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。人的皮肤通常会因疤痕的形成而愈合，这可能会导致严重的情绪困扰和 身体残疾。美国每年出现1亿个新的疤痕，尽管许多产品 它们的市场定位是预防疤痕，但效果并不明显。因此，对机制的阐明 潜在的疤痕形成和组织再生可能会带来新的见解，对 促进创伤后皮肤再生的治疗方法的发展。耳洞闭合和伤口- 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例子 无疤痕形成的伤口，包括毛囊和皮脂腺。使用这两种模式，我们 证明了瞬时受体蛋白A1(TRPA1)的局部药理激活 在皮肤上表达感觉神经，促进再生。这种愈合的改善依赖于真皮树突状细胞 细胞通过白介素23激活γδΤ细胞。引人注目的是，TRPA1的局部激活促进了组织 远距离损伤区域的再生，表明循环因子可能是由 伴随旁分泌机制。我们的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更全面的分子理解 涉及多种细胞类型的信号通路，促进哺乳动物组织再生。在目标1中，我们 使用光遗传学、小鼠模型和单细胞基因组学相结合的方法来研究TRPA1在 在我们的两种创伤模型中，皮肤感觉神经是促进组织再生的必要条件和充分条件 并确定TRPA1表达神经元如何局部激活免疫细胞的分子机制。在……里面 目的2，我们用小鼠模型阐明γδT细胞及其效应细胞因子是如何促进全身性的 在我们的两个创伤模型中，无疤痕组织再生。我们的目标共同定义了细胞的机制 神经、免疫细胞和皮肤之间的相互作用，并成功完成，将有助于我们的总体目标 开发新的疗法来促进人类无疤痕皮肤的再生。

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.