ABSTRACT
Adult mammalian wounds, with rare exception, heal with fibrotic scars that severely disrupt tissue architecture and function. Regenerative medicine seeks methods to avoid scar formation and restore the original tissue structures. We show in three adult mouse models that pharmacologic activation of the nociceptor TRPA1 on cutaneous sensory neurons reduces scar formation and can also promote tissue regeneration. Local activation of TRPA1 induces tissue regeneration on distant untreated areas of injury, demonstrating a systemic effect. Activated TRPA1 stimulates local production of interleukin-23 (IL-23) by dermal dendritic cells, leading to activation of circulating dermal IL-17-producing γδ T cells. Genetic ablation of TRPA1, IL-23, dermal dendritic cells, or γδ T cells prevents TRPA1-mediated tissue regeneration. These results reveal a cutaneous neuroimmune-regeneration cascade triggered by topical TRPA1 activators that promotes adult mammalian tissue regeneration, presenting a new avenue for research and development of therapies for wounds and scars.
Subject(s)
Regeneration , Skin Physiological Phenomena , TRPA1 Cation Channel/physiology , Adjuvants, Immunologic , Animals , Cicatrix/chemically induced , Cicatrix/immunology , Female , Imiquimod , Inflammation/chemically induced , Inflammation/immunology , Intraepithelial Lymphocytes/immunology , Intraepithelial Lymphocytes/physiology , Male , Mice, Inbred C57BL , Mice, SCID , Mice, Transgenic , Skin/immunology , TRPA1 Cation Channel/immunology , Wound HealingABSTRACT
Circulating factors in the blood and lymph support critical functions of living tissues. Parabiosis refers to the condition in which two entire living animals are conjoined and share a single circulatory system. This surgically created animal model was inspired by naturally occurring pairs of conjoined twins. Parabiosis experiments testing whether humoral factors from one animal affect the other have been performed for more than 150 years and have led to advances in endocrinology, neurology, musculoskeletal biology, and dermatology. The development of high-throughput genomics and proteomics approaches permitted the identification of potential circulating factors and rekindled scientific interest in parabiosis studies. For example, this technique may be used to assess how circulating factors may affect skin homeostasis, skin differentiation, skin aging, wound healing, and, potentially, skin cancer.
Subject(s)
Biomedical Research/methods , Dermatology/methods , Parabiosis/methods , Research Design , Skin Physiological Phenomena , Animals , Models, AnimalABSTRACT
Physicians have observed that surgical wounds in the elderly heal with thinner scars than wounds in young patients. Understanding this phenomenon may reveal strategies for promoting scarless wound repair. We show that full-thickness skin wounds in aged but not young mice fully regenerate. Exposure of aged animals to blood from young mice by parabiosis counteracts this regenerative capacity. The secreted factor, stromal-derived factor 1 (SDF1), is expressed at higher levels in wounded skin of young mice. Genetic deletion of SDF1 in young skin enhanced tissue regeneration. In aged mice, enhancer of zeste homolog 2 (EZH2) and histone H3 lysine 27 trimethylation are recruited to the SDF1 promoter at higher levels, and pharmacologic inhibition of EZH2 restores SDF1 induction and prevents tissue regeneration. Similar age-dependent EZH2-mediated SDF1 suppression occurs in human skin. Our findings counter the current dogma that tissue function invariably declines with age and suggest new therapeutic strategies in regenerative medicine.
