Meta-Analysis: Harnessing dental pulp mesenchymal stem cells for inducing reparative dentin: A synthesis of mechanisms and therapeutic strategies

Aim: To systematically review and quantitatively synthesize in vivo evidence on the efficacy of dental pulp mesenchymal stem cells (DP-MSCs) and their derived secretome/extracellular vesicles (EVs) in inducing reparative dentin formation, and to analyze the key molecular mechanisms involved.

Materials and Methods: A systematic search of PubMed, Embase, Web of Science, and Scopus was conducted for studies published from inception to January 2024. Controlled animal studies and human clinical trials that evaluated the application of DP-MSCs (or their derivatives) for dentin regeneration and reported histomorphometric outcomes (e.g., dentin bridge thickness, area) were included. Pooled mean differences (MD) with 95% confidence intervals (CI) were calculated using a random-effects model. Subgroup analyses were performed based on cell source (allogeneic vs. autologous), carrier scaffold, and use of conditioned media (CM) or EVs.

Results: Twenty-eight studies (26 animal, 2 human) met the inclusion criteria. Pooled analysis revealed that DP-MSC-based therapies significantly increased reparative dentin formation compared to control groups (MD = 245.51 µm, 95% CI: 189.21 to 301.81, p < 0.001). Subgroup analysis showed high efficacy for allogeneic cells (MD = 228.34 µm, p < 0.001) and scaffold-based delivery (MD = 267.90 µm, p < 0.001). Notably, the use of cell-free derivatives, specifically CM/EVs, also yielded a significant effect (MD = 195.63 µm, p < 0.001), suggesting potent paracrine mechanisms. Key associated mechanisms included upregulation of dentinogenic markers (DSPP, DMP-1, BMP-2), angiogenesis (VEGF), and downregulation of inflammatory cytokines.

Conclusion: DP-MSCs and their secretome are highly effective in promoting reparative dentinogenesis in vivo. This effect is mediated through a multifaceted paracrine signaling network that orchestrates cell recruitment, differentiation, and angiogenesis. The proven efficacy of cell-free strategies represents a paradigm shift towards more clinically translatable, off-the-shelf therapies for vital pulp therapy and regenerative endodontics.