Single-Cell transcriptomic analysis reveals distinct cellular and molecular signatures of human oral mucosa and skin.

Oral mucosal wounds heal faster and with minimal scarring compared to skin injuries, yet the underlying mechanisms remain poorly understood. To explore the cellular and molecular basis of this difference, we performed single-cell RNA sequencing (scRNA-seq) on paired, uninjured human oral mucosa and skin tissues from the same donors. This approach enabled the construction of a comprehensive single-cell transcriptomic atlas, facilitating direct comparison of cellular composition, gene expression profiles, and intercellular communication between the two tissues. Our analysis revealed distinct tissue-specific heterogeneity among keratinocytes, fibroblasts, immune cells, and endothelial cells. Oral keratinocytes exhibited signatures associated with proliferation and metabolic activity, while oral fibroblasts and immune cells expressed gene profiles suggestive of pro-regenerative and anti-fibrotic functions. Cell-cell communication analysis indicated that endothelial cells in oral mucosa participate in interactions that may promote rapid tissue remodeling. Although our data were derived from uninjured tissues, the identified differentially expressed genes and enriched pathways suggest potential regulatory networks that may underlie the distinct wound-healing behaviors of oral mucosa and skin. A subset of these genes was validated by RT-PCR in both autologous and allogeneic samples across different age and sex groups, confirming the robustness and reproducibility of our findings. This study provides the first single-cell transcriptomic comparison of intact human oral mucosa and skin under steady-state conditions, establishing a foundational atlas that reveals intrinsic tissue-specific features and identifies candidate targets for promoting scarless healing.