Reconstructed cell-cell interfaces with spatially defined mechanical and molecular components: biomimetic microenvironments to elucidate how extracellular mechanochemical signals are sensed and transmitted at the intercellular junctions

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Cells in the epithelium establish intimate contact with their neighbors at molecular and mechanical level through the intercellular junctions. During the formation of stratified epithelium, like the skin epidermis, intercellular junctions in keratinocytes undergo a dynamic rearrangement in their spatial distribution, accompanied by reorganization of the actin cytoskeleton and the consequent changes in the epithelial cell tension. To which extent the mechanical and/or molecular components at the intercellular junctions, or the coordination of both, primarily drive differentiation of keratinocytes into the several suprabasal layers of the epidermis is not clearly understood. The 3D distribution of the junctional proteins and associated intracellular structures is crucial for polarization and formation of stratified epithelium, but is very hard to capture in classical culture models. Refining our ability to mimic the cell-cell interfaces in keratinocytes, which are specific for the different layers in the epidermis, will facilitate our progress in understanding cell junction biology. This project will investigate the external signals integrated by intercellular junctions that trigger and support keratinocyte differentiation and formation of functional stratified skin epithelium. For this purpose, a reductionist mimetic model of the keratinocyte intercellular interface, able to capture relevant molecular and mechanical cues and form intercellular-like junctions, will be developed. These model microenvironments will be customized to reconstruct the specific cellular microenvironment of keratinocytes within the different layers of stratified skin epithelium, including the polarity in the distribution of intercellular junctions. With this platform we will investigate how mechanical and chemical signals are integrated by adherens junctions and desmosomes, and how these cues regulate keratinocyte differentiation. By precisely regulating the distribution of intercellular adhesion interfaces, the density of adhesive ligands on these interfaces, and their mechanical properties we can start to decipher how each of these parameters contribute to epidermal morphogenesis.