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

Regeneration of the dentin-pulp complex is essential for tooth integrity and function. However, the inherent cell heterogeneity limits our understanding of lineage-specific subsets critical for efficient odontogenesis and regenerative outcomes. Here, we demonstrated that CD24+ human dental papilla cells (hDPCs) exhibit robust odontogenic differentiation capacity and 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/SIRT1 axis where elevated BMP signaling sustains SIRT1 expression and promotes mitochondrial metabolism and odontogenic capacity. Furthermore, BMP signaling induces VEGF expression, enhancing neovascularization via paracrine effects. CD24 is also a downstream marker of BMP signaling, though it does not directly mediate differentiation. Together, CD24+ hDPCs represent a regeneration-competent subpopulation that integrates mitochondrial metabolism and signaling crosstalk to enable coordinated dentin-pulp regeneration, representing a translationally relevant cell source for dental tissue engineering.