Research Article

Developmental cell programs are co-opted in inflammatory skin disease

See allHide authors and affiliations

Science  22 Jan 2021:
Vol. 371, Issue 6527, eaba6500
DOI: 10.1126/science.aba6500

You are currently viewing the abstract.

View Full Text

Log in to view the full text

Log in through your institution

Log in through your institution

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

Structured Abstract


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.


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.


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, 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.


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.

View Full Text

Stay Connected to Science