Gli1⁺ Periodontal Crestal Stem Cells Orchestrate Cervical Periodontal Homeostasis and Regeneration via Cxcl12–Shh/Ihh Signaling

ABSTRACT: Reconstruction of periodontal tissue damaged by injury or disease is a long-standing clinical goal, yet its practice is hampered by a lack of mechanistic understanding of periodontal regeneration. We investigated the periodontal crestal region (POCR) in the cervical area of the mouse molar, which is exposed to oral bacteria and other substances and provides frontline protection against external insults. The POCR supports the tooth and comprises the periodontal ligament (PDL), alveolar bone, and the dentogingival junction. Using genetic lineage tracing and single-cell profiling, we identified a distinct Gli1+ cell population in the POCR that contains periodontal crestal stem cells (PCSCs), which give rise to osteoblasts, PDL cells, and gingival cells in vivo, and similar Gli1⁺ PCSCs are present in human POCR. The Gli1⁺ PCSCs are required for periodontal tissue maintenance and in a POCR injury model, they expand in response to injury induced niche factors, including chemokine (CXC motif) ligand 12 (Cxcl12) and Sonic/Indian Hedgehog (Shh/Ihh). Upregulated chemokine expression and Hedgehog signaling were also observed in human periodontitis tissues. Furthermore, we show that Gαs, which regulates both Cxcl12 and Shh/Ihh pathways, is essential for periodontal lineage determination and cellular plasticity. Loss of Gαs in Gli1⁺ PCSCs induces ankylosis by promoting their osteogenic differentiation, whereas a Gαs gain of function mutation identified in the human Fibrodysplasia (FD) favors PDL cell fate. These findings identify Gli1⁺ PCSCs as key regulators of periodontal homeostasis and repair, providing new cellular and molecular insights into periodontal regeneration and disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE346113 | GEO | 2026/09/08

REPOSITORIES: GEO