Researchers have determined a way to potentially minimize or eliminate scarring in wounded skin, by further decoding the scar-promoting role of a specific class of dermal fibroblast cells in mice. By preventing these cells from expressing the transcription factor Engrailed-1 (En-1), Shamik Mascharak and colleagues reprogrammed these cells to take on a different identity, capable of regenerating wounded skin - including the restoration of structures such as hair follicles and sweat glands that are absent in scarred skin tissue. With further development and testing, their discovery could lead to therapies to reduce or completely avoid scarring in human patients. Fibroblast cells that express En-1 - called Engrailed-1 lineage-positive fibroblasts (EPFs) - have been implicated in scar formation, but the precise underlying mechanisms have remained unknown. Mascharak et al. noted that, while the progenitor cells of EPFs do not express En-1 in newborn and infant mice, fully functional EPFs are a known feature of skin wounds in adult mammals. Accordingly, they set out to determine whether EPFs proliferate in mammals as they age, or whether they expand locally at wound sites in response to new damage. Through a series of cell transplantation and genetic tracing experiments to explore the expression of En-1 in wounded mouse skin, Mascharak et al. found evidence for a closely related type of cells, called Engrailed-1 lineage-negative fibroblasts (ENFs), that do not express En-1. Mechanical signals activate the canonical Yes-associated protein (YAP) pathway in ENF cells, which in turn prompts the cells to begin expressing En-1, completing their transformation to scar-promoting EPF cells. By blocking the YAP pathway by either administering the inhibitor compound verteporfin or knocking out the YAP gene, Mascharak et al. encouraged these cells to retain their identity as ENFs, enabling the cells to rebuild the wounded skin, complete with regenerated sweat glands and hair follicles. "Tissue scarring is a leading cause of morbidity and mortality worldwide," note Piotr Konieczny and Shruti Naik in a related Focus. "The findings by Mascharak et al. thus hold great promise not only for [anti-scarring] therapies but also for the simultaneous activation of the skin's regenerative properties."