Inflammation-Regeneration Axis of Dental Pulp Stem Cells: Wnt/NF-κB Crosstalk

Inflammation critically determines dental pulp regenerative outcomes, with dental pulp stem cells (DPSCs) orchestrating tissue homeostasis through differentiation, self-renewal and immunomodulation processes dynamically regulated by Wnt/β-catenin and NF-κB signaling crosstalk. Given the rising therapeutic potential of Wnt-targeted interventions in dental tissue engineering, elucidating these molecular interactions under pathological conditions is essential for developing regenerative therapeutics capable of simultaneously promoting reparative dentinogenesis while resolving inflammatory insults.

This perspective review aims to: (1) critically evaluate existing literature on lipopolysaccharide (LPS)-mediated modulation of dental pulp stem cell (DPSC) fate, addressing inconsistencies in LPS concentrations, bacterial sources and inflammatory models; (2) identify methodological gaps in current standardisation and elucidate molecular mechanisms governing Wnt/NF-κB signaling crosstalk in DPSCs under acute versus chronic inflammatory conditions; and (3) assess the therapeutic potential of GSK3β inhibitors and exosome-based interventions for dentine-pulp regeneration.

A comprehensive literature search was conducted across PubMed/MEDLINE, Scopus and Web of Science Core Collection for publications through November 2025. Search strategies combined four thematic domains: (1) cell populations ("dental pulp stem cell" OR "DPSC"); (2) signaling pathways ("Wnt" OR "β-catenin" AND "NF-κB" OR "crosstalk"); (3) biological processes ("odontogenic differentiation" OR "immunomodulation" OR "macrophage polarization"); (4) inflammatory context ("pulpitis" OR "inflammation" OR "LPS"). Articles were screened for relevance to Wnt/NF-κB interactions in dental pulp regeneration under inflammatory conditions.

Evidence demonstrates context-dependent Wnt/NF-κB crosstalk in DPSC fate specification. Low-dose LPS (< 1 μg/mL) stimulates reparative responses through coordinated Wnt/NF-κB activation, whereas sustained high-dose exposure (> 1 μg/mL) suppresses Wnt signaling via NF-κB-driven DKK1 upregulation, attenuating differentiation capacity. While no direct evidence links Wnt/NF-κB crosstalk to DPSC self-renewal, both pathways independently maintain stemness. Critically, DPSCs and macrophages exhibit reciprocal regenerative interactions: DPSC-derived Wnt3a polarises macrophages toward the anti-inflammatory M2 phenotype, while M2-secreted Wnt7b enhances DPSC odontogenic differentiation by suppressing NF-κB expression. However, standardised inflammation models remain lacking, hindering comprehensive elucidation of context-dependent mechanisms. Developing such models would clarify how inflammation temporally and spatially influences regenerative outcomes across clinical scenarios.