Cellular beauty is skin deep Human skin works as barrier, preventing the entry of pathogens, among other functions. Reynolds et al. used single-cell sequencing to generate an atlas of the human skin from both developing and adult sources, identifying differences and similarities across heterogeneous populations of skin cells. In this atlas, gene expression in the two disease states studied—atopic dermatitis and psoriasis—varied from that in a healthy adult, suggesting that a fetal skin signature is expressed in adult inflamed skin. Furthermore, differences in immune cell composition between healthy fetal and adult skin and that of individuals suffering from disease were observed. Science, this issue p. eaba6500 Transcriptomes of more than 500,000 skin cells suggest that inflammatory skin diseases reactivate a developmental cell program. INTRODUCTION Human skin provides vital protection from water loss and from external insult through structural adaptations and interplay with the innate and adaptive immune systems. The skin develops and functions in an aquatic environment in utero but rapidly adapts to a contrasting set of physical and pathogenic challenges after birth. The changes that take place across this complex multicellular system during development and upon perturbation by immune-mediated inflammatory diseases are poorly understood. A detailed study will facilitate the development of therapeutic interventions for inflammatory skin disease. RATIONALE We generated a comprehensive atlas of human skin in early prenatal life, in adulthood, and during inflammatory skin disease by profiling the transcriptomes of more than 500,000 single cells. We analyzed human embryonic skin between 7 and 10 post-conception weeks, healthy adult skin surplus from mammoplasty surgery, and skin biopsies from patients affected by atopic dermatitis (AD) and psoriasis, two common inflammatory skin diseases. Additionally, we performed single-cell T cell receptor analysis to assess T cell clonality in disease. Validation experiments were conducted at the protein level and used mass cytometry, flow cytometry, and immunostaining in situ of skin biopsies from healthy skin and patients with AD and psoriasis, including a cohort of AD patients before and during treatment with oral methotrexate. RESULTS Thirty-four cell states were identified in healthy human skin across the collective dataset, with dynamic changes in the nature and abundance of single-cell gene expression profiles identified across embryonic and adult life and upon perturbation during inflammatory skin disease. This resource can be accessed via an interactive browsable web portal, https://developmentcellatlas.ncl.ac.uk/datasets/hca_skin_portal. Analyses revealed that the immune system of first-trimester embryonic skin consists mainly of innate lymphocytes and macrophages. In adult skin, we defined two inferred trajectories for keratinocyte differentiation and the presence of endothelial cells that formed dilated postcapillary venules. We revealed a migratory dendritic cell (DC) signature in healthy adult skin that is conserved in murine DCs. The migratory DC signature was also evident in the developing human thymus and additional disease states. We identified clonally expanded disease-associated cytotoxic T cells (Tc IL13/IL22 cells) in lesional AD and Tc17/T helper 17 (TH17) cells in lesional psoriasis. We demonstrated the reemergence of prenatal cellular programs mediated by Mac2 macrophages via the chemokine CXCL8 interacting with the venular capillary marker ACKR1 on VE3 vascular endothelial cells in diseased skin. This interaction is implicated in lymphocyte recruitment and angiogenesis. We identified and validated in situ the expansion of Mac2 and VE3 in lesional AD and lesional psoriasis skin, their close apposition in AD and psoriasis tissue, and their reduction in AD skin during methotrexate treatment, which aligned with an improvement in the clinical severity of disease in this patient cohort. CONCLUSION Our single-cell atlas of human skin from prenatal life, healthy adults, and AD and psoriasis patients highlights the dynamic nature of cutaneous homeostasis and immunity. Our study provides insights into perturbed and co-opted developmental cellular programs in inflammatory skin disease. These results may provide potential future translational targets to improve the diagnosis and molecular classification of these diseases and to guide treatment strategies. The human skin cell atlas. We used single-cell RNA sequencing to build human skin cell atlases across development, homeostasis, and disease; the analyses were supported by various validation modalities. By delineating cell states in embryonic skin, healthy adult skin, and inflammatory skin diseases (atopic dermatitis and psoriasis), we identified a reemergence of developmental programs in disease mediated by interactions between Mac2 and VE3. APCs, antigen-presenting cells; CyTOF, cytometry by time-of-flight; LC, Langerhans cell; NK, natural killer cell; VE, vascular endothelial cell; Mac, macrophage; ILC, innate lymphoid cell. The skin confers biophysical and immunological protection through a complex cellular network established early in embryonic development. We profiled the transcriptomes of more than 500,000 single cells from developing human fetal skin, healthy adult skin, and adult skin with atopic dermatitis and psoriasis. We leveraged these datasets to compare cell states across development, homeostasis, and disease. Our analysis revealed an enrichment of innate immune cells in skin during the first trimester and clonal expansion of disease-associated lymphocytes in atopic dermatitis and psoriasis. We uncovered and validated in situ a reemergence of prenatal vascular endothelial cell and macrophage cellular programs in atopic dermatitis and psoriasis lesional skin. These data illustrate the dynamism of cutaneous immunity and provide opportunities for targeting pathological developmental programs in inflammatory skin diseases.

