Stress vesicles link epidermal mechanotransduction to stem cell differentiation

The skin exhibits extraordinary plasticity, enabling it to adapt to mechanical changes in the environment. While transient deformations are accommodated without lasting structural effects, sustained mechanical stress induces durable tissue changes. To investigate if these responses are mediated by shifts in epidermal stem cell fate, we employed two-photon intravital imaging to visualize epidermal cells in live skin subjected to acute mechanical forces. Mechanical force triggered the formation of intracellular "stress" vesicles within epidermal stem cells that filled with extracellular fluid and progressively enlarged, deforming the nucleus. Lineage tracing analyses revealed that the extent of nuclear deformation can predict cell fate outcomes. Moreover, mechanical stress caused sustained elevation of intracellular calcium in basal epidermal stem cells, and conditional deletion of the mechanosensitive ion channel Piezo1 disrupted calcium dynamics and increased stress vesicle formation. Using human skin xenografts, we demonstrated that stress vesicles are conserved in mammalian skin. Together, these findings identify stress vesicles as key mediators linking mechanical stress, calcium signaling, and epidermal stem cell fate.