Mapping Connective Tissue Molecular Blueprints to Illuminate Human Keratinized and Non-Keratinized Oral Mucosa

A fundamental question in oral science is elucidating the factors that underpin the distinct tissue characteristics of human keratinized and non-keratinized mucosa. Clinical autotransplantation and large animal studies have observed that intrinsic regulation within connective tissue defines mucosal phenotypes, emphasizing the need for in-depth molecular characterization, which remains largely unexplored. This study aimed to map the molecular blueprints of in situ connective tissues and isolated fibroblasts of human keratinized oral mucosa (gingiva, GIN) and non-keratinized oral mucosa (alveolar mucosa, ALV). Distinct variations were observed in extracellular matrix composition, retinoic acid metabolism (closely associated with keratinization), and immune function between GIN and ALV. GIN displayed higher expression of collagen-related genes (notably COL1 and COL3) and lower expression of elastin-related genes. In GIN, the retinol metabolism pathway was enriched, with downregulation of retinoic acid synthesis and upregulation of its catabolism. In contrast, the complement and coagulation cascade were notably upregulated in ALV, with significantly elevated expression of C3. This study is the first to systematically dissect and compare the molecular profiles of connective tissue in GIN and ALV providing foundational insights that could drive future advancements in mucosal phenotype modulation and regenerative therapies.