The Journal of investigative dermatology最新文献

Isotretinoin, the gold-standard treatment for severe acne, effectively targets major pathogenic factors but carries teratogenic risks. Its precise mechanism of action remains incompletely understood. Computational approaches, such as connectivity mapping, can offer insights into a drug's mechanism and identify alternative compounds as potential novel therapeutics for acne. In this study, we investigated the transcriptomic response in nonlesional skin of 18 patients with severe acne prior to isotretinoin therapy (baseline) and after 1, 8, and 20 weeks of therapy and 6 months after therapy. Our analysis revealed that isotretinoin induced significant early and sustained suppression of metabolic pathways, including oxidative phosphorylation, lipid metabolism, and mTORC1 signaling. Immunofluorescence staining in acne patient skin for phosphorylated S6, a downstream marker of mTORC1, corroborated decreased mTORC1 signaling as early as 1 week of therapy. In addition, connectivity mapping identified mTOR inhibitors as top candidates that mimic isotretinoin's transcriptomic signature. These findings enhance our understanding of isotretinoin's mechanism and highlight mTORC1 as a potential target for developing safer, nonteratogenic acne treatments.

To elucidate the complex effects of acute UVR on the skin, we exposed mouse skin to UVB and performed transcriptomic profiling of the epidermis, deep dermis, and adipose tissue. Spatial transcriptomic analysis revealed gene expression changes in the epidermis, dermis, and adipose. Whereas CD45⁺ immune cells showed differential expression of chemokines, cytokines, and acute-phase proteins, cytokeratin⁺ epidermal cells upregulated genes related to cellular stress and damage, structural remodeling, and apoptosis. Single-cell RNA sequencing 12 hours after UVR identified 4849 differentially expressed genes, with the epidermis and endothelial cells showing the highest differentially expressed gene counts. Pathway analysis of upregulated genes in the epidermis revealed enrichment in VEGF, HIPPO, complement, IL-6, and apoptosis signaling pathways. In endothelial cells, receptor-ligand analysis highlighted endothelial cells as key targets of CXCL chemokines and C3. In fibroblasts, UVR triggered the upregulation of inflammatory activation markers alongside genes associated with glucose metabolism. Cross-species comparison of UVR-responsive differentially expressed genes between mice and humans revealed strong concordance, particularly in TGF-β- and TNF-associated pathways. These results highlight the sequential activation of keratinocytes, fibroblasts, endothelial, and immune cells, providing mechanistic insights into how UVR can initiate or exacerbate autoimmune processes such as those observed in cutaneous lupus.

Signaling interactions between the dermal papilla and neighboring stem cells (SCs) in the hair germ and bulge regulate new follicle growth in the hair cycle. To study these interactions, the 3 populations had been profiled together by now-outdated microarrays or separately by bulk RNA sequencing. Recent single-cell transcriptomics established signatures of dermal papilla, bulge SCs, and hair germ SCs, but low detection sensitivity limited the depth of gene expression discovery. In this study, we define the transcriptomes of dermal papilla cells, bulge SCs, hair germ SCs, epidermal and follicle epithelial cells and dermal fibroblasts-after flow sorting each population from 4 neighboring mouse back skin regions-to gain deeper insights into the unique gene expression programs of hair follicle SCs and their instructive niche. With cross-comparisons of 56 whole-transcriptome measurements, we classify cell type-specific molecular signatures of enriched genes with unprecedented sensitivity. Joint analysis with signatures from 15 leading studies published in the last 20 years revealed many previously undescribed dermal papilla, bulge SC, and hair germ SC genes in mouse and human counterparts. With ligand-receptor mapping and CellChat analyses, we then uncover comprehensive cell-cell communication insights. Finally, we provide our transcriptome data in a full update of our Hair-GEL repository along with numerous signature and other gene tables for easy exploration of gene expression in hair follicle SCs and their niche.