Jag2 patterns early differentiation in the epidermal stem cell layer

ABSTRACT Adult stem cell function depends on continuous input from the surrounding microenvironment. However, the cues that pattern this function in high turnover tissue that undergo continuous cellular remodeling remain poorly understood. Here we demonstrate that inputs from epithelial neighbors at distinct stages of differentiation cooperatively influence cell fate in the skin epidermis. Stem cells initiate differentiation of their neighbors via the Notch ligand Jag2, linking fate decisions to the composition of the local stem cell environment. When this signal is lost, misoriented divisions and engagement with distinct ligands in the suprabasal layers can partially restore upward flux differentiating cells. Although these mechanisms help to sustain barrier function, they ultimately disrupt tissue architecture, underscoring the need for balanced fates in the stem cell compartment. Together, our findings demonstrate that distinct cellular environments reinforce early epidermal differentiation, with stem cells themselves acting as key mediators of cell fate and tissue organization.