Spatial-temporal dynamics of collective chemosensing

Abstract

Although the process of chemosensing by individual cells is intrisically stochastic, multicellular organisms exhibit highly regulated responses to external stimulations. Two key elements to understand the deterministic features of chemosensing are intercellular communications and the role of pacemaker cells. To characterize the collective behavior induced by these two factors, we study the spatial-temporal calcium dynamics of fibroblast cells in response to ATP stimulation. We find that closely packed cell colonies exhibit faster, more synchronized, and highly correlated responses compared to isolated cells. In addition, we demonstrate for chemosensing the existence of pacemaker cells and how the presence of gap junctions impact the first step of the collective response. By further comparing these results with the calcium dynamics of cells embedded in thin hydrogel films, where intercellular communication is only possible via diffusing molecules, we conclude that gap junctions are required for synchronized and highly correlated responses among cells in high density colonies. In addition, in high density cell colonies, both communication channels lead to calcium oscillations following the stimulation by external ATP. While the calcium oscillations associated with cells directly exposed to external flows were transient, the oscillations of hydrogel trapped cells can persist with a fundamental frequency and higher harmonics. Our observations and measurements highlight the crucial role of intercellular signaling for generating regulated spatial and temporal dynamics in cell colonies and tissues. emergent behavior | cell signaling C ells constantly sense their local chemical environment and make decisions based upon the information received. This process, known as chemosensing, is intrinsically stochastic. Not only do the chemical perturbations fluctuate in space and time, but even for uniform stimulations, the responses vary significantly from cell to cell (1). Despite this variability, multicellular organisms are capable of performing highly regulated, consistent responses, which are crucial to maintain the normal functionality of complex life systems (2).Achieving coordinated collective responses requires individual cells to exchange information with each other within the population. For example, in the process of quorum-sensing, bacteria synthesize and secrete signaling molecules into the extracellular space. Once the concentration of the molecules, which encodes information of cell density, reaches a threshold value, bacteria transform to a different state thus generating collective behavior (3). Similarly, when a population of the social amoebae Dictyostelium discoideum is stimulated by external cAMP (cyclic adenosine 3,5-monophosphate), more cAMP is released by each cell into the extracellular space. Because Dictyostelium undergoes quiescent to oscillatory transitions as a function of external cAMP concentration, the collective response of Dictyostelium to cAMP can be dramatically different from the response o...

Dynamic Sampling and Information Encoding in Biochemical Networks

“…Because the model is minimal, we anticipate that it can be extended to answer more general questions about information encoding on a large, multicellular scale. This is particularly desirable, as understanding collective information processing is a new frontier in systems biophysics (19,23,27,(32)(33)(34). On the other hand, many interesting questions, such as the precise functional form of MI v ðnÞ and the dependence of mutual information on nonlinear effects such as feedback, bifurcations, and coupling of multiple timescales, may require more realistic models beyond noisy harmonic oscillators.…”

“…To measure the calcium dynamics of fibroblast cells in response to external ATP stimuli, we employ microfluidic devices for cell culture and solution delivery as described previously (19,23). In brief, NIH 3T3 cells (ATCC, Manassas, VA) are cultured in polydimethylsiloxane (PDMS)-bounded flow channels, as shown in record fluorescent images of the cell monolayer at 1 Hz for a total of 10 min (Flash 2.8, Hamamatsu Photonics).…”

“…The samples were prepared according to previously reported protocol (19). Briefly, NIH 3T3 cells were cultured in standard growth media (Dulbecco's modified Eagle's medium supplemented with 10% bovine calf serum and 1% penicillin).…”

Quantifying collective behavior in mammalian cells

“…The elegant experiments of Sun et al (1) demonstrate that fibroblasts exhibit collective chemosensing in which the spatial and temporal characteristics depend on cell density and connectivity. These similarities to social behavior in unicellular organisms suggest other factors, such as population size (4), that may influence collective chemosensing in fibroblasts.…”

“…Understanding the role of intercellular communications for collective behavior in mammalian cells thus demands sensitive measurements of responses to chemical signals. In PNAS, Sun et al (1) quantify the spatiotemporal evolution of calcium response to ATP stimulation in fibroblasts. They find that the response of dense colonies of cells to ATP stimulation is faster and more synchronized than that of isolated cells.…”