The Effect of the Inflammatory Microenvironment on Odontogenic Differentiation of Dental Pulp Stem Cells

The dental pulp not only serves as the tooth's nutritional core but also creates a finely tuned microenvironment that is enriched with blood vessels, nerves, extracellular matrix components, and signaling molecules, all of which guide the fate of resident dental pulp stem cells (DPSCs). Trauma and microbial invasion disrupt this niche, leading to pulpitis and necrosis. Although conventional root canal treatment preserves the tooth's structure by removing infected pulp, it can increase tooth brittleness and impede root development in immature permanent teeth. Harnessing DPSCs' multipotency for pulp regeneration promises to restore the natural pulp-dentin complex in situ. Importantly, DPSCs encounter an inflammatory microenvironment composed of pathogen-associated molecular patterns, a spectrum of pro- and anti-inflammatory cytokines, diverse immune cell phenotypes, and altered matrix signals. While earlier work examined the isolated effects of mediators such as lipopolysaccharide, tumor necrosis factor-alpha, or macrophage-derived exosomes on odontogenic differentiation, this review focuses on how these mediators collectively interact in both synergistic and antagonistic ways within the inflammatory niche. We systematically delineate how these collective stimuli converge on wingless/integrated/beta-catenin, mitogen-activated protein kinase, nuclear factor kappa-B (NF-κB), and bone morphogenetic protein/Sma and Mad related protein pathways to modulate key odontogenic markers (runt-related transcription factor 2, dentin sialophosphoprotein, dentin matrix protein 1, alkaline phosphatase) and mineralization outcomes. By applying a microenvironment-centric lens, we reveal novel targets and strategies to recalibrate inflammation, steer DPSCs toward reparative odontogenesis, and ultimately enhance the efficacy of regenerative endodontic therapies.