中文翻译：

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发育细胞程序在炎症性皮肤病中被增选


细胞之美是皮肤深层的 人体皮肤具有屏障作用，可防止病原体进入等功能。雷诺兹等人。使用单细胞测序生成发育中和成人来源的人类皮肤图谱，识别不同皮肤细胞群体之间的差异和相似之处。在该图谱中，研究的两种疾病状态（特应性皮炎和牛皮癣）的基因表达与健康成人的基因表达不同，表明胎儿皮肤特征在成人发炎的皮肤中表达。此外，还观察到健康胎儿和成人皮肤以及患有疾病的个体之间的免疫细胞组成存在差异。科学，本期第 14 页。 eaba6500 超过 500,000 个皮肤细胞的转录组表明，炎症性皮肤病会重新激活发育细胞程序。简介 人类皮肤通过结构适应以及与先天和适应性免疫系统的相互作用，提供重要的保护，防止水分流失和外部损伤。皮肤在子宫内的水生环境中发育和发挥功能，但在出生后迅速适应一系列截然不同的物理和致病挑战。人们对这个复杂的多细胞系统在发育过程中以及在免疫介导的炎症性疾病的干扰下发生的变化知之甚少。详细的研究将有助于开发炎症性皮肤病的治疗干预措施。基本原理我们通过分析超过 500,000 个单细胞的转录组，生成了产前早期、成年期和炎症性皮肤病期间人类皮肤的综合图谱。 我们分析了受孕后 7 至 10 周的人类胚胎皮肤、乳房整形手术剩余的健康成人皮肤，以及特应性皮炎 (AD) 和牛皮癣（两种常见的炎症性皮肤病）患者的皮肤活检。此外，我们还进行了单细胞 T 细胞受体分析，以评估疾病中的 T 细胞克隆性。在蛋白质水平上进行了验证实验，并使用了质量细胞术、流式细胞术和对健康皮肤以及 AD 和银屑病患者的皮肤活检进行原位免疫染色，其中包括一组口服甲氨蝶呤治疗前和治疗期间的 AD 患者。结果在整个集体数据集中，在健康的人类皮肤中鉴定出了 34 种细胞状态，在胚胎和成年生命以及炎症性皮肤病期间的扰动下鉴定出单细胞基因表达谱的性质和丰度的动态变化。该资源可以通过交互式可浏览门户网站 https://developmentcellatlas.ncl.ac.uk/datasets/hca_skin_portal 访问。分析显示，早孕期胚胎皮肤的免疫系统主要由先天淋巴细胞和巨噬细胞组成。在成人皮肤中，我们定义了角质形成细胞分化的两个推断轨迹以及形成扩张的毛细血管后微静脉的内皮细胞的存在。我们在健康成人皮肤中发现了鼠树突状细胞中保守的迁移树突状细胞 (DC) 特征。迁移性 DC 特征在人类胸腺发育和其他疾病状态中也很明显。我们在病变 AD 中鉴定出克隆扩增的疾病相关细胞毒性 T 细胞（Tc IL13/IL22 细胞），在病变银屑病中鉴定出 Tc17/T 辅助 17 (TH17) 细胞。 我们证明了 Mac2 巨噬细胞通过趋化因子 CXCL8 与患病皮肤 VE3 血管内皮细胞上的小静脉毛细血管标记物 ACKR1 相互作用介导的产前细胞程序的重新出现。这种相互作用涉及淋巴细胞募集和血管生成。我们原位鉴定并验证了 Mac2 和 VE3 在病变 AD 和病变银屑病皮肤中的扩增、它们在 AD 和银屑病组织中的紧密并置以及在甲氨蝶呤治疗期间它们在 AD 皮肤中的减少，这与疾病临床严重程度的改善相一致在这个患者队列中。结论 我们的产前人类皮肤、健康成人、AD 和牛皮癣患者的单细胞图谱强调了皮肤稳态和免疫的动态性质。我们的研究提供了对炎症性皮肤病中受干扰和增选的发育细胞程序的见解。这些结果可能提供潜在的未来转化目标，以改善这些疾病的诊断和分子分类并指导治疗策略。人体皮肤细胞图谱。我们使用单细胞 RNA 测序来构建跨越发育、稳态和疾病的人类皮肤细胞图谱；这些分析得到了各种验证方式的支持。通过描绘胚胎皮肤、健康成人皮肤和炎症性皮肤病（特应性皮炎和牛皮癣）中的细胞状态，我们发现了由 Mac2 和 VE3 之间的相互作用介导的疾病发育程序的重新出现。 APC，抗原呈递细胞； CyTOF，飞行时间细胞计数法； LC，朗格汉斯池； NK，自然杀伤细胞； VE，血管内皮细胞； Mac，巨噬细胞； ILC，先天淋巴细胞。 皮肤通过胚胎发育早期建立的复杂细胞网络提供生物物理和免疫保护。我们对来自发育中的人类胎儿皮肤、健康成人皮肤以及患有特应性皮炎和牛皮癣的成人皮肤的超过 500,000 个单细胞的转录组进行了分析。我们利用这些数据集来比较发育、稳态和疾病的细胞状态。我们的分析显示，在特应性皮炎和牛皮癣中，妊娠早期皮肤中先天免疫细胞富集，疾病相关淋巴细胞克隆扩增。我们发现并原位验证了特应性皮炎和牛皮癣皮损皮肤中产前血管内皮细胞和巨噬细胞细胞程序的重新出现。这些数据说明了皮肤免疫的活力，并为针对炎症性皮肤病的病理发育计划提供了机会。