Identification of tooth germ ectomesenchymal stem cells for human tooth development

During the development of cranio-maxillofacial region, cranial neural crest cells (CNCCs) migrate from the neural crest to the ectomesenchyme, which contribute to the development of the majority of cranio-maxillofacial tissue, including the main body of tooth. However, the differentiation routine and fate decision, especially in human, by which CNCCs differentiate and participate in tooth development remain elusive. In this study, we utilized single-cell RNA sequencing (scRNA-seq) to map the cellular landscape of the embryonic human mandible, clarifying the differentiation trajectory from CNCCs to the odontogenic lineage. Notably, we identified a population of SLITRK6+ cranial neural crest (CNC)-derived progenitor cells within the odontogenic lineage. They were found exclusively in both embryonic and postnatal tooth germs but absent in fully developed tissues, with robust proliferative capacity, dentin-pulp differentiation potential, and osteogenic ability, which may be a population of tooth germ ectomesenchymal stem cells that crucial for the development of dental root and periodontium. This study reveals the fate and differentiation process of CNCCs from the perspective of tooth development, elucidating the unique distribution and biological significance of SLITRK6+ CNC-derived cells in tooth development, and offers new insights into tooth development and regenerative research.