Oral mucosa provides the first barrier against oral disease, coordinating mechanical forces and constant interactions with the oral microbiome. Numerous inter-related cell types constitute the adult gingiva; however, the molecular identities of individual cells remained unclear. Periodontitis is a chronic inflammatory condition that causes irreversible destruction of the tooth supporting structures, gingiva, ligament and bone. The extent of heterogeneity within the gingiva and how specific cell types are affected during the course of disease progression are two questions that I sought to investigate. Using single-cell RNA sequencing, I define the unique composition and heterogeneity of human gingival cells in health and the changing cellular dynamics throughout disease progression. I describe a large-scale remodelling of structural and immune cell types in disease; lymphocytic and myeloid subpopulations that promote an inflammatory state are activated, whilst mesenchymal and epithelial populations are depleted. I found that a quantitative change in cellular populations is accompanied by qualitative changes in cell molecular phenotype. I provide evidence of cellular heterogeneity within the human gingiva mesenchyme, identifying previously unknown subpopulations with unique transcriptional signatures. Importantly, I demonstrate that mesenchymal remodelling in periodontitis is heterogenous, occurring in a cell type specific manner, where populations involved in tissue maintenance are compromised, and pro-inflammatory ones persist or expand. I also generated a cell-cell interaction network, based on correlated profiles across cell types, elucidating how disease perturbations to these interactions might contribute to disease progression. Finally, I describe how an in vitro environment directs mesenchymal cell transcriptional identity. These findings are of relevance to regenerative medicine approaches and the better understanding of periodontitis pathogenesis.
|Date of Award
|1 Sept 2021
|Paul Sharpe (Supervisor) & Ana Angelova Volponi (Supervisor)