Spatial multiomics decipher fibroblast–macrophage dynamics in systemic sclerosis

作者：Zhijian Li, Aleix Rius Rigau, Wenjie Xie, Linlin Huang, Wenjing Ye, Yinan Li, Alexandru‐Emil Matei, Christina Bergmann, Xian Shao, Hejian Zou, Jiucun Wang, Luca Pinello, Jörg H. W. Distler, Rui He, Minrui Liang · 发表于：Annals of the Rheumatic Diseases · 年份：2025 · DOI：10.1016/j.ard.2025.04.025 · 被引用次数：25 · 研究领域：Systemic Sclerosis and Related Diseases、Single-cell and spatial transcriptomics、Inflammatory Myopathies and Dermatomyositis

OBJECTIVES: Stromal-immune crosstalk shapes the pathogenic microenvironment of systemic sclerosis (SSc), but the spatial regulatory networks underlying fibrogenesis remain poorly defined. We aimed to explore tissue organisation and cell coordination in SSc skin, providing spatiotemporal insights into disease mechanisms and bridging the gap between omics discovery and precision medicine. METHODS: We performed spatial transcriptomics on skin biopsies from 10 patients with diffuse cutaneous SSc and 4 healthy controls using the 10× Visium platform. These findings were confirmed using higher-resolution Stereo-seq transcriptomics, spatial proteomics, and single-cell RNA sequencing data from patients with SSc, SSc mouse models, and wound-healing reindeer models. In vivo and in vitro studies were conducted to validate the key regulatory pathways. RESULTS: Fourteen skin biopsies were analysed, revealing significant expansion of fibrotic niches enriched with fibroblasts and macrophages in SSc, correlating with clinical severity. We revealed disease-specific cell states of fibroblasts and macrophages and evaluated their spatial dependency and cell-cell communication. Stratification based on signature genes enabled the identification of patients with SSc with progressive disease and treatment-nonresponsive phenotype. ACKR3 (a CXCL12 decoy receptor) was selectively expressed in myofibroblast progenitors, which diminished during differentiation towards mature myofibroblast, potentially ser...