A biomechanical switch regulates the transition towards homeostasis in oesophageal epithelium

Epithelial cells rapidly adapt their behaviour in response to increasing tissue demands. However, the processes that finely control these cell decisions remain largely unknown. The postnatal period covering the transition between early tissue expansion and the establishment of adult homeostasis provides a convenient model with which to explore this question. Here, we demonstrate that the onset of homeostasis in the epithelium of the mouse oesophagus is guided by the progressive build-up of mechanical strain at the organ level. Single-cell RNA sequencing and whole-organ stretching experiments revealed that the mechanical stress experienced by the growing oesophagus triggers the emergence of a bright Krüppel-like factor 4 (KLF4) committed basal population, which balances cell proliferation and marks the transition towards homeostasis in a yes-associated protein (YAP)-dependent manner. Our results point to a simple mechanism whereby mechanical changes experienced at the whole-tissue level are integrated with those sensed at the cellular level to control epithelial cell fate.