Rius Rigau Aleix, Liang Minrui, Devakumar Veda, Neelagar Ranjana, Matei Alexandru-Emil, Györfi Andrea-Hermina, Bergmann Christina, Filla Tim, Fedorchenko Vladyslav, Schett Georg, Distler Jörg H W, Li Yi-Nan
Department of Internal Medicine 3 - Rheumatology and Clinical Immunology, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Bayern, Germany.
Deutsches Zentrum Immuntherapie (DZI), Erlangen University Hospital, Erlangen, Bayern, Germany.
Ann Rheum Dis. 2024 Oct 23. doi: 10.1136/ard-2024-226336.
Transcriptomic data demonstrated that fibroblasts are heterogeneous with functionally diverse subpopulations. Although fibroblasts are key effector cells of fibrotic diseases such as systemic sclerosis (SSc), they have not yet been characterised spatially at the cellular level. Here, we aimed to investigate fibroblast subpopulations using imaging mass cytometry (IMC) as a proteomic-based, spatially resolved omics approach.
We applied IMC to deconvolute the heterogeneity of 49 969 cells including 6501 fibroblasts at the single-cell level, to analyse their spatial distribution and to characterise their cellular niches in skin sections of patients with SSc and controls in situ.
We identified 13 different subpopulations of fibroblasts in SSc and control skin, the proportion increases in five fibroblast subpopulations (myofibroblasts, FAP, S1PR, Thy1;ADAM12;PU.1 and ADAM12;GLI1 fibroblasts) and decreases in three subpopulations (TFAM, PI16;FAP and Thy1;ADAM12 fibroblasts). Several fibroblast subpopulations demonstrated spatial enrichment and altered cellular interactions in SSc. The proportion of S1PR-fibroblast positively correlated with more extensive skin fibrosis, whereas high numbers of PI16;FAP-fibroblasts were associated with milder skin fibrosis. The frequency of aberrant cellular interaction between S1PR and ADAM12;GLI1-fibroblasts also positively associated with the extent of skin fibrosis in SSc.
Using IMC, we demonstrated profound changes in composition and localisation of the majority of fibroblast subpopulations in SSc skin. These findings may provide a rationale for specific targeting of deregulated fibroblast subpopulations in SSc. Quantification of S1PR-fibroblast and PI16;FAP-fibroblasts may offer potential for patient stratification according to severity of skin fibrosis.
转录组数据表明成纤维细胞具有异质性，存在功能多样的亚群。尽管成纤维细胞是系统性硬化症（SSc）等纤维化疾病的关键效应细胞，但尚未在细胞水平上对其进行空间特征描述。在此，我们旨在使用成像质谱流式细胞术（IMC）作为基于蛋白质组学的、空间分辨的组学方法来研究成纤维细胞亚群。
我们应用IMC在单细胞水平上解析包括6501个成纤维细胞在内的49969个细胞的异质性，分析它们的空间分布，并原位表征它们在SSc患者和对照皮肤切片中的细胞微环境。
我们在SSc和对照皮肤中鉴定出13种不同的成纤维细胞亚群，五个成纤维细胞亚群（肌成纤维细胞、FAP、S1PR、Thy1;ADAM12;PU.1和ADAM12;GLI1成纤维细胞）的比例增加，三个亚群（TFAM、PI16;FAP和Thy1;ADAM12成纤维细胞）的比例降低。几个成纤维细胞亚群在SSc中表现出空间富集和细胞间相互作用改变。S1PR成纤维细胞的比例与更广泛的皮肤纤维化呈正相关，而大量的PI16;FAP成纤维细胞与较轻的皮肤纤维化相关。SSc中S1PR与ADAM12;GLI1成纤维细胞之间异常细胞间相互作用的频率也与皮肤纤维化程度呈正相关。
使用IMC，我们证明了SSc皮肤中大多数成纤维细胞亚群的组成和定位发生了深刻变化。这些发现可能为特异性靶向SSc中失调的成纤维细胞亚群提供理论依据。S1PR成纤维细胞和PI16;FAP成纤维细胞的定量可能为根据皮肤纤维化严重程度对患者进行分层提供潜力。
