Abstract
Wound healing is a complex, multi-phase process that allows the skin to repair damage to the tissue and restore its protective barrier function. Although chronic and non-healing wounds are a major clinical problem, current treatment options are limited by a lack of mechanistic understanding of disease pathology. To gain new insights into the complex nature of the wound healing processes, our group has developed engineered model systems, which allow us to precisely control and study different components of the cellular microenvironment. We have combined micro-patterned surfaces with thiol-yne coupling reactions to create dynamically adhesive substrates on which cell migration can be controlled over both space and time. Using this system, we show that cross-talk between adhesive cues from extracellular matrix and cell-cell interactions dynamically regulate the directionality and collective migration of epithelia. Moreover, the elasticity of the underlying matrix plays an important role in regulating human keratinocyte migration and proliferation, key processes for wound re-epithelialisation. Downstream of these external cues, the actin cytoskeleton and serum response factor signaling as central mediators in the mechanical regulation of keratinocyte growth, migration, and terminal differentiation. Together, these studies provide new insights into the mechanisms by which physical and mechanical forces regulate cell function within the skin and have important implications for wound healing and tissue repair.