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

TL;DR

Partially reprogramming some skin cells in mice improves healing by changing nearby cells and their environment.

Contribution

Mosaic partial reprogramming of the epidermis enhances skin repair by influencing neighboring cells and niches.

Findings

Mosaic reprogramming of epidermal cells promotes healing even without injury.

Wound healing is accelerated in both healthy and hyperglycemic mouse models.

Dermal healing shows reduced scarring and altered blood vessel formation.

Abstract

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.

Here, the authors show that transient, mosaic induction of Yamanaka factors in the epidermis can promote skin repair beyond reprogramming cells. They also influence neighboring epithelial cells and immune–mesenchymal niches by reshaping injury response programs.

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