Modulating Cellular Responses to Mechanical Forces to Promote Wound Regeneration

Significance: Skin scarring poses a major biomedical burden for hundreds of millions of patients annually. However, this burden could be mitigated by therapies that promote wound regeneration, with full recovery of skin's normal adnexa, matrix ultrastructure, and mechanical strength. Recent Advances: The observation of wound regeneration in several mouse models suggests a retained capacity for postnatal mammalian skin to regenerate under the right conditions. Mechanical forces are a major contributor to skin fibrosis and a prime target for devices and therapeutics that could promote skin regeneration. Critical Issues: Wound-induced hair neogenesis, Acomys "spiny" mice, Murphy Roths Large mice, and mice treated with mechanotransduction inhibitors all show various degrees of wound regeneration. Comparison of regenerating wounds in these models against scarring wounds reveals differences in extracellular matrix interactions and in mechanosensitive activation of key signaling pathways, including Wnt, Sonic hedgehog, focal adhesion kinase, and Yes-associated protein. The advent of single-cell "omics" technologies has deepened this understanding and revealed that regeneration may recapitulate development in certain contexts, although it is unknown whether these mechanisms are relevant to healing in tight-skinned animals such as humans. Future Directions: While early findings in mice are promising, comparison across model systems is needed to resolve conflicting mechanisms and to identify conserved master regulators of skin regeneration. There also remains a dire need for studies on mechanomodulation of wounds in large, tight-skinned animals, such as red Duroc pigs, which better approximate human wound healing.