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Dynamic intracellular mechanical cues facilitate collective signaling responses.

ABSTRACT: Collective 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.

SUBMITTER: Che B

PROVIDER: S-EPMC8091894 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Dynamic intracellular mechanical cues facilitate collective signaling responses.

Che Bingchen B Zhao Wei W Liu Yanan Y Sun Dan D Jing Guangyin G Bai Jintao J Feng Xiqiao X Zhang Ce C

iScience 20210403 5

Collective 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 <i>in vivo</i> 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 ...[more]

PMID: 33997681

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Project description:Cadherin-based adherens junctions and desmosomes help stabilize cell-cell contacts with additional function in mechano-signaling, while clustered protocadherin junctions are responsible for directing neuronal circuits assembly. Structural models for adherens junctions formed by epithelial cadherin (CDH1) proteins indicate that their long, curved ectodomains arrange to form a periodic, two-dimensional lattice stabilized by tip-to-tip trans interactions (across junction) and lateral cis contacts. Less is known about the exact architecture of desmosomes, but desmoglein (DSG) and desmocollin (DSC) cadherin proteins are also thought to form ordered junctions. In contrast, clustered protocadherin (PCDH)-based cell-cell contacts in neuronal tissues are thought to be responsible for self-recognition and avoidance, and structural models for clustered PCDH junctions show a linear arrangement in which their long and straight ectodomains form antiparallel overlapped trans complexes. Here, we report all-atom molecular dynamics simulations testing the mechanics of minimalistic adhesive junctions formed by CDH1, DSG2 coupled to DSC1, and PCDHγB4, with systems encompassing up to 3.7 million atoms. Simulations generally predict a favored shearing pathway for the adherens junction model and a two-phased elastic response to tensile forces for the adhesive adherens junction and the desmosome models. Complexes within these junctions first unbend at low tensile force and then become stiff to unbind without unfolding. However, cis interactions in both the CDH1 and DSG2-DSC1 systems dictate varied mechanical responses of individual dimers within the junctions. Conversely, the clustered protocadherin PCDHγB4 junction lacks a distinct two-phased elastic response. Instead, applied tensile force strains trans interactions directly, as there is little unbending of monomers within the junction. Transient intermediates, influenced by new cis interactions, are observed after the main rupture event. We suggest that these collective, complex mechanical responses mediated by cis contacts facilitate distinct functions in robust cell-cell adhesion for classical cadherins and in self-avoidance signaling for clustered PCDHs.

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Dynamic intracellular mechanical cues facilitate collective signaling responses.

Publications

Dynamic intracellular mechanical cues facilitate collective signaling responses.

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