Tissue stiffening during the transition from wound healing to regenerative bud formation activates a Piezo1-Yap1 mechanosensitive cascade that translates mechanical signals into a transcriptional program conferring regenerative competence, and artificial activation of this cascade is sufficient to induce de novo regeneration in otherwise non-regenerative tissues.

Epimorphic regeneration encompasses several stages, such as wound healing, formation of a regenerative bud and regenerative outgrowth. The signatures that define each stage have been well studied, yet little is known about the mechanisms that coordinate cell state transitions across regenerative stages. Here, we show that stiffening of wounded epithelial tissues is essential for the formation of a prospective regenerative bud and, in turn, for the transition from wound healing to bud formation. Mechanistically, to detect prospective bud stiffening, cells use a mechanosensitive cascade involving Piezo1-dependent Yap1 activation. We also determined that this cascade is required for the acquisition of a transcriptional profile that endows bud cells with regenerative competence. Notably, the activation of this Piezo1-Yap1 mechanosensitive cascade in nonregenerative contexts is sufficient to induce the formation of competent bud-like structures, which are sufficient to drive de novo regeneration in these otherwise incompetent tissues. Taken together, our results reveal a mechanical state at the boundary between wound healing and regenerative bud formation, which is essential for synchronizing the transition between these pivotal stages of regeneration. More broadly, these findings support the general idea that the physical properties of tissues integrate with molecular frameworks to actuate cell state transitions during morphogenesis.