Abstract
SummaryCollective behavior emerges in diverse life machineries, e.g., the immune responses to dynamic stimulations. The essential questions that arise here are that whether and how cells in vivo collectively respond to stimulation frequencies higher than their intrinsic natural values, e.g., the acute inflammation conditions. In this work, we systematically studied morphological and signaling responses of population fibroblasts in an interconnected cell monolayer and uncovered that, besides the natural NF-κB oscillation frequency of 1/90 min−1, collective signaling response emerges in the cell monolayer at 1/20 min−1 TNF-α input periodicity as well. Using a customized microfluidic device, we independently induced dynamic chemical stimulation and cytoskeleton reorganization on the stand-alone cells to exclude the effect of cell-cell communication. Our results reveal that, at this particular frequency, chemical stimulation is translated into dynamic intracellular mechanical cues through RAC1-medicated induction of dynamic cell-cell connections and cytoskeleton reorganizations, which synergize with chemical input to facilitate collective signaling responses.
Highlights
Collective behavior is the outcome of interactions among individual cells
At this particular frequency, chemical stimulation is translated into dynamic intracellular mechanical cues through RAC1-medicated induction of dynamic cell-cell connections and cytoskeleton reorganizations, which synergize with chemical input to facilitate collective signaling responses
We studied the effects of dynamic intracellular mechanical cues, which result from the collective morphological responses, on the signaling activities of population cells in an interconnected cell monolayer (ICM)
Summary
Collective behavior is the outcome of interactions among individual cells. The short-range cell-cell and cellextracellular matrix (ECM) interactions allow the living tissues to undergo drastic behavioral transitions for biological functions such as migration, embryogenesis, and tumorigenesis (Roure et al, 2005; Lecaudey and Gilmour, 2006; Friedl and Wolf, 2003). In the crowded cellular environment of biological tissues, the local tissue architecture (Box et al, 2019) and the motion and deformation dynamics of individual cells (Pan et al, 2016) generate propagating physical signals, which affect intracellular signaling cascades. The fibroblast-collagen matrix can set free soluble cytokines under external mechanical actuations, which activate intra-cellular signaling pathways (Wells and Discher, 2008). These results indicate that dynamic mechanical cues resulting from inter-cell interactions can affect the intra-cellular activities. How mechanical cues facilitate population cells adapting to the ever-changing chemical environment and the correlation between collective cellular behaviors and optimal tissue functions remain unexplored
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