Wnt-directed CXCL12-expressing apical papilla progenitor cells drive tooth root formation

The tooth root is a critical component of the tooth anchored to surrounding alveolar bones. Tooth root formation is driven by cells in the apical papilla (AP) that generate new dentin-forming odontoblasts at the root-forming front. Mesenchymal stem cells have been isolated from AP for regenerative use; however, how AP cells physiologically coordinate tooth root formation remains undefined. We find that CXCL12(+) cells emerge in AP under hypoxic environments at the onset of tooth root formation. Using Cxcl12-creER-based cell-lineage analysis, we further find that CXCL12(+) AP cells contribute not only to odontoblasts but also to cementum-forming cementoblasts of the elongating root, while showing plasticity to alveolar bone osteoblasts under regenerative conditions. Canonical Wnt inactivation inhibits odontoblast fates of CXCL12(+) AP cells and induces substantial root truncation, with their aberrant fibroblast fates suppressed by TGF-β receptor inhibitor galunisertib. Therefore, CXCL12(+) AP cells maintain odonto-cementogenic fates in a Wnt-dependent manner, identifying these cells as pivotal dental mesenchymal progenitor cells driving tooth root formation with substantial plasticity.