Epithelial-Mesenchymal Plasticity and Endothelial-Mesenchymal Transition in Cutaneous Wound Healing

Epithelial and endothelial cells possess the inherent plasticity to undergo morphological, cellular, and molecular changes leading to their resemblance of mesenchymal cells. A prevailing notion has been that cutaneous wound reepithelialization involves partial epithelial-to-mesenchymal transition (EMT) of wound-edge epidermal cells to enable their transition from a stationary state to a migratory state. In this review, we reflect on past findings that led to this notion and discuss recent studies that suggest a refined view, focusing predominantly on in vivo results using mammalian excisional wound models. We highlight the concept of epithelial-mesenchymal plasticity (EMP), which emphasizes a reversible conversion of epithelial cells across multiple intermediate states within the epithelial-mesenchymal spectrum, and discuss the critical importance of restricting EMT for effective wound reepithelialization. We also outline the current state of knowledge on EMP in pathological wound healing, and on endothelial-to-mesenchymal transition (EndMT), a process similar to EMT, as a possible mechanism contributing to wound fibrosis and scar formation. Harnessing epithelial/endothelial-mesenchymal plasticity may unravel opportunities for developing new therapeutics to treat human wound healing pathologies.