Mechanical input shapes cell fate decisions during development and regeneration in many systems, yet the mechanisms of this cross-talk are often unclear. In regenerating Hydra tissue spheroids, periodic osmotically driven inflation and deflation cycles generate mechanical stimuli in the form of tissue stretching. Here, we demonstrate that tissue stretching during inflation is important for the appearance of the head organizer—a group of cells that secrete the Wnt3 ligand. Exploiting time series RNA expression profiles, we identify the up-regulation of Wnt signaling as a key readout of the mechanical input. In this system, the levels of Wnt3 expression correspond to the levels of stretching, and Wnt3 overexpression alone enables successful regeneration in the absence of mechanical stimulation. Our findings enable the incorporation of mechanical signals in the framework of Hydra patterning and highlight the broad significance of mechanochemical feedback loops for patterning epithelial lumens.