August 4, 2025

Single-cell Resolution Spatial Transcriptomics Delineates the Inflammatory Landscape of Human Dental Pulp: Regional Crosstalk and Therapeutic Implications

JZJianmao ZhengSun Yat-sen University FZFengyuan ZhangShanxi University YKYuanyuan KongNanjing Agricultural University

Key Points

Single-cell resolution spatial transcriptomics identifies distinct cellular populations in inflamed dental pulp.
Nine major cell types were mapped, highlighting significant changes in inflammatory fibroblasts and immune cells.
Increased activity of inflammatory pathways like TGFβ and MAPK correlates with pulpitis severity.
Findings could guide targeted vital pulp therapy, advancing treatment strategies for dental diseases.

Abstract

Abstract This study utilized single-cell resolution spatial transcriptomics (Visium HD) to investigate the spatial cellular architecture and molecular interactions in healthy and inflamed dental pulp, aiming to explore the pathological mechanisms of pulpitis and identify novel targets for vital pulp therapy. Spatial transcriptomic sequencing was performed on dental pulp tissues from two healthy individuals and two pulpitis patients, with integrated analyses including Seurat clustering, cell trajectory inference, GO enrichment, CellphoneDB interaction network modeling, and PROGENy pathway activity assessment to compare cellular heterogeneity and signaling regulation. Nine major cell types (fibroblasts, progenitor cells, endothelial cells, neural cells, plasma cells, B cells, T cells, monocytes, and macrophages) were identified, and their spatial distribution was mapped. Subclustering and differential expression analysis revealed that fibroblast (e.g., APOL2+/CCN2+) and progenitor cell (e.g., CDK5R1+/CCRL2+) subclusters exacerbated fibrosis and immune activation, while TMPRSS4+/CST5+ fibroblasts were critical for homeostasis. Pro-inflammatory endothelial subclusters (IGHG1+/CXCL13+) expanded, while anti-inflammatory subclusters (SERPINA5+/SERPINA3+) diminished, leading to vascular-immune imbalance. Upregulation of immunoglobulin genes and downregulation of MBP disrupted neural function, while inflamed pulp showed increased B cells and macrophages, decreased T cells and monocytes, and downregulated PTN. Inflammatory pathways (PI3K, EGFR, TGFβ, MAPK, Estrogen, NF-κB) were upregulated, with enhanced TGFβ signaling in endothelial cells. Intercellular interaction analysis showed altered APP-CD74 signaling in endothelial-macrophage interactions and disrupted CXCL14-mediated communication between immune and endothelial cells. These findings implicate cellular remodeling, including PTN downregulation, APP suppression, CXCL14 deficiency, CXCR4 upregulation, and TGFβ activation, as key drivers of pulpitis progression.

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