The Hippo pathway drives the cellular response to hydrostatic pressure

Cells need to rapidly integrate multiple mechanical and chemical stimuli in order to ensure precise context dependent responses. This requires dynamic cellular signalling that ensure homeostasis and plasticity when needed. A less well understood process is cellular response to elevated interstitial fluid pressure. Here using quantitative label-free digital holographic imaging, combined with genome editing, biochemistry and confocal imaging, we analyse the temporal cellular response to cyclic hydrostatic pressure. Upon elevated cyclic hydrostatic pressure, the cell responds by rapid, dramatic and reversible changes in cellular volume. We show that YAP/TAZ, the co-transcriptional regulators of the Hippo signalling pathway, control cell volume and that cells without YAP/TAZ have lower plasma membrane tension. YAP/TAZ drive the cellular response to hydrostatic pressure, a process that is at least partly mediated via clathrin-dependent endocytosis. Upon elevated oscillating hydrostatic pressure, YAP/TAZ are activated and induce TEAD mediated transcription of cellular components involved in dynamic regulation of cell volume and extracellular matrix. This cellular response confers a feedback loop that allows the cell to robustly respond to changes in interstitial fluid pressure.