Cellular and molecular control of periodontal tissue regeneration

Periodontal diseases (PDs) are major causes of tooth loss and a significant public health burden in the world. Reconstruction of healthy periodontal tissue damaged by injury or diseases is a major goal of periodontal treatment. The periodontium supports and invests the tooth and is composed of alveolar bone (bone lining the too socket), periodontal ligament (PDL), part of the gingiva facing the tooth (dentogingival junction) and the root cementum. In the periodontal apparatus, the alveolar bone (AB) is connected via PDL and the gingiva to the tooth in the periodontal crestal region (POCR). Maintaining periodontal tissue integrity is essential for mammals to maintain tooth functions and prevent the spread of local and systemic infections via periodontal pocket. Periodontal stem cells have been identified in the periodontal ligament within the apical PDL space and gingival connective tissue. However, major questions remain unanswered. First, it is unknown whether there are distinct stem cell populations in the POCR that give rise to AB, PDL and gingiva. Second, it is unknown how stem cells residing in the POCR are regulated for homeostatic tissue maintenance and regeneration after injury by coordinating differentiation into distinct cell lineages. Lastly, it is unknown whether and how the periodontal stem cells are altered in a severe inflammatory environment that causes periodontal tissue defects, and whether the involved mechanisms can be employed to achieve more predictable and efficient periodontal tissue regeneration. Elucidating these fundamental questions will advance current knowledge of periodontal stem cells and promote natural periodontal tissue regeneration. We are beginning to tackle these key questions in our preliminary studies and we specifically focus on the POCR in the adult periodontal cervical tissue of the tooth, as this area is exposed to oral bacteria and other substances and forms front-line protection for the deeper periodontal and dental tissues, and yet is under-investigated. We have identified periodontal crestal stem cells (PCSCs), which included Gli1+ cells that played important roles in POCR regeneration. We postulate that the crestal region contains PCSCs that coordinate periodontal tissue regeneration, and injury-induced PCSC niche factors Cxcl12 and Shh promote PCSC activation, lineage-specific differentiation, and POCR regeneration. This central hypothesis will be tested in the following Specific Aims: 1) To characterize the PCSC properties and their activation by injury; 2) To determine the signaling pathways that regulate PCSC activation and lineage-specific differentiation during periodontal tissue repair; 3) To determine the role of Cxcl12 and Shh in periodontal tissue regeneration in a periodontitis mouse model with more severe inflammation. Successful completion of the aims will advance current knowledge of periodontal stem cells and their regulation to provide new insights into prevention of PDs and promote predictable periodontal tissue regeneration b y harnessing the natural ability of periodontal stem cells. Project Number: 5R01DE033991-02 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Dental and Craniofacial Research (NIDCR) | Principal Investigator: Yingzi Yang | Institution: HARVARD MEDICAL SCHOOL, BOSTON, MA | Award Amount: $547,435 | Activity Code: R01 | Study Section: Oral, Dental and Craniofacial Sciences Study Section[ODCS] View on NIH RePORTER: https://reporter.nih.gov/project-details/11322098