O17 Keratinocyte nuclear morphology and spatial transcriptomic profiling of recessive dystrophic epidermolysis bullosa skin

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ID: 318349
2026
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Abstract
Abstract Introduction and aims Recessive dystrophic epidermolysis bullosa (RDEB) is a rare inherited blistering disorder caused by loss of type VII collagen (C7). RDEB is characterized by chronic wounds, fibrosis and aggressive cutaneous squamous cell carcinoma (SCC). Recent work from our group has identified nuclear envelope changes associated with C7 loss in cultured keratinocytes. We aimed to examine keratinocyte nuclear morphology following C7 loss in RDEB skin and organotypic models, and to assess spatial transcriptomic differences between RDEB skin, RDEB SCC and healthy skin. Methods Three-dimensional human skin organotypic models were generated using N/TERT-1 keratinocytes with stable short hairpin (sh)RNA-mediated C7 knockdown (shC7) or control shRNA (shC). Nuclear morphology was assessed by immunofluorescence staining for Lamin A/C, Lamin B1, Lamin B2, SUN1, SUN2 and Emerin, with quantitative analysis of keratinocyte nuclear area and mean fluorescence intensity (n = 4 organotypics per condition). Parallel analyses were performed on skin of patients with RDEB (n = 3) and healthy control skin (n = 4). Group comparisons were performed using an unpaired two-tailed Welch’s t-test. Spatial transcriptomic profiling (Visium HD) was performed on RDEB skin, RDEB SCC and healthy control skin, followed by clustering, manual annotation and spatial mapping. Results Loss of C7 was associated with increased keratinocyte nuclear area in organotypic cultures and epidermis of patients with RDEB. shC7 organotypic models showed reduced SUN2 immunofluorescence intensity and more basally distributed SUN2 and Lamin B1 staining compared with controls. Spatial transcriptomic analysis resolved distinct epidermal, dermal and tumour-associated cell populations. Stressed basal keratinocyte and immune cell clusters were prominent in RDEB skin and RDEB SCC compared with healthy controls. Nuclear lamina genes including LMNA, LMNB1 and LMNB2 were enriched in basal keratinocyte clusters, including stressed basal keratinocytes. Conclusions C7 loss is associated with altered keratinocyte nuclear morphology in human skin and organotypic models. Spatial transcriptomic analysis identifies disease-associated epidermal and immune cell populations RDEB skin and SCC.
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Authors Syed F H Shah, Simranpreet Kaur Summan, Elena Giusto, Matthew Caley, John A McGrath, Jemima E. Mellerio, Emanuel Rognoni, Edel A. O’Toole
Journal the british journal of dermatology
Year 2026
DOI
10.1093/bjd/ljag151.017
URL
Keywords Keywords not found

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