Spatial Transcriptomics-Inspired Targeted Hydrogel for Dental Pulp Therapy via Strengthen Macrophage Communication

Tissue repair depends on how inflammatory cues drive regenerative cell-state transitions; a process poorly understood in human tissues. Human dental pulp provides an accessible, structurally well-defined injury model with robust clinical responses, facilitating in situ investigations of inflammatory signaling and endogenous regeneration. Here, we integrated high-resolution spatial transcriptomics with single-cell RNA sequencing (scRNA-seq) to chart its cellular ecosystem in health and caries. We resolved five major cell classes and four odontoblast progenitor subtypes, reconstructing their differentiation trajectories. Spatial mapping of immune cells combined with cell-cell communication analysis revealed that macrophages promote progenitor migration and odontoblastic differentiation via platelet-derived growth factor B (PDGFB) signaling. Inspired by this axis, we developed a hydrogel that amplifies macrophage PDGFB delivery via adeno-associated virus (AAV) vectors, which promoted mineralization in vitro and accelerated reparative dentin formation in a direct pulp-capping mouse model. Downstream analyses and pathway perturbation further confirmed the role of the PDGFB-Wnt-RUNX2 signaling axis in these progenitors. This study provides a spatially resolved single-cell framework showing how immune cues direct stem/progenitor fate to orchestrate regeneration, offering a targeted design paradigm for pulp regeneration biomaterials.