. These findings provide insights into collective chemotaxis by combining theoretical modeling with experimentation.cell migration | theoretical modeling | three-dimensional | chemotaxis

“…8). Whereas in 2D, the friction is dominated by the surface area, therefore λ scales as R 2 and we expect the velocity to be independent of the cluster diameter (33).…”

Section: Resultsmentioning

confidence: 88%

Section: Resultsmentioning

confidence: 99%

Modeling and analysis of collective cell migration in an in vivo three-dimensional environment

Cai

Dai

Prasad

et al. 2016

“…Cells are even more sensitive when they are in a group: Cultures of many neurons respond to chemical gradients equivalent to a difference of only one molecule across an individual neuron's axonal growth cone (2), clusters of malignant lymphocytes have a wider chemotactic sensitivity than single cells (3), and groups of communicating epithelial cells detect gradients that are too weak for a single cell to detect (4). More generally, collective chemosensing properties are often very distinct from those in individual cells (3,(5)(6)(7). These observations have generated a renewed interest in the question of what sets the fundamental limit to the precision of gradient sensing in large, spatially extended, often collective sensory systems.…”

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confidence: 99%

Limits to the precision of gradient sensing with spatial communication and temporal integration

Mugler

Levchenko

Nemenman

2016

136

Gradient sensing requires at least two measurements at different points in space. These measurements must then be communicated to a common location to be compared, which is unavoidably noisy. Although much is known about the limits of measurement precision by cells, the limits placed by the communication are not understood. Motivated by recent experiments, we derive the fundamental limits to the precision of gradient sensing in a multicellular system, accounting for communication and temporal integration. The gradient is estimated by comparing a "local" and a "global" molecular reporter of the external concentration, where the global reporter is exchanged between neighboring cells. Using the fluctuation-dissipation framework, we find, in contrast to the case when communication is ignored, that precision saturates with the number of cells independently of the measurement time duration, because communication establishes a maximum length scale over which sensory information can be reliably conveyed. Surprisingly, we also find that precision is improved if the local reporter is exchanged between cells as well, albeit more slowly than the global reporter. The reason is that whereas exchange of the local reporter weakens the comparison, it decreases the measurement noise. We term such a model "regional excitation-global inhibition." Our results demonstrate that fundamental sensing limits are necessarily sharpened when the need to communicate information is taken into account. C ells sense spatial gradients in environmental chemicals with remarkable precision. A single amoeba, for example, can respond to a difference of roughly 10 attractant molecules between the front and the back of the cell (1). Cells are even more sensitive when they are in a group: Cultures of many neurons respond to chemical gradients equivalent to a difference of only one molecule across an individual neuron's axonal growth cone (2), clusters of malignant lymphocytes have a wider chemotactic sensitivity than single cells (3), and groups of communicating epithelial cells detect gradients that are too weak for a single cell to detect (4). More generally, collective chemosensing properties are often very distinct from those in individual cells (3, 5-7). These observations have generated a renewed interest in the question of what sets the fundamental limit to the precision of gradient sensing in large, spatially extended, often collective sensory systems.Fundamentally, sensing a stationary gradient requires at least two measurements to be made at different points in space. The precision of these two or more individual measurements bounds the gradient sensing precision (8, 9). In its turn, each individual measurement is limited by the finite number of molecules within the detector volume and the ability of the detector to integrate over time, a point first made by Berg and Purcell (BP) (8). More detailed calculations of gradient sensing by specific geometries of receptors have since confirmed that the precision of gradient sensing remains limited by ...

“…This result is consistent with other multicell experiments that show that collective chemotaxis is possible in the absence of single-cell chemotaxis. For example, both lymphocytes and neural crest cell clusters have been shown to migrate directionally and to display a much higher chemotactic sensitivity than individual cells (8)(9)(10).…”

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confidence: 99%

“…Furthermore, the model does not incorporate contact inhibition of locomotion during which a cell in contact with other cells attempts to move away from its neighbors (19). These aspects are incorporated into several recent modeling studies for collective chemotaxis (9,20,21) and their relative importance is currently unclear. It is likely, however, that combined theoretical and experimental studies, as presented by Ellison et al (5) and Mugler et al (6), will be instrumental in unraveling the fundamental mechanisms of collective cell motility.…”

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confidence: 99%

Cell–cell communication during collective migration

Rappel

2016

Cell motility plays a critical role in many biological and medical processes, including wound healing, morphogenesis, and cancer metastasis (1). Often, this movement is guided by external chemical cues in the form of chemoattractant gradients. These cues consist of diffusive chemoattractant molecules that bind to surface receptors on the cell membrane and activate intracellular signaling pathways, resulting in a polarized asymmetric cell that chemotaxes in the direction of higher chemoattractant concentrations. How chemotaxis works on a single-cell level has been the subject of many detailed experimental and modeling studies (2, 3). In most physiologically relevant cases, however, cells do not move in isolation but, instead, move in groups. This collective motion is a process that is not yet well understood and may play a critical role in the spreading of cancer (4). In particular, it is not clear whether cells that move within a group communicate with each other and, if so, how this cell-cell communication affects the directionality of the group. In PNAS, Ellison et al. (5) performed experiments that suggest that cell-cell communication plays a critical role in branching morphogenesis of the epithelial tissue in mammary glands. Furthermore, in a companion PNAS study, they present a mathematical model of this communication and derive the fundamental limits of the precision of gradient sensing of this model (6).The experiments by Ellison et al. (5) investigate the collective cellular response of epithelial branches in mammary glands using organoids, 3D in vitro organotypic cultures (7). When placed in a gradient of epidermal growth factor (EGF) Ellison et al. (5) find that the formation and extension of these branches exhibit a significant directional bias toward high EGF concentrations (Fig. 1). Without an EGF gradient, however, branch formation displays no directional bias, implying that the multicellular structure is guided by external EGF cues. Importantly, the EGF gradients are generated in mesoscopic fluidic devices and are stable for several days, allowing the quantification of the branching process over a prolonged period.The simplest possible explanation of the observed collective guidance is that each cell is able to sense the chemoattractant gradient and polarizes, independently of its neighbors. The collective branching motion is then the result of the average motion of individual cells. Things are not that simple, however. Ellison et al. (5) clearly show that single cells, dissociated from the organoid, do not respond to EGF gradients and move around aimlessly (Fig. 1). This result is consistent with other multicell experiments that show that collective chemotaxis is possible in the absence of single-cell chemotaxis. For example, both lymphocytes and neural crest cell clusters have been shown to migrate directionally and to display a much higher chemotactic sensitivity than individual cells (8-10).Another possibility is that a multicellular cluster acts as a large "supercell" with concentration det...