Single-cell transcriptional profiling reveals immunomodulatory properties of stromal and epithelial cells in periodontal immune milieu with diabetes in rats

Periodontitis is the sixth major complication of diabetes. Gingiva, as an important component of periodontal tissues, serves as the first defense barrier against infectious stimuli. However, relatively little is known about cellular heterogeneity and cell-specific changes in gingiva in response to diabetes-associated periodontitis. To characterize molecular changes linking diabetes with periodontitis, we profiled single-cell transcriptome analyses of a total of 45,259 cells from rat gingiva with periodontitis under normoglycemic and diabetic condition. The single-cell profiling revealed that stromal and epithelial cells of gingiva contained inflammation-related subclusters enriched in functions of immune cell recruitment. Compared to normoglycemic condition, diabetes led to a reduction in epithelial basal cells, fibroblasts and smooth muscle cells in gingiva with periodontitis. Analysis of differentially expressed genes indicated that stromal and epithelial populations were reprogrammed towards pro-inflammatory phenotypes promoting immune cell recruitment in diabetes-related periodontitis. In aspect of immune cells, diabetes prominently enhanced neutrophil and M1 macrophage infiltration in periodontitis lesions. Cell-cell communications revealed enhanced crosstalk between stromal/epithelial cells and immune cells mediating by chemokine/chemokine receptor interplay in diabetes-associated periodontitis. Our findings deconvolved cellular heterogeneity of rat gingiva associated with periodontitis and diabetes, uncovered altered immune milieu caused by the disease, and revealed immunomodulatory functions of stromal and epithelial cells in gingival immune niche. The present study improves the understanding of the link between the diabetes and periodontitis and helps in formulating precise therapeutic strategies for diabetes-enhanced periodontitis.