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Leung Lab

Research Overview

Our group studies how injured tissues heal, and in some cases, how injured tissues regenerate without a scar. We have innovated new methods for studying wound healing and tissue regeneration in mice and humans. Based on our own findings, we are actively running clinical trials to bring these therapies to the clinic. Our group also studies inflammatory skin diseases. We are actively collecting human patient samples and performing genomics studies to understand the underlying pathophysiology of disease.

Mammalian Tissue Regeneration

Human skin wounds generally heal with fibrotic scars that disrupt tissue architecture and function. More than 100 million new skin scars appear annually, and scars may cause mental and physical morbidity (e.g., burn victims, scars over joints). Despite a multitude of products, no clinical trials have demonstrated effective scar reduction or prevention. Our lab aims to find ways to heal wounds without scar formation. 

Salamanders have been hailed as champions of regeneration, exhibiting a remarkable ability to regrow tissues, organs, and even whole body parts. Some of this ability have been retained in humans, as human livers can regenerate, and traumatic digit tip amputations in children also heal without scar formation. These examples suggest that the mechanisms driving scarless wound healing, though rarely active, still exist in humans, and we need to figure out ways to re-engage these pathways. Successful human skin regeneration would result in scarless skin healing and return of hair.

Our group and others established that ear hole closure and wound-induced hair neogenesis (WIHN) are two in vivo mouse models of skin injuries healing with scarless tissue regeneration. Punching small holes in the ear has been a classical method of identifying individual mice, because these holes never close and form scars (similar to a human ear-ring hole, left panels of figure). We and others have discovered some strains of mice where the holes close and heal completely with return of original tissue architecture (right panels of figure). WIHN is a model of adult mammalian tissue regeneration, where large wounds on mouse back skin heal with de novo formation of hair follicles, sebaceous glands, and fat. The newly regenerated hair follicles are complex tissues with multiple cell types and a distinct stem cell compartment.

Mouse Ear Regeneration Thomas Leung Lab Penn

We used lineage tracing mouse genetics to show that regenerated ear tissue derived from fate-restricted progenitor cells (each cell type replaced itself), and wounded skin cells express a signaling protein, SDF1, that abrogated this regenerative process. We showed that physiologic aging promotes skin regeneration and decreass scar formation. We used parabiosis (a technique to surgically join two mice together to share a common circulatory system) to demonstrate that age-dependent skin-derived SDF1 drives scar formation in young mice. These results may help explain why dermatologists and plastic surgeons have observed that surgical wounds in the elderly heal with thinner scars than wounds in young patients. 

Recently, we discovered that a sensory nerve-to-immune cell-to skin signaling pathway regulated by transient receptor potential A1 (TRPA1) that promotes scarless skin regeneration. We used three adult mouse models to show that pharmacologic activation of the nociceptor TRPA1 on cutaneous sensory neurons reduces scar formation and can also promote tissue regeneration. Remarkably, local activation of TRPA1 induces tissue regeneration on distant untreated areas of injury, demonstrating a systemic effect. These results present a new avenue for research and development of therapies for wounds and scars. 

We use cutting-edge techniques in molecular biology, developmental biology, and imaging to dissect the molecular and cellular mechanisms, including genomics methods (single-cell RNA-Seq, single-cell ATAC-Seq), CUT&RUN, flow cytometry, lineage tracing, parabiosis, mass cytometry, and 2-photon live imaging. Moreover, we developed a human skin organoid system and xenograft model to facilitate translation of these findings.

Inflammatory Skin Diseases

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Molecular Therapeutics

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