Effects of Recurrent Periodontitis in HSC Function

Periodontitis is a common oral inflammatory condition that is epidemiologically linked to systemic disorders such as cardiovascular disease, rheumatoid arthritis, and type-2 diabetes. The relationship between periodontitis and systemic comorbidities is bidirectional, as proinflammatory diseases can also predispose to and accelerate the progression of periodontitis. Nevertheless, the factors leading to the association between periodontitis and comorbidities remains unclear. The low-grade systemic inflammation caused by periodontitis may contribute to its connection with systemic diseases. Recent studies have shown periodontitis to rewire hematopoietic stem cell (HSC) transcriptional and epigenetic profile, which is the base for trained innate immunity. Further, our own pilot data suggest that periodontitis activates HSC, inducing cell cycle entry and loss of repopulating potential in a sex-dependent way. However, the long-term effects of recurrent periodontitis on HSC function and clonal complexity remain unknown. Importantly, HSCs have limited replicative potential, and repeated acute inflammatory episodes that drive HSC proliferation may contribute to their decline. This decline is believed to be a major factor in the development of age-related hematologic diseases resulting from dysfunctional HSCs, such as clonal hematopoiesis, myeloid leukemias, and anemia. Understanding how inflammation regulates HSC fate and influences the blood system during development, aging, chronic inflammatory diseases, and hematological malignancies is crucial for uncovering the mechanistic foundations of these processes and their potential connections. In this study, we will: 1) establish a model for chronic periodontitis that mimics its long-term effects on HSCs, and 2) define the functional consequences of chronic periodontitis on HSCs, considering sexual dimorphism and local versus systemic effects. The results from this proposal will enhance our understanding of chronic inflammation's impact on HSC function. Moreover, the research outlined here will identify periodontitis as a risk factor for the development of hematopoietic pathologies. This will enable us to expand our studies to interrogate the consequences of this pathology in other tissues, both in isolation and alongside comorbidities, highlighting the importance of oral health in preventing inflammatory diseases. Project Number: 1R21DE036033-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Dental and Craniofacial Research (NIDCR) | Principal Investigator: Antonio Morales-Hernandez | Institution: UNIVERSITY OF MICHIGAN AT ANN ARBOR, ANN ARBOR, MI | Award Amount: $429,000 | Activity Code: R21 | Study Section: Special Emphasis Panel[ZRG1 MSOS-L (04)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11354286