Human CD24+ dental papilla cells are highly competent seed cells for dentin-pulp regeneration via BMP2/SIRT1 metabolic axis

Regeneration of the dentin-pulp complex is essential for the lifelong structural integrity and biological function of damaged teeth. However, the inherent heterogeneity of dental stem cells limits our understanding of lineage-specific subsets critical for efficient odontogenesis and regenerative outcomes. Here, we identify a distinct subpopulation of human dental papilla cells (hDPCs) marked by CD24 expression. CD24+ hDPCs exhibit robust odontogenic differentiation capacity, preferential localization in odontoblast-generating regions during tooth development, and accumulation beneath reparative dentin in carious teeth. Functionally, CD24+ hDPCs drive coordinated regeneration of well-vascularized pulp and structurally integrated dentin tissues in both ectopic murine and preclinical in situ minipig models, significantly outperforming conventional dental pulp stem cells. Mechanistically, we delineate a BMP2-driven metabolic axis where elevated BMP signaling sustains SIRT1 expression and promotes mitochondrial metabolism. Inhibition of BMP signaling disrupts this axis, resulting in WNT signaling activation, reduced SIRT1 expression, compromised antioxidant and autophagic responses, and consequently diminished odontogenic capacity. Furthermore, BMP signaling in CD24+ hDPCs induces VEGF expression, which enhances endothelial cell recruitment and neovascularization via paracrine effects. CD24 is also a downstream marker of odontogenic BMP signaling, reflecting BMP pathway activation and correlating with odontogenic potential, though it does not directly mediate differentiation. Together, our findings characterize CD24+ hDPCs as a regeneration-competent subpopulation that integrates mitochondrial metabolism and signaling crosstalk to enable coordinated dentin and pulp regeneration, representing a translationally relevant cell source for dental tissue engineering.