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VIDEO: Lab-grown human leukemia cells move toward
a pipette tip holding an attractive chemical.
How cells know which way to go
Amoebas aren't the only cells that crawl: Movement is crucial to development, wound healing and immune response, not to mention cancer metastasis. Two new studies shed light on how cells sense and respond to chemical trails.
Two new studies from Johns Hopkins answer long-standing questions about how complex cells sense chemical trails that show them where to go — and the role of a cells' internal "skeleton" in responding to chemical cues. In following these chemical trails, cells steer based on minute differences in concentrations of chemicals between one end of the cell and the other.
"Cells can detect differences in concentration as low as 2 percent. They' can detect small differences whether the background concentration is very high, very low or somewhere in between."
Peter Devreotes, Ph.D., Director, Department of Cell Biology, the Johns Hopkins University School of Medicine.
Working with Pablo Iglesias, Ph.D., a professor of electrical and computer engineering at Johns Hopkins, Devreotes' research group devised a system for watching the response of the cell control center (which directs movement). They then subjected amoebas and human white blood cells to various gradients of chemicals and analyzed the responses.
"Detecting gradient amounts turns out to be a two-step process. First, the side of the cell getting less of the chemical signal just stops responding. Then, the cell control center increases its response to the chemical signal from the other side of the cell, moving toward it."
Ming Tang PhD
The results appeared in Nature Communications on Oct. 27, 2014.
But in order to begin, the cell first must arrange itself into a distinct front and back, according to a study by Devreotes' group. In that experiment, visiting scientist Mingjie Wang PhD, and postdoctoral fellow Yulia Artemenko PhD, tested the role of cell polarity — differences between the front and back of a cell — in responding to a gradient.
Artemenko: "In previous studies, researchers added a drug that totally dismantled the cells' skeleton and therefore eliminated movement. They found that these cells had also lost polarity. We wanted to know whether polarity depended on movement and how polarity itself — independent of the ability to move — helped to detect gradients."
The team used a pharmaceutical cocktail that froze the cells' skeleton in place as researchers observed the response of the cell's control center. Artemenko: "Even though the cells couldn't remodel their skeleton in order to move, they did pick up signals from the gradients, and the response to the gradient was influenced by the frozen skeleton. This doesn't happen if the skeleton is completely gone, so now we know that the skeleton itself, not its ability to remodel, influences the detection of gradients."
The results appear in the Nov. 6 issue of Cell Reports.
Details of how cells move may ultimately help explain the processes of development, immune response, wound healing and even organ regeneration.
Abstract in Nature: "Evolutionarily conserved coupling of adaptive and excitable networks mediates eukaryotic chemotaxis"
Numerous models explain how cells sense and migrate towards shallow chemoattractant gradients. Studies show that an excitable signal transduction network acts as a pacemaker that controls the cytoskeleton to drive motility. Here we show that this network is required to link stimuli to actin polymerization and chemotactic motility and we distinguish the various models of chemotaxis. First, signalling activity is suppressed towards the low side in a gradient or following removal of uniform chemoattractant. Second, signalling activities display a rapid shut off and a slower adaptation during which responsiveness to subsequent test stimuli decline. Simulations of various models indicate that these properties require coupled adaptive and excitable networks. Adaptation involves a G-protein-independent inhibitor, as stimulation of cells lacking G-protein function suppresses basal activities. The salient features of the coupled networks were observed for different chemoattractants in Dictyostelium and in human neutrophils, suggesting an evolutionarily conserved mechanism for eukaryotic chemotaxis.
Other authors on the Nature Communications paper are Mingjie Wang and Changji Shi of The Johns Hopkins University. The work was supported by the National Institute of General Medical Sciences (grant numbers GM28007, GM34933 and GM71920) and a Harold L. Plotnick Fellowship from the Damon Runyon Cancer Research Foundation
Abstract in Cell Reports: "The Directional Response of Chemotactic Cells Depends on a Balance between Cytoskeletal Architecture and the External Gradient"
•Polarized sensitivity to chemoattractants is independent of cytoskeletal dynamics
•Threshold for response is correlated with static F-actin distribution
•Immobilized cells retain characteristic responses to spatial and temporal stimuli
•Overall directional response depends on gradient and internal polarity
Polarized migrating cells display signal transduction events, such as activation of phosphatidylinositol 3-kinase (PI3K) and Scar/Wave, and respond more readily to chemotactic stimuli at the leading edge. We sought to determine the basis of this polarized sensitivity. Inhibiting actin polymerization leads to uniform sensitivity. However, when human neutrophils were “stalled” by simultaneously blocking actin and myosin dynamics, they maintained the gradient of responsiveness to chemoattractant and also displayed noise-driven PIP3 flashes on the basal membrane, localized toward the front. Thus, polarized sensitivity does not require migration or cytoskeletal dynamics. The threshold for response is correlated with the static F-actin distribution, but not cell shape or volume changes, membrane fluidity, or the preexisting distribution of PI3K. The kinetics of responses to temporal and spatial stimuli were consistent with the local excitation global inhibition model, but the overall direction of the response was biased by the internal axis of polarity.
Other authors on the Cell Reports paper are Wenjie Cai and Pablo Iglesias of The Johns Hopkins University. The study was funded by the National Institute of General Medical Sciences (grant numbers GM28007 and GM34933) and the National Natural Science Foundation of China (grant numbers 81000045 and 81000939).
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