Lepr‐Expressing PDLSCs Contribute to Periodontal Homeostasis and Respond to Mechanical Force by Piezo1

Abstract Periodontium supports teeth in a mechanically stimulated tissue environment, where heterogenous stem/progenitor populations contribute to periodontal homeostasis. In this study, Leptin receptor+ (Lepr+) cells are identified as a distinct periodontal ligament stem cell (PDLSC) population by single‐cell RNA sequencing and lineage tracing. These Lepr+ PDLSCs are located in the peri‐vascular niche, possessing multilineage potential and contributing to tissue repair in response to injury. Ablation of Lepr+ PDLSCs disrupts periodontal homeostasis. Hyper‐loading and unloading of occlusal forces modulate Lepr+ PDLSCs activation. Piezo1 is demonstrated that mediates the mechanosensing of Lepr+ PDLSCs by conditional Piezo1‐deficient mice. Meanwhile, Yoda1, a selective activator of Piezo1, significantly accelerates periodontal tissue growth via the induction of Lepr+ cells. In summary, Lepr marks a unique multipotent PDLSC population in vivo, to contribute toward periodontal homeostasis via Piezo1‐mediated mechanosensing.