Department of Internal Medicine 3, Rheumatology and Clinical Immunology (A.R.R., G.S., J.H.W.D., M.L.), Friedrich-Alexander-University Erlangen-Nürnberg and University Hospital Erlangen, Germany.
Deutsches Zentrum Immuntherapie (A.R.R., G.S., J.H.W.D., M.L.), Friedrich-Alexander-University Erlangen-Nürnberg and University Hospital Erlangen, Germany.
Circ Res. 2024 Mar 29;134(7):875-891. doi: 10.1161/CIRCRESAHA.123.323299. Epub 2024 Mar 5.
Systemic sclerosis (SSc) is a connective tissue disease that can serve as a model to study vascular changes in response to inflammation, autoimmunity, and fibrotic remodeling. Although microvascular changes are the earliest histopathologic manifestation of SSc, the vascular pathophysiology remains poorly understood.
We applied spatial proteomic approaches to deconvolute the heterogeneity of vascular cells at the single-cell level in situ and characterize cellular alterations of the vascular niches of patients with SSc. Skin biopsies of patients with SSc and control individuals were analyzed by imaging mass cytometry, yielding a total of 90 755 cells including 2987 endothelial cells and 4096 immune cells.
We identified 7 different subpopulations of blood vascular endothelial cells (VECs), 2 subpopulations of lymphatic endothelial cells, and 3 subpopulations of pericytes. A novel population of CD34;αSMA (α-smooth muscle actin);CD31 VECs was more common in SSc, whereas endothelial precursor cells were decreased. Co-detection by indexing and tyramide signal amplification confirmed these findings. The microenvironment of CD34;αSMA;CD31 VECs was enriched for immune cells and myofibroblasts, and CD34;αSMA;CD31 VECs expressed markers of endothelial-to-mesenchymal transition. The density of CD34;αSMA;CD31 VECs was associated with clinical progression of fibrosis in SSc.
Using spatial proteomics, we unraveled the heterogeneity of vascular cells in control individuals and patients with SSc. We identified CD34;αSMA;CD31 VECs as a novel endothelial cell population that is increased in patients with SSc, expresses markers for endothelial-to-mesenchymal transition, and is located in close proximity to immune cells and myofibroblasts. CD34;αSMA;CD31 VEC counts were associated with clinical outcomes of progressive fibrotic remodeling, thus providing a novel cellular correlate for the crosstalk of vasculopathy and fibrosis.
系统性硬化症（SSc）是一种结缔组织疾病，可作为研究炎症、自身免疫和纤维重塑反应中血管变化的模型。尽管微血管变化是 SSc 的最早组织病理学表现，但血管病理生理学仍知之甚少。
我们应用空间蛋白质组学方法，在原位对血管细胞的异质性进行去卷积，并对 SSc 患者血管龛的细胞变化进行特征描述。对 SSc 患者和对照个体的皮肤活检进行成像质谱细胞分析，共分析了 90755 个细胞，包括 2987 个内皮细胞和 4096 个免疫细胞。
我们鉴定出 7 种不同的血管内皮细胞（VEC）亚群、2 种淋巴管内皮细胞亚群和 3 种周细胞亚群。在 SSc 中更常见的是 CD34；αSMA（α-平滑肌肌动蛋白）；CD31 VEC 的新型群体，而内皮祖细胞减少。通过索引和酪胺信号扩增的共同检测证实了这些发现。CD34；αSMA；CD31 VEC 的微环境富含免疫细胞和肌成纤维细胞，CD34；αSMA；CD31 VEC 表达内皮-间质转化的标志物。CD34；αSMA；CD31 VEC 的密度与 SSc 纤维化的临床进展相关。
使用空间蛋白质组学，我们揭示了对照个体和 SSc 患者血管细胞的异质性。我们鉴定出 CD34；αSMA；CD31 VEC 作为一种新型的内皮细胞群体，在 SSc 患者中增加，表达内皮-间质转化的标志物，并且位于免疫细胞和肌成纤维细胞附近。CD34；αSMA；CD31 VEC 计数与进行性纤维化重塑的临床结局相关，因此为血管病变和纤维化的串扰提供了新的细胞相关性。
