Spatial transcriptomics stratifies psoriatic disease severity by emergent cellular ecosystems

Abstract

Whereas the cellular and molecular features of human inflammatory skin diseases are well characterized, their tissue context and systemic impact remain poorly understood. We thus profiled human psoriasis (PsO) as a prototypic immune-mediated condition with a high predilection for extracutaneous involvement. Spatial transcriptomics (ST) analyses of 25 healthy, active lesion, and clinically uninvolved skin biopsies and integration with public single-cell transcriptomics data revealed marked differences in immune microniches between healthy and inflamed skin. Tissue-scale cartography further identified core disease features across all active lesions, including the emergence of an inflamed suprabasal epidermal state and the presence of B lymphocytes in lesional skin. Both lesional and distal nonlesional samples were stratified by skin disease severity and not by the presence of systemic disease. This segregation was driven by macrophage-, fibroblast-, and lymphatic-enriched spatial regions with gene signatures associated with metabolic dysfunction. Together, these findings suggest that mild and severe forms of PsO have distinct molecular features and that severe PsO may profoundly alter the cellular and metabolic composition of distal unaffected skin sites. In addition, our study provides a valuable resource for the research community to study spatial gene organization of healthy and inflamed human skin.

Serum miRNA profiling identified miRNAs associated with disease severity in psoriasis

“…We identified 11 miRNAs with significantly differential levels in the low and high PASI group compared to healthy individuals, among which three miRNAs (mir‐147b mir‐3614‐5p and miR‐125a‐5p) showed significantly altered levels between low severity and high severity psoriasis patients. Most of these miRNAs were derived from either macrophages, dendritic cells or lymphocytes, further supporting the hypothesis that in a psoriatic individual there is global change in transcriptome profile of immune cells 37 . MiR‐147b and miR‐3614‐5p are elevated in the serum and skin of psoriasis patients, with their levels in the psoriasis patients with high severity being even higher than low severity patients.…”

“…Most of these miRNAs were derived from either macrophages, dendritic cells or lymphocytes, further supporting the hypothesis that in a psoriatic individual there is global change in transcriptome profile of immune cells. 37 MiR-147b and miR-3614-5p are elevated in the serum and skin of psoriasis patients, with their levels in the psoriasis patients with high severity being even higher than low severity patients. MiR-147b is possibly derived from skin epithelial cells and has been reported to be induced upon toll-like receptor (TLR) activation.…”

IL-12/IL23 blockade reveals patterns of asynchronous inflammation in pyoderma gangrenosum

“…Notably, the patients exhibited broadly similar patterns of identified clusters with some specific differences in inflammatory regions (Figure 2B). Specifically, we identified four inflammatory clusters which were absent from previously published spatial transcriptomic annotations of normal human skin (Figure 2B) (19). All four clusters mapped to both patients but the relative abundance of each differed (Figure 2C).…”

Distinct fibroblast subpopulations associated with bone, brain or intrapulmonary metastasis in advanced non‐small‐cell lung cancer

“…Employing the SciBet machine learning prediction model, 13 we mapped our dataset with cell‐type labels from the reference dataset. Furthermore, we applied multimodal integration analysis (MIA) to assess and compare the similarity between our annotation results and the reference data, accounting for potential biases in cell‐type naming 15 …”

“…Furthermore, we applied multimodal integration analysis (MIA) to assess and compare the similarity between our annotation results and the reference data, accounting for potential biases in cell-type naming. 15 MIA employs a hypergeometric test to evaluate the overlap of marker genes between each CAF subtype in our dataset and the reference dataset. Specifically, we considered the top up-regulated marker genes with adjusted p values of .05 or lower and log fold changes greater than .5.…”