Immune microenvironmental regulation of odontogenic differentiation in dental pulp stem cells: mechanisms, signaling networks, and regenerative strategies

Dental pulp stem cells (DPSCs) are a promising cell source for dentin regeneration, but their regenerative behavior is strongly shaped by the local immune microenvironment. This review integrates evidence on immune mediators, immune cell–DPSC interactions, intracellular signaling, and immunomodulatory biomaterials. Particular attention is given to how mediator concentration and exposure duration influence the balance between inflammatory injury and differentiation-associated responses. In one human DPSC model, 1 μg/mL lipopolysaccharide for 24 h increased IL-1β and TNF-α transcript levels 6.9-fold and 4.1-fold, respectively, illustrating the magnitude of the inflammatory response under defined experimental conditions. NF-κB, Wnt, Smad, MAPK, and related pathways link extracellular cues to cell survival, recruitment, and mineralization, although the direction of their effects varies with the stimulus and model. Biomaterials offer ways to influence these responses through factor delivery, ion release, or activation of endogenous signals. Culture mineralization, reparative dentin formation, and functional pulp–dentin regeneration represent different levels of evidence and should guide interpretation of these approaches. Integrating immunology, stem cell biology, and biomaterials science may therefore support more precise and clinically relevant strategies for dentin regeneration.