Single-Cell Genomics Reveals a Novel Cell State During Smooth Muscle Cell Phenotypic Switching and Potential Therapeutic Targets for Atherosclerosis in Mouse and Human.
Single-Cell Genomics Reveals a Novel Cell State During Smooth Muscle Cell Phenotypic Switching and Potential Therapeutic Targets for Atherosclerosis in Mouse and Human.
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DOI：
10.1161/circulationaha.120.048378
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发表时间：
2020-11-24
期刊：
影响因子：
37.8
通讯作者：
Reilly MP
中科院分区：
文献类型：
--
作者：
Pan H;Xue C;Auerbach BJ;Fan J;Bashore AC;Cui J;Yang DY;Trignano SB;Liu W;Shi J;Ihuegbu CO;Bush EC;Worley J;Vlahos L;Laise P;Solomon RA;Connolly ES;Califano A;Sims PA;Zhang H;Li M;Reilly MP
平滑肌细胞（Smooth muscle cells，SMC）通过表型转换在动脉粥样硬化中发挥重要作用。表型转换是指SMC发生去分化、迁移和转分化为其他细胞类型的病理过程。然而，SMC如何参与动脉粥样硬化的病理生理仍然是一个谜。为了揭示动脉粥样硬化过程中SMC转分化的轨迹，并确定疾病治疗的分子靶点，我们结合了SMC命运图和小鼠和人动脉粥样硬化斑块的单细胞RNA测序。我们还对分离的SMC衍生细胞进行了细胞生物学实验，进行了整合的人类基因组学研究，并在体内和体外进行了靶向SMC衍生细胞的药理学研究。我们发现SMC在动脉粥样硬化过程中转变为中间细胞状态，这在人颈动脉和冠状动脉的动脉粥样硬化斑块中也被发现。SMC衍生的中间细胞，称为“SEM”细胞，是多能的，并且可以分化为巨噬细胞样和纤维软骨细胞样细胞，以及向SMC表型返回。视黄酸（RA）信号被确定为SMC向SEM细胞转变的调节剂，并且RA信号在有症状的人类动脉粥样硬化中失调。人类基因组学揭示了RA信号靶基因位点中冠状动脉疾病（CAD）的全基因组关联研究（GWAS）信号的富集以及CAD风险等位基因与这些基因表达抑制之间的相关性。全反式维甲酸（ATRA），一种用于急性早幼粒细胞白血病的抗癌药物，激活RA信号传导，阻断SMC向SEM细胞的转化，减少动脉粥样硬化负荷，促进纤维帽稳定性。细胞特异性命运作图、单细胞基因组学和人类遗传学的整合为SMC生物学的复杂性增加了新的见解，并揭示了动脉粥样硬化性心血管疾病中SMC转变的治疗靶向调节途径。
Smooth muscle cells (SMC) play significant roles in atherosclerosis via phenotypic switching, a pathological process in which SMC dedifferentiation, migration and transdifferentiation into other cell types. Yet, how SMC contribute to pathophysiology of atherosclerosis remains elusive. 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 employed pharmacological studies targeting SMC-derived cells both in vivo and in vitro. We found that SMC 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, were multipotent and could differentiate into macrophage-like and fibrochondrocyte-like cells, as well as return towards 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 (GWAS) signals for coronary artery disease (CAD) in RA signaling target gene loci and correlation between CAD risk alleles and repressed expression of these genes. Activation of RA signaling by all-trans retinoic acid (ATRA), an anti-cancer drug for acute promyelocytic leukemia, blocked SMC transition to SEM cells, reduced atherosclerotic burden and promoted fibrous cap stability. Integration of cell-specific fate mapping, single-cell genomics and human genetics adds novel insights into the complexity of SMC biology and reveals regulatory pathways for therapeutic targeting of SMC transitions in atherosclerotic cardiovascular disease.