Single-cell RNA sequencing reveals genes relevant to periodontal therapy and periodontitis

Periodontal therapy leverages intercellular and intertissue interactions between epithelium and stroma, which mediate healing and regeneration. Importantly, grafting stroma from different regions elicits different healing responses: transplantation of gingival stroma can convert alveolar mucosa into keratinized gingiva, and vice versa. This striking clinical observation suggests that the stromal tissues of oral mucosa and gingiva provide distinct instructional signals. Our aims were to investigate the molecular differences between mucosa and gingiva and the impact of periodontal infection on intertissue interactions. We used human single-cell RNA-sequencing (RNA-seq) data to compare gene expression patterns and intercellular interactions of: <i>1</i>) adult oral mucosa and gingiva and <i>2</i>) healthy gingiva and periodontitis-affected gingiva. Altered gene expression in junctional epithelial cells in periodontitis included not only inflammatory but also antioxidant genes, reflecting the potential of oral tissues to maintain health and resist bacterial infection. Many ligand/receptor genes were also enriched in junctional epithelium, highlighting intercellular interactions. Oral mucosal and gingival stroma expressed distinct genes related to signaling and extracellular matrix associated with their tissue phenotypes: for example, collagens and secreted protein acidic and cysteine-rich (<i>SPARC</i>) in the gingiva, and elasticity-related coagulation factor XIII A chain (<i>F13A1</i>) in the mucosa. Ligand-receptor analyses predicted endothelial cells and fibroblasts as the primary senders of signaling ligands. Notably, autocrine signaling was predicted to be prevalent within periodontitis-affected fibroblasts, suggesting potential autofeedback regulation in periodontitis. We present unbiased single-cell molecular characterizations of human oral tissues in health and periodontitis. These findings lay the groundwork for future research into periodontal therapies.<b>NEW & NOTEWORTHY</b> To explore differences between oral mucosa and gingiva in health and disease, we analyzed human single-cell RNA-sequencing data. In periodontitis, altered gene expression in junctional epithelium included not only inflammatory but also antioxidant genes, reflecting the potential of oral tissues to resist bacterial infection. Each cell type-fibroblasts, endothelial, and immune cells-expressed genes that distinguished mucosa from gingiva, as well as healthy from diseased gingiva. These findings provide insights into periodontitis and periodontal therapy.