Preconditioned skin cells enable faster and more effective wound healing

It is well known that students who prepare in advance perform better on exams. Now, it appears that the skin can do the same.

Rather than scrambling to repair itself only after injury occurs, a Korean research team has demonstrated that preconditioning a subset of skin cells into a "ready state" enables the tissue to initiate rapid and effective healing immediately upon injury.

A collaborative study led by Professor Sekyu Choi at POSTECH (Pohang University of Science and Technology), alongside Professor Jong Kyoung Kim, and researchers Minjun Kwak, Eunjun Choi, Yemin Jo, together with collaborators from the Institute for Basic Science, the Catholic University of Korea, and the University of Washington, reveals how partial cellular reprogramming of skin epidermal cells reshapes surrounding cells and the tissue microenvironment to accelerate wound healing. The findings were published in Nature Communications.

The skin, the body's outermost barrier, is constantly exposed to injury. While minor wounds typically heal within days in healthy individuals, healing can take months-or fail entirely-in elderly patients or those with conditions such as diabetes. To address this challenge, regenerative medicine is increasingly turning to cellular reprogramming.

This process commonly relies on four proteins known as the Yamanaka factors(Oct4, Sox2, Klf4, and c-Myc), which can revert cells to an embryonic-like state. However, fully reprogrammed cells carry a major drawback: uncontrolled growth and dedifferentiation, raising the risk of tumor formation and limiting clinical applicability.

Rather than full reprogramming, the team adopted a more restrained approach-what they describe as a "gentle rewind." Crucially, they applied this selectively to a subset of cells. Instead of exposing all cells to the four transcription factors, only a limited number were targeted-and even these were not fully reset, but merely shifted into a slightly more youthful state. This strategy, termed mosaic partial reprogramming, represents a deliberately cautious, dual-layered intervention that both limits the number of targeted cells and moderates the extent of reprogramming.

In animal models, even in the absence of injury, the skin entered a "pre-regenerative mode." Not only the reprogrammed cells, but also neighboring normal cells, immune cells, and the broader tissue microenvironment began to change. This coordinated response was driven by activation of key signaling pathways-including PI3K-AKT, EGFR, and HIF-1α-which are central to cell survival, growth, and adaptation to hypoxic conditions. In effect, cells were signaling to one another: "An injury may be coming-let's prepare."

When wounds were subsequently introduced, the benefits became even more pronounced. New epithelial layers formed more rapidly, blood vessel growth and immune responses were more precisely regulated, and overall healing accelerated. Scarring was also reduced. Notably, these improvements were observed even under diabetic conditions, where wound healing is typically impaired.

"This study is the first to show that manipulating only a fraction of cells can reshape the state of the skin tissue as a whole through intercellular communication," said Professor Choi. First author Minjun Kwak added, "Our findings could lay the groundwork not only for therapies targeting chronic wounds in diabetic or elderly patients, but also for anti-aging technologies and the development of regenerative medicines and biomaterials."

The research was supported by the Artificial Blastema Cell-based Regenerative BioTherapeutics Program (Ministry of Science and ICT and the Ministry of Health and Welfare) (), the Excellent Young Researchers Program, the Basic Research Program, the Development of Immune Mechanism Control Technology Program, and the ATLAS-Based Stem Cell Therapy Development Project for Intractable Diseases (Ministry of Science and ICT).