Extrinsic And Intrinsic Factors Influencing Homeostasis And Repair In Oral Tissues
Abstract
The oral tissues, including gingiva and buccal mucosa, heal rapidly with minimal scar formation. Although in the oral cavity, the palatal mucosa is associated with excessive scarring in response to injury. In this thesis, first, I investigated the complex relationship between cells and their microenvironment using wound healing models in which extracellular matrix composition and mechanical stiffness affect cellular responses during acute wound repair. I also determined how intrinsic differences of cells recruited during healing contribute to wound resolution.
In Chapter 2, I first investigated cell-extrinsic factors, specifically the influence of the pro-fibrotic matricellular protein periostin on palatal healing. Using a genetic deletion strategy, it was determined that in the palate periostin modulates myofibroblast differentiation and fibronectin synthesis in a manner dependent on the stiffness of the microenvironment surrounding the cells.
In chapter 3, I focused on the role of extracellular periostin on periodontal ligament (PDL) fibroblast phenotype using in vitro assays and gene-expression analyses. These findings suggest that the influence of periostin is context dependent; matrix-bound periostin does not promote or inhibit mineralization of the PDL, but the addition of exogenous periostin to isolated PDL fibroblasts resulted in increased mineralization concomitant with changes in gene expression.
In chapter 4, to explore cell-intrinsic differences, a lineage tracing approach was used to trace populations of cells derived from embryonic Foxd1- and NG2- expressing progenitors during development, homeostasis, and excisional wound healing. I show in the palate that Foxd1-lineage progeny associate with blood vessels in development and adult tissues, after injury, they expand but remain associated with neovascular structures. In contrast, NG2-lineage progeny associate with fibroblasts in healthy adult tissues and post-injury contribute to myofibroblast populations.
In conclusion, the studies in this thesis have further defined the complex interactions that exist between resident cells and their micro-environment using the palate as a model system. The data from this thesis provides important information for the design of future therapeutics for oral wounds, and also contributes to a growing understanding of fibroblast heterogeneity and how divergent populations contribute to different processes during wound repair.