Mesenchymal Stem Cell Exosomes for Periodontal Regeneration Project Summary/Abstract Periodontitis is an inflammatory disease caused by dysbiotic microbiota, leading to destruction of the tooth supporting complex, which includes the cementum, periodontal ligament and alveolar bone. Regeneration of the periodontium, although feasible, remains a great challenge to clinicians. Mesenchymal stem cells (MSCs) hold a great promise in regenerative medicine. Increasing evidence suggests that the regenerative effects of MSCs are largely mediated by their secretome. Exosomes are nanoscopic, lipid bilayer organelles secreted by most cell types. Exosomes have emerged as a novel modulator in intercellular communications through transfer of their bioactive cargos, which include microRNAs (miRNAs). Exosomes produced by stem cells have been shown to have comparable therapeutic outcomes to that of cell delivery. However, the potential of exosome therapy in periodontal regeneration is still unknown. In our preliminary studies, we isolated and purified exosomes secreted by human bone marrow mesenchymal stem cells. These exosomes were mitogenic and chemotactic to recipient cells and also had an anti-inflammatory function. Distinct RNA signatures were found in MSC exosomes, where small RNA was highly abundant. Through RNA sequencing, we further identified a group of miRNAs that was significantly enriched in exosomes. Therefore, our data strongly suggest that MSC exosomes may be a potential therapeutic agent for periodontal diseases. We hypothesize that exosome delivery will promote periodontal tissue regeneration and this effect may be mediated by the enriched exosomal miRNAs. To test this hypothesis, we will: 1) determine whether delivery of MSC exosomes will promote periodontal regeneration in an experimental periodontitis model in rodents; 2) investigate the role of miRNAs in exosome-mediated periodontal tissue regeneration. Our long term goal is to develop a cell-free therapy to promote periodontal regeneration. Results from this study will build on the body of preliminary data to support an R01 grant application that will further elucidate the safety and efficacy of stem cell exosome therapy for periodontal diseases in large animals and early human clinical trials. It will also help us better understand the mechanisms of exosome-induced tissue regeneration, which will provide a foundation for the future optimization of the exosome therapy. 1