Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22908, USA; Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA.
Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA.
Cell Rep. 2023 Nov 28;42(11):113380. doi: 10.1016/j.celrep.2023.113380. Epub 2023 Nov 10.
Coronary artery disease (CAD) is characterized by atherosclerotic plaque formation in the arterial wall. CAD progression involves complex interactions and phenotypic plasticity among vascular and immune cell lineages. Single-cell RNA-seq (scRNA-seq) studies have highlighted lineage-specific transcriptomic signatures, but human cell phenotypes remain controversial. Here, we perform an integrated meta-analysis of 22 scRNA-seq libraries to generate a comprehensive map of human atherosclerosis with 118,578 cells. Besides characterizing granular cell-type diversity and communication, we leverage this atlas to provide insights into smooth muscle cell (SMC) modulation. We integrate genome-wide association study data and uncover a critical role for modulated SMC phenotypes in CAD, myocardial infarction, and coronary calcification. Finally, we identify fibromyocyte/fibrochondrogenic SMC markers (LTBP1 and CRTAC1) as proxies of atherosclerosis progression and validate these through omics and spatial imaging analyses. Altogether, we create a unified atlas of human atherosclerosis informing cell state-specific mechanistic and translational studies of cardiovascular diseases.
冠状动脉疾病（CAD）的特征是动脉壁中粥样斑块的形成。CAD 的进展涉及血管和免疫细胞谱系之间复杂的相互作用和表型可塑性。单细胞 RNA 测序（scRNA-seq）研究强调了谱系特异性转录组特征，但人类细胞表型仍存在争议。在这里，我们对 22 个 scRNA-seq 文库进行了综合荟萃分析，生成了包含 118578 个细胞的人类动脉粥样硬化综合图谱。除了描述颗粒状细胞类型多样性和细胞间通讯外，我们还利用这个图谱深入了解平滑肌细胞（SMC）的调节。我们整合全基因组关联研究数据，揭示了调节后的 SMC 表型在 CAD、心肌梗死和冠状动脉钙化中的关键作用。最后，我们确定了成纤维肌细胞/纤维软骨样 SMC 标志物（LTBP1 和 CRTAC1）作为动脉粥样硬化进展的替代标志物，并通过组学和空间成像分析进行了验证。总之，我们创建了一个统一的人类动脉粥样硬化图谱，为心血管疾病的细胞状态特异性机制和转化研究提供了信息。
