The Immunoregulatory Architecture of the Adult Oral Cavity

作者：Bruno Fernandes Matuck, Khoa Huynh, Diana Pereira, Quinn T. Easter, XiuYu Zhang, Meik Kunz, Aditya Pratapa, Brittany T Rupp, Nikhil Kumar, Ameer Ghodke, Alex Predeus, Lilli Szabo, Stefan Hartmann, Nadja Harnischfeger, Zohreh Khavandgar, Margaret Beach, Paola Pérez, Benedikt S Nilges, Maria Moreno, Kang I. Ko, Rohit Singh, PURUSHOTHAMA RAO TATA, Sarah A. Teichmann, Adam J. Kimple, Sarah Pringle, Kai Kretzschmar, Blake M. Warner, Inês Sequeira, Jinze Liu, Kevin M. Byrd · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2024 · DOI：10.1101/2024.12.01.626279 · 被引用次数：12 · 研究领域：Salivary Gland Disorders and Functions、Periodontal Regeneration and Treatments、Mesenchymal stem cell research

The immunoregulatory architecture of human oral tissues remains poorly defined despite their central role as barrier interfaces. We present the first integrated single cell and dual platform spatial proteotranscriptomic atlas of oral tissues, profiling >250,000 single-cell transcriptomes and >4 million spatially-resolved cells across 13 niches. Using our AI enabled AstroSuite (TACIT, Constellation, STARComm, hist2omics), we defined tissue cellular neighborhoods (TCNs) and multicellular interaction modules (MCIMs) in health, revealing peri-epithelial fibroblast-centered hubs enriched for effector cytokines. We harmonized eight fibroblast subtypes (universal, immune, peri-epithelial, peri-vascular, peri-neural, APC like, stress-responsive, and myofibroblasts) with stress-responsive subtypes partitioning between mucosae (Type I) and glands (Type II). Spatial multiomics mapped receptor ligand circuits and showed mucosal stress-responsive fibroblasts as immunoregulatory hubs. In chronic periodontitis, niche-aware integration of healthy and diseased datasets revealed rewiring of fibroblast phenotypes and ligand::receptor networks into interdigitated inflammatory and reparative niches. Disease neighborhoods exhibited fragmentation, expansion of MHC_I, MHC_II;, and PDL1; fibroblasts, and predicted spatial engagement with T cells at ectopic lymphoid structures. Drug2Cell analysis highlighted druggable stromal::immune networks. Together, this proteotranscriptomic atlas positions fibrob...