Necessary for Complete Skin Regeneration - Study Using Unique Fetal Mice Model

Regeneration constitutes one of the most critical areas of contemporary medicine. In highly developed organisms such as mammals, when an adult animal sustains a skin injury, the structure rarely undergoes complete regeneration during the healing process, resulting in scar formation. Presently, there exists no clinical methodology to entirely restore scar tissue to its original condition. Conversely, fetal skin wounds can regenerate up to a specific developmental stage without leaving scars. Consequently, there has been considerable interest in identifying the developmental stage during late fetal growth at which the skin loses its capacity for complete regeneration, transitioning instead to a scarring phenotype akin to that of adult mammals. By concentrating on the regeneration of skin texture and dermal structures, we successfully delineated, for the first time, the transition point of wound healing from the fetal to the adult phenotype. Our findings revealed that wounds inflicted before embryonic day (E) ۱۳ achieved full regeneration of the three-dimensional texture, a process that involved the formation of actin cables at the wound margins. However, wounds sustained after E۱۴ failed to regenerate the skin texture. Additionally, we observed that complete regeneration, as seen in E۱۳, necessitates that the wound closes without disrupting the positional relationship between the epidermis and dermis. While dermal structures regenerate up to E۱۶, wounds incurred post-E۱۷ heal as scars characterized by dermal fibrosis and a lack of skin appendages, similar to adult wounds. Thus, to achieve complete skin regeneration akin to early embryonic stages, it is essential to stimulate the interaction between the epidermis and dermis alongside the formation of actin cable on the edge of the wound in later stage. Recently, we have managed to regulate scar formation within the uterus by modulating the activity of Rac۱ and AMP-activated protein kinase (AMPK)—molecules integral to cell migration and actin dynamics—through pharmacological administration or genetic manipulation, thereby inducing the formation of actin cables. Moreover, we have been identifying genes, cellular populations, and signaling pathways involved in complete skin regeneration and scarring via comprehensive genetic analyses or single-cell transcriptome analysis. Our discoveries may pave the way for future treatments aimed at achieving complete skin regeneration without scarring.