Foxp4+ Mandibular Skeletal Stem Cells Orchestrate Bone/Tooth Development and Regeneration

The identity of stem/progenitor cells that drive mandible/tooth development and regeneration remains poorly understood. Here, we show that cranial neural crest-derived Foxp4+ mesenchymal cells condense to form Meckels cartilage, and simultaneously promote mandible development and tooth germ formation. In postnatal mandibles, Foxp4+ cells localize in the endosteum, periosteum and dental pulp, which undergo osteogenesis and odontogenesis under steady state, as well as chondrogenesis during fracture repair. Importantly, transplantation of embryonic or adult Foxp4+CD200+CD105- mandibular skeletal stem cells (mdSSCs) generate ectopic bone and tooth. In contrast, genetic ablation of Foxp4+ cells severely impairs mandible/tooth development and delays fracture healing. Mechanistically, we find that primary cilia critically regulate mdSSC maintenance and differentiation into bone and tooth. FOXP4+PDPN+CADM1+ mdSSCs also exist in adult human mandible, which generate ectopic bone and intact tooth upon transplantation into immunodeficient mice. Taken together, we identify Foxp4+ mdSSCs with potential therapeutic applications in regenerating mandibular bone and tooth.