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CD24+ human dental papilla cells as translational seed cells for dentin-pulp regeneration via BMP2/SIRT1 metabolic axis

ABSTRACT: Regeneration of the dentin-pulp complex is a central goal in dental tissue engineering, essential for restoring both 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 to 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 in which elevated BMP signaling sustains SIRT1 expression and promotes mitochondrial metabolism. Inhibition of BMP signaling disrupts this axis, activating WNT signaling, reducing SIRT1 expression, compromising antioxidant and autophagic responses, and consequently diminishing odontogenic capacity. Furthermore, BMP signaling in CD24⁺ hDPCs induces VEGF expression, enhancing endothelial cell recruitment and neovascularization via paracrine effects. CD24 also acts as a downstream marker of odontogenic BMP signaling, reflecting BMP pathway activation and correlating with odontogenic potential, although 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.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE303466 | GEO | 2026/04/26

REPOSITORIES: GEO

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Project description:Purpose: To compare the transcriptional changes of genes in dental pulp tissues with different degrees of inflammatory severity and investigate the role of RAD54B in inflamed human dental pulp cells (hDPCs) Methods: Normal, carious, and pulpitis human dental pulp tissues were collected. Total RNA extracted were subjected to RNA-sequencing and gene expression profiles were further studied by Gene Ontology (GO) and KEGG pathway analysis. DEGs (differentially expressed genes) in homologous recombination repair (HRR) were validated with qRT-PCR. The expression of RAD54B and TNF-α in human dental pulp tissues was detected by immunohistochemistry. HDPCs were cultured and RAD54B level in hDPCs was detected after LPS stimulation using western blot. CCK-8 was applied to investigate the cell proliferation of hDPCs transfected with negative control (Nc) small interfering RNA (siRNA), RAD54B siRNA, P53 siRNA or both siRNAs with or without LPS stimulation. Flow cytometry was applied to detect the cell cycle distribution, and western blot and immunofluorescence were utilized to analyze the expression of RAD54B, P53 and P21 under the above treatments. One-way and two-way ANOVA followed by LSD posttest were used for statistical analysis. Results: RNA-sequencing results identified DEGs among three groups. KEGG pathway analysis revealed enrichment of DEGs in Replication and Repair pathway. HRR and non-homologous end joining (NHEJ) components were further verified and qRT-PCR results were basically consistent with the sequencing data. RAD54B, a HRR accessory factor highly expressed in carious and pulpitis tissues compared to normal pulp, was chosen as our gene of interest. High RAD54B expression was confirmed in inflamed human dental pulp tissues and LPS-stimulated hDPCs. Upon RAD54B knockdown, P53 and P21 expressions in hDPCs were upregulated whereas the cell proliferation was significantly downregulated, accompanied with increased G2/M phase arrest. After inhibiting P53 expression in RAD54B-knockdown hDPCs, P21 expression and cell proliferation were reversed. Conclusions: Gene expression profiles of normal, carious and pulpitis human dental pulp tissues were revealed. HRR components was elucidated to function in dental pulp inflammation. Among HRR DEGs, RAD54B could regulate the cell proliferation of inflamed hDPCs via P53/P21 signaling. This research not only deepens our understanding of dental pulp inflammation but also provides a new insight to clarify the underlying mechanisms.

Project description:Tooth decay, also known as dental caries, is a prevalent oral health problem that significantly reduces an individual's quality of life; however, it can be effectively managed through restorative treatments. The condition primarily affects the enamel and dentin structures and can be treated before it progresses to the pulp chamber. Even in cases where the caries does not reach the pulp, microbial products from the lesion can still penetrate the pulp chamber, potentially inducing stress on pulp cells, including dental pulp stem cells (DPSCs). Even in the absence of direct pulpal exposure, microbial by-products originating from carious lesions may diffuse through dentinal tubules, potentially exerting stress on pulpal cells, including dental pulp stem cells (DPSCs). In this study, we performed a comparative analysis of the biological and proteomic profiles of DPSCs isolated from carious teeth that had not reached the pulp and those isolated from healthy teeth. In this study, we conducted a comparative analysis of the biological and proteomic profiles of dental pulp stem cells (DPSCs) isolated from clinically asymptomatic teeth with deep dentinal caries that had not reached the pulp and those isolated from healthy teeth. After evaluation of biological mechanisms such as senescence and apoptosis, we examined both the whole-cell proteome and secretome of these DPSCs by conducting a shotgun proteomics approach. Our findings indicate that the DPSC population isolated from decayed teeth exhibited a significantly higher proportion of senescent cells compared to the control group. Proteomic analysis further revealed that DPSCs from decayed teeth activated specific signaling pathways in response to microbial products, manifesting an inflammatory profile. Additionally, we observed an upregulation in the expression of proteins associated with extracellular matrix (ECM) remodeling and components of the senescence-associated secretory phenotype (SASP), both of which are hallmarks of the senescence process. This study highlights that even in the absence of direct pulp involvement, microbial stress resulting from caries can impact DPSCs within the pulp. The study reveals that DPSCs can be affected by microbial signals from carious lesions, even when the pulp appears clinically intact. The activation of senescence and inflammatory mechanisms in these affected cells may have deleterious effects on other critical tissues within the organism. Consequently, restorative treatments should consider targeting not only the decayed tissue but also the senescent cells within the pulp that may have been affected by the microbial stress induced by caries.

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CD24+ human dental papilla cells as translational seed cells for dentin-pulp regeneration via BMP2/SIRT1 metabolic axis

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