Neuroimmune Control of Scarless Skin Regeneration

项目摘要 脊椎动物通过两个基本的生物过程修复皮肤损伤：疤痕形成和组织 再生人类皮肤通常愈合疤痕形成，这可能会导致严重的情绪困扰， 身体残疾。在美国，每年出现一亿个新的疤痕，尽管许多产品 用于预防疤痕，但效果一般。因此，阐明机制 潜在的疤痕形成和组织再生可能会导致新的见解，具有深远的影响， 促进创伤后皮肤再生的治疗方法的发展。把耳洞堵上- 诱导毛发新生（WIHN）是成年哺乳动物可以再生全层皮肤的两个实例 无疤痕形成的伤口，包括毛囊和皮脂腺。使用这两种模型，我们 证明了瞬时受体蛋白A1（TRPA 1）的局部药理学激活， 在皮肤感觉神经上表达促进再生。这种改善的愈合取决于真皮树突状细胞 细胞通过白细胞介素23激活γδ Τ细胞。引人注目的是，TRPA 1的局部激活促进组织 再生在遥远的受伤地区，这表明一个循环因素可能是诱导与 伴随的旁分泌机制。我们的研究结果揭示了一种新的皮肤神经免疫再生 途径，该领域的一个根本性进展将是对 涉及促进哺乳动物组织再生的多种细胞类型的信号通路。目标1： 使用光遗传学，小鼠模型和单细胞基因组学的组合来研究TRPA 1是否在 在我们的两种创伤模型中，皮肤感觉神经对于促进组织再生是必要的和充分的 并确定TRPA 1表达神经元如何局部激活免疫细胞的分子机制。在 目的2：我们利用小鼠模型阐明γδ T细胞及其效应细胞因子如何促进全身性免疫反应， 在我们的两个创伤模型中无疤痕组织再生。总之，我们的目标是定义细胞的机制， 神经，免疫细胞和皮肤之间的串扰，成功完成将有助于我们的总体目标 开发新型疗法以促进人类无疤痕皮肤再生。

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.