Mosaic partial epidermal reprogramming remodels neighbors and niches to refine skin homeostasis and repair

Adult stem cells and their niches communicate intricately for tissue maintenance and regeneration. However, effectively coordinating these complex interactions is challenging. Here, we demonstrate that transient dedifferentiation of a fraction of epithelial stem cell progenies orchestrates beneficial changes within the entire skin’s cellular networks to favor repair. We achieved this by inducing a mosaic and reversible expression of reprogramming factors (Oct-4, Sox2, Klf4, and c-Myc) in the mouse epidermis. This in vivo partial epidermal reprogramming not only affected the partially reprogrammed cells, but also their microenvironment, including neighboring epithelial cells and T cells, conferring widespread healing characteristics even in the absence of injury. When a wound was introduced, these collective changes accelerated re-epithelialization in both wild-type and a hyperglycemic mouse disease model. Furthermore, the effects extended to dermal healing, leading to reduced scarring and altered angiogenesis. In conclusion, our work reveals that mosaic partial reprogramming of the epidermis influences various cell types within the skin during homeostasis and repair, leading to enhanced cutaneous wound healing.