Li Zhijian, Rius Rigau Aleix, Xie Wenjie, Huang Linlin, Ye Wenjing, Li Yi-Nan, Matei Alexandru-Emil, Bergmann Christina, Shao Xiaohang, Zou Hejian, Wang Jiucun, Pinello Luca, Distler Jörg H W, He Rui, Liang Minrui
Broad Institute of MIT and Harvard, Cambridge, MA, USA; Molecular Pathology Unit, Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA.
Department of Internal Medicine 3, Rheumatology and Clinical Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen, Erlangen, Germany; Deutsches Zentrum Immuntherapie (DZI), FAU Erlangen-Nürnberg and University Hospital Erlangen, Erlangen, Germany.
Ann Rheum Dis. 2025 Jul;84(7):1231-1245. doi: 10.1016/j.ard.2025.04.025. Epub 2025 May 22.
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.
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.
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 serving to regulate CXCL12/CXCR4-mediated proinflammatory macrophage recruitment. Inhibition of CXCR4 attenuated skin and lung fibrosis in experimental fibrosis mouse models.
Our spatially resolved atlas uncovered dynamic fibroblast-macrophage interplay as a hallmark of fibrotic niche expansion. These findings offer spatiotemporal insights into disease mechanisms and pave the way for advanced mechanistic and therapeutic studies, bridging the gap between omics discovery and precision medicine.
基质-免疫相互作用塑造了系统性硬化症（SSc）的致病微环境，但纤维化形成背后的空间调控网络仍不清楚。我们旨在探索SSc皮肤中的组织结构和细胞协调，提供疾病机制的时空见解，并弥合组学发现与精准医学之间的差距。
我们使用10× Visium平台对10例弥漫性皮肤SSc患者和4例健康对照的皮肤活检组织进行了空间转录组学分析。这些发现通过更高分辨率的Stereo-seq转录组学、空间蛋白质组学以及来自SSc患者、SSc小鼠模型和伤口愈合驯鹿模型的单细胞RNA测序数据得到证实。进行体内和体外研究以验证关键调控途径。
分析了14份皮肤活检组织，发现SSc中富含成纤维细胞和巨噬细胞的纤维化微环境显著扩大，与临床严重程度相关。我们揭示了成纤维细胞和巨噬细胞的疾病特异性细胞状态，并评估了它们的空间依赖性和细胞间通讯。基于特征基因的分层能够识别出具有进行性疾病和治疗无反应表型的SSc患者。ACKR3（一种CXCL12诱饵受体）在肌成纤维细胞祖细胞中选择性表达，在向成熟肌成纤维细胞分化过程中减少，可能用于调节CXCL12/CXCR4介导的促炎巨噬细胞募集。抑制CXCR4可减轻实验性纤维化小鼠模型中的皮肤和肺部纤维化。
我们的空间分辨图谱揭示了动态的成纤维细胞-巨噬细胞相互作用是纤维化微环境扩张的标志。这些发现为疾病机制提供了时空见解，为深入的机制和治疗研究铺平了道路，弥合了组学发现与精准医学之间的差距。
