Slenders Lotte, Wesseling Marian, Wei Siting, Boltjes Arjan, Kapteijn Daniek M C, van de Kraak Petra, Depuydt Marie A C, Prange Koen H M, van den Dungen Noortje A M, Benavente Ernest D, de Kleijn Dominique P V, de Borst Gert J, de Winther Menno P J, den Ruijter Hester M, Owens Gary K, Pasterkamp Gerard, Mokry Michal
Central Diagnostics Laboratory, Department of Laboratories, Pharmacy and Biomedical Genetics, University Medical Center Utrecht, University Utrecht, Utrecht, the Netherlands.
Laboratory of Experimental Cardiology, Department of Cardiology, University Medical Center Utrecht, University Utrecht, Utrecht, the Netherlands.
Vascul Pharmacol. 2025 Jun;159:107498. doi: 10.1016/j.vph.2025.107498. Epub 2025 May 1.
Endothelial cells within atherosclerotic plaques can differentiate into a mesenchymal-like phenotype through endothelial-to-mesenchymal transition (EndoMT). Our understanding of the molecular mechanisms underlying EndoMT in human atherosclerosis remains limited. Current gene expression signatures are often derived from in vitro experiments or animal studies and typically reflect genes upregulated in fully differentiated mesenchymal cell states, while genes upregulated during the process are omitted. To address this knowledge gap, we utilized in silico lineage tracing in single-cell transcriptomic (scRNA-seq) data from human plaque tissues to identify the EndoMT gene expression signature.
We constructed three candidate EndoMT lineages across subpopulations of ECs and SMCs in human carotid scRNA-seq data (n = 46). We examined gene expression over the course of these lineages and identified a core signature of 73 genes upregulated in EndoMT. Upregulation of those genes was confirmed in EndoMT trajectories of other human datasets derived from plaque tissue and in Cdh5-Cre Rosa-eYFP apoE lineage-traced mice. Analysis of human carotid plaque bulk RNA-seq data (632 patients) found the association of core gene signature with fibrous and more stable histological phenotypes.
This study defines the core gene signature of EndoMT in human atherosclerotic plaques, which can serve as a reference for future studies and gene set enrichment analysis.
动脉粥样硬化斑块内的内皮细胞可通过内皮-间充质转化（EndoMT）分化为间充质样表型。我们对人类动脉粥样硬化中EndoMT潜在分子机制的理解仍然有限。目前的基因表达特征通常来自体外实验或动物研究，通常反映在完全分化的间充质细胞状态下上调的基因，而在此过程中上调的基因则被忽略。为了填补这一知识空白，我们利用人类斑块组织单细胞转录组（scRNA-seq）数据中的计算机谱系追踪来识别EndoMT基因表达特征。
我们在人类颈动脉scRNA-seq数据（n = 46）中的内皮细胞（ECs）和平滑肌细胞（SMCs）亚群中构建了三个候选EndoMT谱系。我们检查了这些谱系过程中的基因表达，并确定了在EndoMT中上调的73个基因的核心特征。在源自斑块组织的其他人类数据集的EndoMT轨迹以及Cdh5-Cre Rosa-eYFP载脂蛋白E谱系追踪小鼠中证实了这些基因的上调。对人类颈动脉斑块批量RNA-seq数据（632名患者）的分析发现核心基因特征与纤维性和更稳定的组织学表型相关。
本研究定义了人类动脉粥样硬化斑块中EndoMT的核心基因特征，可为未来研究和基因集富集分析提供参考。
