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Skin Cell Atlas Elucidates Pathological Cell States Underlying Inflammatory Skin Diseases

NEW YORK – As part of the Human Cell Atlas effort to map every cell type in the human body, researchers in the UK, Israel, and the US have developed a new comprehensive atlas of developing and adult skin called the Skin Cell Atlas, and have used it to elucidate the cellular processes that underlie inflammatory skin diseases such as psoriasis and atopic dermatitis (AD).

In a study published on Thursday in Science, the researchers said they profiled the transcriptomes of more than 500,000 single cells from developing human fetal skin, healthy adult skin, and adult skin with AD and psoriasis, and used the data to compare cell states across development, homeostasis, and disease. Their analysis revealed an enrichment of innate immune cells in skin during the first trimester, clonal expansion of disease-associated lymphocytes in AD and psoriasis, and an in situ re-emergence of prenatal vascular endothelial cell and macrophage cellular programs in AD and psoriasis lesional skin.

"Our findings identified the re-emergence of programs seen during human development in inflammatory skin disease that can be targeted as new treatment strategies," co-corresponding author Muzlifah Haniffa, a professor of dermatology and immunology at Newcastle University, said. "The interactions between endothelial cells and macrophages appear to be involved in recruiting white blood cells and formation of new blood vessels, mediating skin inflammation."

Further, she added, the study provides "a detailed cellular map of the human skin, which can guide tissue engineering approaches to differentiate skin from stem cells for regenerative medicine applications."

The researchers used single-cell RNA sequencing (scRNA-seq) to analyze human embryonic skin between seven and 10 post-conception weeks, healthy adult skin surplus from mammoplasty surgery, and skin biopsies from AD and psoriasis patients. They also performed single-cell T cell receptor analysis to assess T cell clonality in disease. In total, they analyzed 528,253 sequenced skin cells and derived differentially expressed genes to annotate the cell clusters, from which 34 cell states were identified.

To evaluate the establishment of specific cell states during development and their temporal evolution in adult skin, the researchers compared their adult skin scRNA-seq data with their embryonic or fetal scRNA-seq data, and found that the immune system of first-trimester embryonic skin consisted mainly of innate lymphocytes and macrophages.

The researchers also found a signature of migratory dendritic cells (DC) 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. Surprisingly, they noted, the migratory DC signature is also present across disease states such as tonsillitis, ascites, lung cancer, and rheumatoid arthritis. The investigators had also previously reported the expression of migratory genes in fetal thymic medullary DCs, which suggests that developmental gene programs are used in adult tissue homeostasis and are augmented in disease.

They then identified clonally expanded disease-associated cytotoxic T cells in lesional AD and T helper 17 cells in lesional psoriasis, and demonstrated the re-emergence 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. They also observed a reduction of Mac2 macrophages and VE3 cells in AD skin during methotrexate treatment, which aligned with an improvement in the clinical severity of disease in the patient cohort taking the drug.

"Dissecting the precise interplay of known angiogenic triggers, such as hypoxia, Wnt, STAT3, and b-catenin signaling, will pave the way toward a mechanistic understanding of VE3 expansion. Establishing the intrinsic and tissue-extrinsic factors that drive the Mac2 state acquisition in disease may innovate anti-inflammatory strategies" the authors concluded.