# Neuroimmune Control of Scarless Skin Regeneration

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2021 · $357,500

## Abstract

Project Abstract
Vertebrates repair skin injury through two fundamental biological processes: scar formation and tissue
regeneration. Human skin generally heals with scar formation, which may cause severe emotional distress and
physical disability. One hundred million new scars appear annually in the US, and although many products are
marketed for scar prevention, their results are modest. Consequently, the elucidation of mechanisms
underlying scar formation and tissue regeneration may result in new insights with far reaching implications in
the development of therapeutics that promotes skin regeneration after wounding. Ear hole closure and wound-
induced hair neogenesis (WIHN) are two instances where adult mammals can regenerate full-thickness skin
wounds without scar formation, including hair follicles and sebaceous glands. Using both models, we
demonstrated that topical pharmacologic activation of transient receptor protein A1 (TRPA1), a receptor
expressed on skin sensory nerves promotes regeneration. This improved healing depends on dermal dendritic
cells activating γδ Τ cells through interleukin 23. Strikingly, local activation of TRPA1 promotes tissue
regeneration in distant injured areas, suggesting that a circulating factor may be induced with an
accompanying paracrine mechanism. Our results reveal a new cutaneous neuroimmune-regeneration
pathway, and a fundamental advance for the field would be a more comprehensive molecular understanding of
signaling pathways involving multiple cell types that promotes mammalian tissue regeneration. In Aim 1, we
use a combination of optogenetics, mouse models, and single-cell genomics to investigate whether TRPA1 on
skin sensory nerves is necessary and sufficient to promote tissue regeneration in our two wounding models
and to identify the molecular mechanisms of how TRPA1 expressing neurons locally activate immune cells. In
Aim 2, we use mouse models to elucidate how γδ T cells and their effector cytokines promote systemic
scarless tissue regeneration in our two wounding models. Together, our aims define mechanisms of cellular
cross talk between nerves, immune cells, and skin, and successful completion will contribute to our overall goal
of developing novel therapies to promote scarless skin regeneration in humans.

## Key facts

- **NIH application ID:** 10276722
- **Project number:** 1R01AR079483-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Thomas H. Leung
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $357,500
- **Award type:** 1
- **Project period:** 2021-07-20 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10276722

## Citation

> US National Institutes of Health, RePORTER application 10276722, Neuroimmune Control of Scarless Skin Regeneration (1R01AR079483-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10276722. Licensed CC0.

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