A Predictive Model for Coupling Cell Division Orientation to Tissue Mechanics During Epithelial Morphogenesis

Stratified epithelial tissues such as the skin epidermis maintain barrier integrity through coordinated cell proliferation, differentiation or delamination, and tissue-scale mechanical forces. During development, the orientation of basal cell divisions governs whether daughter cells remain attached to the basement membrane or delaminate, yet the mechanical principles linking the orientation of division plane to stratification remain unclear. Here, we extend a three-dimensional vertex model of stratified epithelia, comprising the basement membrane, basal, and suprabasal layers to explore how division-plane orientation shapes epidermal architecture. The model incorporates developmental stage–specific changes in heterotypic interfacial tensions (arising from actomyosin contractility and adhesion at the basal-suprabasal interface) and wetting tensions (from integrin-mediated adhesions at the basal–basement interface) that have been quantified previously in experiments. By systematically varying these mechanical parameters, we investigate how wetting, heterotypic tension, orientation, and tissue fluidity collectively influence the outcome of cell division. This framework aims to reveal strategies by which the embryo generates stratified phenotypes across developmental stages and can be extended to study how altered division orientation contributes to epithelial cell transformation in cancer.