Thursday, November 21, 2024
11/21/2024
Project Summary This R16 grant application proposes to investigate the molecular mechanism underlying apoptosis of periodontal mesenchymal stem cells (MSCs) induced by exposure to Porphyromanas gingivalis (Pg). Periodontitis is an inflammatory bone resorption lesion caused by dysbiosis of the periodontal microbiome. A critical pathologic manifestation of periodontitis is the irreversible loss of connective tissue and alveolar bone which, in part, results from the regulated cell death of fibroblasts and osteoblasts. It is well established that periodontal fibroblasts and osteoblasts are differentiated from mesenchymal stem cells (MSCs) present in the periodontium. However, it is largely unknown whether MSCs in periodontal tissue can also be affected by regulated cell death and diminish the regenerative potential. Therefore, the long-term goal of the proposed study is to understand the molecular mechanism underlying the retarded regeneration of connective tissue and alveolar bone in periodontitis by targeting the regulated cell death induced in GMSCs, leading to the development of a therapeutic prevention strategy. Our preliminary data indicate that the keystone oral pathogen P. gingivalis (Pg), but not other periodontal bacteria, can cause atypical cell death of periodontal MSCs, but not epithelial cells, as characterized by the extracellular release of decondensed chromatin contents. Emerging studies have revealed that only neutrophils and macrophages die via the release of decondensed chromatin contents (DNA, Histone and HMGB1) in response to stimulation with TLR ligands. This phenomenon termed as “Neutrophil Extracellular Trap Death [=osis] (NETosis)” is known to elicit inflammation in several diseases, including sepsis, cancer, and autoimmune diseases. We herein for the first time termed such Stem cell Extracellular Chromatin release Death (SECosis). According to our results, exposure of THP1 cells (human monocytic cell line) to SECosis products elevated the production of IL-1β compared to that of Pg alone or GMSCs alone, suggesting the proinflammatory potential of SECosis. It is established that a eukaryote enzyme peptidyl arginine deiminase (PAD) plays a role in eliciting the NETosis by Histone H3 citrullination that untangles the chromatin. Interestingly is described that among the periodontal bacteria, only Pg produces PAD. We showed Stimulation of GMSCs with (PAD)-knockout Pg diminished induction of IL-1β from THP1 indicating that Pg-PAD may be engaged in the induction of extracellular release of decondensed chromatin contents. This hypothesis will be assessed in the following Aims: (Aim1) To establish the property of Pg, and the role of Pg-PAD, in the induction of SECosis. (Aim2) To elucidate the molecular mechanism underlying the SECosis-mediated IL-1β production by monocytes. This study will elucidate role of Pg in the regulated cell death specifically induced in GMSCs, in turn retarding the regenerative potential of periodontal tissue.
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