Single-Cell Genomics Reveals a Novel Cell State During Smooth Muscle Cell Phenotypic Switching and Potential Therapeutic Targets for Atherosclerosis in Mouse and Human

作者：Huize Pan, Chenyi Xue, Benjamin J. Auerbach, Jiaxin Fan, Alexander C. Bashore, Jian Cui, Dina Y. Yang, Sarah B. Trignano, Wen Liu, Jianting Shi, Chinyere O. Ihuegbu, Erin Bush, Jeremy Worley, Lukas Vlahos, Pasquale Laise, Robert A. Solomon, E. Sander Connolly, Andrea Califano, Peter A. Sims, Hanrui Zhang, Mingyao Li, Muredach P. Reilly · 发表于：Circulation · 年份：2020 · DOI：10.1161/circulationaha.120.048378 · 被引用次数：649 · 研究领域：Single-cell and spatial transcriptomics、Atherosclerosis and Cardiovascular Diseases、Neutrophil, Myeloperoxidase and Oxidative Mechanisms

BACKGROUND: Smooth muscle cells (SMCs) play significant roles in atherosclerosis via phenotypic switching, a pathological process in which SMC dedifferentiation, migration, and transdifferentiation into other cell types. Yet how SMCs contribute to the pathophysiology of atherosclerosis remains elusive. METHODS: To reveal the trajectories of SMC transdifferentiation during atherosclerosis and to identify molecular targets for disease therapy, we combined SMC fate mapping and single-cell RNA sequencing of both mouse and human atherosclerotic plaques. We also performed cell biology experiments on isolated SMC-derived cells, conducted integrative human genomics, and used pharmacological studies targeting SMC-derived cells both in vivo and in vitro. RESULTS: We found that SMCs transitioned to an intermediate cell state during atherosclerosis, which was also found in human atherosclerotic plaques of carotid and coronary arteries. SMC-derived intermediate cells, termed "SEM" cells (stem cell, endothelial cell, monocyte), were multipotent and could differentiate into macrophage-like and fibrochondrocyte-like cells, as well as return toward the SMC phenotype. Retinoic acid (RA) signaling was identified as a regulator of SMC to SEM cell transition, and RA signaling was dysregulated in symptomatic human atherosclerosis. Human genomics revealed enrichment of genome-wide association study signals for coronary artery disease in RA signaling target gene loci and correlation between coronary...