Local mechanical heterogeneity drives epidermal cell delamination

Delamination within stratified epithelia like the skin epidermis describes the detachment and upward motion of cells originating from the basal layer. Despite its fundamental importance for tissue development, homeostatic regeneration and repair, the mechanisms that drive delamination remain a longstanding open question. Upward motion follows cell shape changes, which are inherently driven by physical forces, but their role is elusive. Here, we investigate delamination in stratifying keratinocytes by combining imaging, force measurements and theoretical modeling. We identify a local change in force balance between differentiating cells and their environment as the key step initiating delamination. Within a homogeneous cell layer with apically polarized contractility, differentiation leads to actomyosin remodeling, redistributing cellular force exertion to the basal side. Such mechanical heterogeneity then results in differentiating cells experiencing and inward basal and outward apical forces that manifest in the formation of a +1 force defect and promote shape changes culminating in upward motion. Simultaneously, delaminating cells actively pull on their underlying neighbors, generating convergent tissue flows which close the basal layer below. Together, we propose a general physical description of delamination initiation, which may act across various multilayered epithelia.