Title : The role of gingival fibroblasts in periodontal diseases and regeneration
Abstract:
Gingival fibroblasts (GFs) represent an abundant cell population of oral connective tissue. Their primary function is production and remodeling of extracellular matrix (ECM) and release of growth factors to maintain tissue integrity and structure, tissue regeneration and wound healing. These “canonical” functions of GFs can be affected in pathological conditions under various stimuli, such as, genetic factors, infections, some medications. Sustained exposure on pathological factors may induce phenotypic and functional variation of GFs. This phenomenon is observed in patients with gingival overgrowth (GO), a rare and painless condition, manifested by pathological and progressive enlargement of gingival tissue. Our previous studies revealed excessive production of collagen type I (Col I) by cultured fibroblasts from GO donors, elevated levels of HSP47, TGF?β1 and CTGF, and a shift in the TIMP?1/MMP?1 ratio, altogether indicating the fibrotic phenotype of GFs. Unlike fibroblasts derived from overgrowths, which did not present recurrence, fibroblasts derived from fibrotic and recurrent overgrowths showed high rate of proliferation in vitro. These results were confirmed by dense connective tissue with numerous blood vessels and abundant fibroblasts detected in tissue biopsies from recurrent GO.
GFs also represent the first line of defense against oral pathogens and are considered an important component of the innate immune system. However, their chronic activation due to persistent interaction with oral bacteria, which involves the secretion of large quantities of cytokines, chemokines, matrix-degrading enzymes, and prostaglandins, significantly contributes to pathogenesis of periodontitis (PD), the most common inflammatory disease of bacterial origin, characterized by the progressive degradation of the supporting tissues of the teeth, including the periodontal ligament and alveolar bone, and ultimately leading to tooth loss. Though the etiology of PD is multifactorial and modified by environmental and behavioral factors, one of key etiologic agent is the Gram-negative, anaerobic bacterium, Porphyromonas gingivalis, which induces dysbiosis, effectively manipulating the host immune system to create a nutrient-rich, inflammatory microenvironment promoting the initiation and progression of PD. Our studies demonstrated efficient adhesion/invasion of GFs and activation of prostaglandin E2 (PGE2)-dependent pathway by P. gingivalis, an effect mediated by peptidylarginine deiminase (PPAD)-catalyzed citrullination of P. gingivalis Fim A protein and more pronounced in GFs from PD patients compared to healthy donors, suggesting the involvement of epigenetic regulation in the pathogenesis of PD. Furthermore, we observed that immune activation of GFs is determined by heterogeneity of ppad gene sequence and biochemical properties of produced variant(s) and correlated with periodontal tissue damage and the stage of PD progression.
Our more recent study investigated the reprogramming efficiency of GFs from PD and healthy donors to induced pluripotent stem cells (iPSCs). Analyses of the pluripotency markers Tra-1-60, Tra-1-81, and SSEA-4 showed ~95% of pluripotent cells among both tested cell lines, which was also confirmed by the negative pluripotency marker SSEA-1 identified in ~5% of analysed cells.
Taking together, beside the classical functions, our data revealed the functional plasticity and ability of GFs to serve as a source of therapeutic cells for tissue regeneration in periodontal diseases.
