A Novel CD24+ Subpopulation For Pulpitis Traeatment And Pulp Regeneration

The pulp regeneration strategy is important to treat pulpitis and pulp necrosis. Yet the key functional subpopulation and mechanism that governs the odontogenic fate decisions remain largely unknown. In our study, a heterogeneous human CD24+ dental papilla stem cell with strong odontogenic differentiation potential was identified from dental papilla tissue through fluorescence-activated cell sorting, and the latent odontogenic mechanism was revealed through transcriptome analysis. We found that CD24+ cells not only play a dominant role in deep caries defense but also functional pulp-dentin regeneration, which was verified by an ectopic pulp regeneration mice model and a clinical scale in situ minipig model. Transplantation of CD24+ cells efficiently reconstructed pulp tissue with robust neo-dentin formation and neovascularization that resembled the native pulp tissue. The success rate was significantly higher than dental pulp stem cells. Mechanistically, we proposed a novel regulatory paradigm, wherein BMP2-derived BMP signaling orchestrates SIRT1-mediated mitochondrial metabolic reprogramming to regulate the odontogenic fate commitment. Inhibition of BMP signaling led to the downregulation of SIRT1 expression, antioxidant capacity, autophagy, mitochondrial biogenesis, ultimately resulting in mitochondrial metabolic dysfunction and odontogenic fate impairment. Moreover, we unveiled that high BMP signaling activity upregulated VEGF expression in CD24+ cells, which enhanced HUVECs migration and angiogenesis during pulp regeneration. These findings unveiled promising insights into the specific therapeutic strategies based on human CD24+ dental papilla stem cells and mitochondrial metabolic manipulation, with novel and promising applications in pulpitis and pulp necrosis treatments.