TUESDAY, 16 FEBRUARY 2021Article updated 3 March 2021
A recent study, published in Science, reveals that cells from patients with inflammatory skin diseases share many of the same molecular pathways as developing skin cells. The study is part of the Human Cell Atlas initiative, an international scientific collaboration bringing together biologists, clinicians, physicists, and bioinformaticians to answer fundamental biological questions. In this study, researchers from King’s College London, the Wellcome Sanger Institute, and Newcastle University used single-cell RNA sequencing (scRNA-seq) to determine the molecular signature of cells in human skin with single-cell resolution. This information will be an invaluable resource for scientists and clinicians to monitor, diagnose, and treat human diseases.
Skin immune cells destroy invading pathogens and play critical roles in wound healing and repair. Disruption to the skin’s immune system underlies a broad spectrum of inflammatory skin diseases, including psoriasis and atopic dermatitis (eczema). However, what initiates the inflammation central to these diseases is not well understood. Current treatments, which tend to include general immunosuppressants rather than targeted therapies, often bring about problematic side-effects for patients.
Researchers used a technique called ‘fluorescence-activated cell sorting’ (FACS) to characterise the various cell types present in skin from healthy adults and patients with the inflammatory skin conditions psoriasis and eczema. In the inflamed skin, there was an expansion of disease-associated white blood cells, including cytotoxic T cells and macrophages. The researchers used antibody staining to identify a subpopulation of vascular endothelial cells, called VE3 cells, that are thought to regulate white blood cell movement through the skin. In the inflamed skin, more of these VE3 endothelial cells were found, linking this observed increase in white blood cells in inflamed skin to potential functional changes within the endothelial cell population.
The researchers then used scRNA-seq to compare gene expression profiles of healthy and inflamed adult skin cells to embryonic, developing skin cells. During development, cells become specialised, or “differentiated”, in a process whereby specific molecular pathways are turned on or off impart specific characteristics to each unique cell-type. In some cancers, genetic mutations cause dormant, developmentally-associated molecular programmes to turn back on, leading to the uncontrolled proliferation of the cells. Whether reactivation of such developmental programmes contribute to inflammatory skin disease pathogenesis was a key question of this study.The researchers discovered that the cells from inflamed tissue share gene expression patterns with developing skin cells, indicating that cellular processes from development become reactivated during inflammatory skin disease. The scRNA-seq experiments revealed that both the VE3 vascular endothelial cells identified in inflamed adult skin and the vascular endothelial cells present in developing skin express genes that regulate white blood cell movement and blood vessel formation. A subpopulation of white blood cells, called Mac-2 macrophages, was also found to be more abundant in inflamed skin. Skin-resident macrophages promote immune cell recruitment and blood vessel formation in the skin during development. However, in adult skin most macrophages perform other functions instead. Surprisingly, the transcriptomic data reveals that the Mac-2 macrophages are molecularly more similar to embryonic macrophages than to other subpopulations of adult macrophages.
Treatment with the immunosuppressant methotrexate was associated with a significant reduction in both VE3 endothelial cells and Mac-2 macrophages in eczema patients, and this reduction correlated with an improvement in patients’ symptoms. This suggests that macrophage and endothelial cell gene programmes, which normally support blood vessel formation and white blood cell seeding in the skin during development, may contribute to disease pathogenesis in eczema and psoriasis too!
Professor Muzlifah Haniffa, co-senior author from Newcastle University and Associate Faculty at the Wellcome Sanger Institute, said: “This Skin Cell Atlas reveals specific molecular signals sent by healthy developing skin to summon immune cells and form a protective layer. We were amazed to see that eczema and psoriasis skin cells were sending the same molecular signals, which could over-activate immune cells and cause the disease. This had never been seen before. Discovering that developing cell pathways re-emerge is a huge leap in our understanding of inflammatory skin disease, and offers new routes for finding treatments”.
One of the strengths of this study is that the cells characterised are primary human cells — cells were harvested from patients and analysed directly without being cultured in vitro. This minimises any potential alterations to the cells’ gene expression profiles and best reflects in vivo conditions. Another advantage of this study is the astonishing molecular detail achieved. Transcriptomic analysis at a single-cell resolution allows new cell subtypes — with unique molecular signatures and characteristics — to be identified. With this enhanced understanding of cell biology, we may soon gain insight into the molecular mechanisms underlying diseases with similar inflammatory aetiologies, from rheumatoid arthritis to cardiovascular disease.
This study takes us one step closer towards an exciting conceptual revolution in modern medicine. In the future, diagnoses will be made by analysing patients’ cells to identify the molecular mechanisms underlying their symptoms. Ultimately, these advances provide the opportunity for more of us to live healthier, better-quality lives.
Lauren Lee is a PhD student in the Molecular Immunity Unit at the Department of Medicine.
Gary Reynolds, Peter Vegh, James Fletcher, Elizabeth F. M. Poyner, Emily Stephenson, Issac Goh, Rachel A. Botting, Ni Huang, Bayanne Olabi, Anna Dubois, David Dixon, Kile Green, Daniel Maunder, Justin Engelbert, Mirjana Efremova, Krzysztof Polański, Laura Jardine, Claire Jones, Thomas Ness, Dave Horsfall, Jim McGrath, Christopher Carey, Dorin-Mirel Popescu, Simone Webb, Xiao-nong Wang, Ben Sayer, Jong-Eun Park, Victor A. Negri, Daria Belokhvostova, Magnus D. Lynch, David McDonald, Andrew Filby, Tzachi Hagai, Kerstin B. Meyer, Akhtar Husain, Jonathan Coxhead, Roser Vento-Tormo, Sam Behjati, Steven Lisgo, Alexandra-Chloé Villani, Jaume Bacardit, Philip H. Jones, Edel A. O’Toole, Graham S. Ogg, Neil Rajan, Nick J. Reynolds, Sarah A. Teichmann, Fiona M. Watt, Muzlifah Haniffa. Developmental cell programs are co-opted in inflammatory skin disease. Science, 2021; 371 (6527): eaba6500 DOI: 10.1126/science.aba6500