Network Characteristics of Collective Chemosensing

Bo Sun, Guillaume Duclos, and Howard A. Stone

Phys. Rev. Lett. 110, 158103 – Published 9 April 2013

Abstract

The collective chemosensing of nonexcitable mammalian cells involves a biochemical network that features gap junction communications and heterogeneous single cell activities. To understand the integrated multicellular chemosensing, we study the calcium dynamics of micropatterned fibroblast cell colonies in response to adenosine triphosphate (ATP) stimulation. We find that the cross-correlation function between the responses of individual cells decays with topological distance as a power law for large colonies and much faster for smaller colonies. Furthermore, the strongly correlated cell pairs tend to form clusters and are more likely to exceed the percolation threshold. At a given topological distance, the cross-correlations exhibit characteristics of Poisson distributions, which allows us to estimate the unitary conductance of a single gap junction which is in good agreement with direct experimental measurements.

Received 29 November 2012

DOI:https://doi.org/10.1103/PhysRevLett.110.158103

Authors & Affiliations

Bo Sun^1,*, Guillaume Duclos², and Howard A. Stone¹

¹Department of Mechanical and Aerospace Engineering, Princeton University, Princeton, New Jersey 08544, USA
²Physico-Chimie Curie, Centre National de la Recherche Scientifique, UMR 168, Institut Curie, 26, rue d’Ulm, F-75248 Paris Cedex 05, France

^*Present address: Department of Physics, Oregon State University, Corvallis, Oregon 97331, USA.

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Vol. 110, Iss. 15 — 12 April 2013

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Images

Figure 1
The experiment setup. (a) Flow devices were made by sealing micropatterned glass and PDMS channels. By using photolithography, cell repellent (interpenetrated polyethylene glycol and acrylamide) and cell adhesive (gelatin) proteins are coated on the glass substrates with a desired geometry. (b) Representative response curves obtained by averaging fluorescent intensity of 40 pixels for each cell on each frame. The small transient calcium increase due to flow perturbations has relaxed before the arrival of ATP (vertical dashed line) and only the subsequent ATP-induced calcium dynamics is analyzed. (c), (d) Typical fluorescent images of a continuous cell sheet and colonies of finite size. Scale bar $100 μ m$ .Reuse & Permissions
Figure 2
The mean cross-correlations vary with topological distances. (a) The triangulation based on cell locations defines the topological distance between cells. Examples of cell pairs with topological distances $D$ ranging from 1 to 3 are linked in different colors. For clarity, only a few links of $D > 1$ are shown. (b) The normalized histogram of cross-correlations for a typical experiment (continuous sheet, $[ATP] = 100 μ M$ ). 3000 cell pairs for each topological distance were used for each histogram. (c) The mean cross-correlations decay as $D$ increases. At least 3 independent experiments were conducted for each condition (colony geometry and [ATP]), and $\sim 3000$ pairs are sampled to calculate the mean cross-correlations. (d) At moderate [ATP], mean cross-correlations that decay with topological distance can be fit with power-law functions ( $RMSD < 0.005$ ). Legend abbreviations: $x μ M$ , [ATP]; contin., continuous cell sheet; pacid, treatment with palmitolic acid; $y μ m$ , edge dimensions of cell colonies with square a geometry.Reuse & Permissions
Figure 3
The cluster distribution of strong correlators for cutoff fraction $q = 0.15$ . (a) The probability $P (s > x)$ of a cell belonging to a cluster larger than size $x$ , where $x$ is the number of cells in a cluster formed by linking strong correlators. At least 3 experiments at each given [ATP] were used to obtain the average probabilities. For each experiment, 2000 realizations of its corresponding reference network were simulated and averaged to obtain the reference probability distributions $P_{ref}$ . For continuous monolayers, and given cutoff fraction, $P_{ref}$ only depends weakly on [ATP]. (b) The deviation of probability distributions between experimental networks and their corresponding reference graphs $P_{\exp } - P_{ref}$ for continuous cell sheets at different [ATP]. (c), (d) The probability distributions and the difference between experiment and their corresponding reference networks for finite-sized colonies stimulated with $100 μ M$ ATP. Legend abbreviations: as in Fig. 2; exp., experimental results; ref., simulation results of reference networks.Reuse & Permissions
Figure 4
The statistics of cross-correlations. Means and variances of nearest-neighbor cross-correlations (filled symbols) for different ATP concentrations and colony sizes fall near a line $y = 0.3 x$ . Cross-correlations of larger topological distances (empty symbols) scatter around the same line. Each point is calculated from $\sim 3000$ cell pairs from at least 3 experiments of each given condition. Legend abbreviations are the same as in Fig. 2.Reuse & Permissions

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