Superhero scarless skin

Dr. Thomas Leung’s lab recently published an exciting paper in Science Immunology highlighting the nerve-skin-immune axis and its role in scarring and regeneration. Dr. Leung was supported by an SBDRC P&F Grant and utilized several of the Cores for the work. Below, we had the opportunity to learn about motivation for the work, current status, and future directions directly from Dr. Leung.

Everyone pictures a salamander regenerating an arm or tail, but human organ regeneration remains an aspiration only realized in superhero comic books and movies. Human skin wounds generally heal with a scar, where fibrous tissue replaces the lost original tissue and causes destruction of associated tissue structures; human scars are firm and never exhibit hair. More than 100 million new skin scars appear annually, and no treatments prevent or reduce scar formation. In addition to the loss of the original tissue function, some scars also cause significant functional impairment, for example keloid scars, burn scars, and scars over joints, and result in clinically significant mental health distress. Successful human skin regeneration would result in scarless skin healing and return of full tissue function and mental well-being. We recently discovered a novel signaling pathway in mammals, involving nerve-to-immune cell-to-skin communication, that reduces scar formation and promotes skin regeneration.

We discovered that activation of the transient receptor protein A1 (TRPA1) on skin nerves reduces scar formation and promotes tissue regeneration in 3 different mouse models of wounding. Moreover, local activation of TRPA1 promoted tissue regeneration on distant injured skin, suggesting a systemic effect. We demonstrated that activation of this receptor on skin nerves stimulates a signaling cascade that culminates in the recruitment of a unique population of immune cells, γδ T-cells, to the wounded area. Absence of γδ T-cells prevented TRPA1-mediated scar reduction and tissue regeneration, indicating that these cells are critically involved in this process.

We are translating these findings and running a clinical trial to test whether this pathway reduces scar formation in humans. We screened known drugs and compounds for one that activates TRPA1. We discovered that imiquimod cream, an FDA-approved topical drug already used in medical clinics to treat skin cancer and warts, activates TRPA1. We are designing a clinical trial to test if topical 5% imiquimod cream reduces the recurrence of pathological scars (e.g., keloid scars).