Cell-cell communication, which enables cells to coordinate their activity and is essential for growth, development and function, is usually ascribed a chemical or electrical origin. However, cells can exert forces and respond to environment elasticity and to mechanical deformations created by their neighbours 1-13 . The extent to which this mechanosensing ability facilitates intercellular communication remains unclear. Here we demonstrate mechanical communication between cells directly for the first time, providing evidence for a long-range interaction that induces long-lasting alterations in interacting cells. We show that an isolated cardiac cell can be trained to beat at a given frequency by mechanically stimulating the underlying substrate. Deformations are induced using an oscillatory mechanical probe that mimics the deformations generated by a beating neighbouring cardiac cell. Unlike electrical field stimulation, the probe-induced beating rate is maintained by the cell for an hour after the stimulation stops, implying that long-term modifications occur within the cell. These long-term alterations provide a mechanism for cells that communicate mechanically to be less variable in their electromechanical delay. Mechanical coupling between cells therefore ensures that the final outcome of action potential pacing is synchronized beating. We further show that the contractile machinery is essential for mechanical communication.Here we sought to separate the mechanical component of intercellular communication from indirect effects, such as a change in the amount or type of secreted chemo-attractants. We did so by introducing a 'mechanical cell' . The 'mechanical cell' consists of a probe that mimics the mechanical aspect of a cell by generating substrate deformations identical to the ones induced by a neighbouring beating cell. Previous studies have shown that mechanical stimulation of a quiescent cell or an engineered cardiac construct can induce beating 12,14 . However, in those studies, the magnitude and direction of forces applied were not controlled as to mimic the magnitude and direction of forces applied by cells. In addition, the duration of stimulation was extremely brief and the cells did not synchronize with the probe. These studies therefore did not provide a demonstration or characterization of cellular mechanical communication.Here, we use a 'mechanical cell' to apply deformations identical to those generated by an aligned beating cardiac cell both in magnitude and in directionality. We show that such deformations can synchronize cell beating. This provides clear evidence for mechanical cellular communication. Training of both quiescent and spontaneously beating cells takes up to 10-15 min and the induced beating frequency persists for over an hour after stimulation had stopped. These results demonstrate that mechanical communication is a unique type of interaction that is both long ranged and induces long-lasting alterations in interacting cells. We further demonstrate that mechanical communication...
Highlights d The mechanical properties of the chordotonal organ are altered in Pericardin mutants d Loss of Pericardin drives a transition from compression to bending in the cap cell d Compressive strain within the cap cell is essential for proper sensing d The results can be interpreted using a simplified model of an elastic beam
Summary Cells can communicate mechanically by responding to mechanical deformations generated by their neighbors. Here, we describe a new role for mechanical communication by demonstrating that mechanical coupling between cells acts as a signaling cue that reduces intrinsic noise in the interacting cells. We measure mechanical interaction between beating cardiac cells cultured on a patterned flexible substrate and find that beat-to-beat variability decays exponentially with coupling strength. To demonstrate that such noise reduction is indeed a direct consequence of mechanical coupling, we reproduce the exponential decay in an assay where a beating cell interacts mechanically with an artificial stochastic ‘mechanical cell’. The mechanical cell consists of a probe that mimics the deformations generated by a stochastically beating neighboring cardiac cell. We show that noise reduction through mechanical coupling persists long after stimulation stops and identify microtubule integrity, NOX2, and CaMKII as mediators of noise reduction.
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