Biology subjects

Du-Harpur, X.

Publications and source records attributed to Du-Harpur, X..

3 recordsLinked to original sources

bioRxiv2025

Pathogenic Keratinocyte States and Fibroblast Niches Define the Tissue Microenvironment in Severe Hidradenitis Suppurativa

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease characterized by recurrent painful abscesses and tunnels in flexural sites. The mechanisms driving HS pathogenesis, particularly the roles of keratinocytes and fibroblasts in the HS inflammatory microenvironment, remain poorly understood. To characterise the cellular and molecular landscape of HS, we analyzed lesional skin from severe HS patients using single-cell RNA-sequencing and spatial transcriptomics to identify keratinocyte states and patterns of cellular interactions, with a focus on fibroblast-keratinocyte crosstalk. We identified a migratory S100+ pathogenic keratinocyte state enriched in HS lesions and observed spatially distinct fibroblast populations associated with different tissue compartments. COL6A5+ fibroblasts were preferentially co-localised with undifferentiated keratinocyte states, whereas APOD+ fibroblasts with enriched in immune cell-rich regions containing activated B and plasma cells consistent with tertiary lymphoid organ (TLO)-like structures. Ligand-receptor inference and spatial co-localisation analyses predicted extensive fibroblast-keratinocyte and fibroblast-immune interactions within HS lesions. Together, these data define the cellular organisation of the HS tissue microenvironment and identify spatially distinct stromal and epithelial niches associated with severe disease. These findings provide a framework for understanding how epithelial, stromal and immune cell populations coexist within HS lesions and may help to explain the limited efficacy of therapies targeting individual inflammatory pathways in the treatment of HS.

cell biology↗

bioRxiv2023

Multi-scale spatial mapping of cell populations across anatomical sites in healthy human skin and basal cell carcinoma

Our understanding of how human skin cells differ according to anatomical site and tumour formation is limited. To address this we have created a multi-scale spatial atlas of healthy skin and basal cell carcinoma (BCC), incorporating in vivo optical coherence tomography, single cell RNA sequencing, spatial global transcriptional profiling and in situ sequencing. Computational spatial deconvolution and projection revealed the localisation of distinct cell populations to specific tissue contexts. Although cell populations were conserved between healthy anatomical sites and in BCC, mesenchymal cell populations including fibroblasts and pericytes retained signatures of developmental origin. Spatial profiling and in silico lineage tracing support a hair follicle origin for BCC and demonstrate that cancer-associated fibroblasts are an expansion of a POSTN+ subpopulation associated with hair follicles in healthy skin. RGS5+ pericytes are also expanded in BCC suggesting a role in vascular remodelling. We propose that the identity of mesenchymal cell populations is regulated by signals emanating from adjacent structures and that these signals are repurposed to promote the expansion of skin cancer stroma. The resource we have created is publicly available in an interactive format for the research community. Significance statementSingle cells RNA sequencing has revolutionised cell biology, enabling high resolution analysis of cell types and states within human tissues. Here, we report a comprehensive spatial atlas of adult human skin across different anatomical sites and basal cell carcinoma (BCC) - the most common form of skin cancer - encompassing in vivo optical coherence tomography, single cell RNA sequencing, global spatial transcriptomic profiling and in situ sequencing. In combination these modalities have allowed us to assemble a comprehensive nuclear-resolution atlas of cellular identity in health and disease.

cell biology↗

bioRxiv2020

CD147 (BSG) but not ACE2 expression is detectable in vascular endothelial cells within single cell RNA sequencing datasets derived from multiple tissues in healthy individuals

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is associated with a wide range of systemic manifestations. Several observations support a role for vascular endothelial dysfunction in the pathogenesis including an increased incidence of thrombotic events and coagulopathy and the presence of vascular risk factors as an independent predictor of poor prognosis. It has recently been reported that endothelitis is associated with viral inclusion bodies suggesting a direct role for SARS-CoV-2 in the pathogenesis. The ACE2 receptor has been shown to mediate SARS-CoV-2 uptake and it has been proposed that CD147 (BSG) can function as an alternative cell surface receptor. To define the endothelial cell populations that are susceptible to infection with SARS-CoV-2, we investigated the expression of ACE2 as well as other genes implicated in the cellular entry of SARS-Cov-2 in the vascular endothelium through the analysis of single cell sequencing data derived from multiple human tissues (skin, liver, kidney, lung and intestine). We found that CD147 (BSG) but not ACE2 is detectable in vascular endothelial cells within single cell sequencing datasets derived from multiple tissues in healthy individuals. This implies that either ACE2 is not expressed in healthy tissue but is instead induced in response to SARS-Cov2 or that SARS-Cov2 enters endothelial cells via an alternative receptor such as CD147.

genomics↗