Microanatomy of the Human Atherosclerotic Plaque by Single-Cell Transcriptomics.
Microanatomy of the Human Atherosclerotic Plaque by Single-Cell Transcriptomics.
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DOI：
10.1161/circresaha.120.316770
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发表时间：
2020-11-06
影响因子：
20.1
通讯作者：
Pasterkamp G
中科院分区：
文献类型：
--
作者：
Depuydt MAC;Prange KHM;Slenders L;Örd T;Elbersen D;Boltjes A;de Jager SCA;Asselbergs FW;de Borst GJ;Aavik E;Lönnberg T;Lutgens E;Glass CK;den Ruijter HM;Kaikkonen MU;Bot I;Slütter B;van der Laan SW;Yla-Herttuala S;Mokry M;Kuiper J;de Winther MPJ;Pasterkamp G
文本中提供了补充数字内容。动脉粥样硬化病变以其细胞异质性而闻名，但人类斑块细胞内的分子复杂性尚未得到充分评估。使用单细胞转录组学和染色质可及性，我们获得了更好地了解人类动脉粥样硬化的病理生理学基础。我们对人颈动脉粥样硬化斑块进行了单细胞RNA和单细胞ATAC测序，以确定起作用的细胞并确定其转录组和表观基因组特征。我们鉴定了14种不同的细胞群，包括内皮细胞、平滑肌细胞、肥大细胞、B细胞、髓样细胞和T细胞，并鉴定了多种细胞活化状态，提示了细胞相互转化。在内皮细胞群中，我们定义了具有血管生成能力和内皮细胞向间质细胞转化的明显迹象的亚群。CD4+和CD8+ T细胞显示出基于活化的亚类，每个亚类都从细胞毒性逐渐下降到更静止的表型。骨髓细胞包括2个促炎性巨噬细胞群体，显示IL（白细胞介素）1B或TNF（肿瘤坏死因子）表达，以及表达TREM2（骨髓细胞2上表达的触发受体）并显示纤维化促进表型的泡沫细胞样群体。ATACseq数据鉴定了与骨髓亚群相关的特异性转录因子和两种细胞类型之间相互激活的T细胞细胞因子谱。最后，使用公共全基因组关联研究数据识别的心血管疾病易感基因在病变巨噬细胞、内皮细胞和平滑肌细胞中特别富集。这项研究提供了一个基于转录组的人类动脉粥样硬化斑块的细胞景观，并强调了疾病部位的细胞可塑性和细胞间通讯。对动脉粥样硬化中起作用的细胞群落的详细定义将促进基于细胞的新型干预靶点的映射，这些靶点与人类疾病的治疗具有直接的功能相关性。
Supplemental Digital Content is available in the text. Atherosclerotic lesions are known for their cellular heterogeneity, yet the molecular complexity within the cells of human plaques has not been fully assessed. Using single-cell transcriptomics and chromatin accessibility, we gained a better understanding of the pathophysiology underlying human atherosclerosis. We performed single-cell RNA and single-cell ATAC sequencing on human carotid atherosclerotic plaques to define the cells at play and determine their transcriptomic and epigenomic characteristics. We identified 14 distinct cell populations including endothelial cells, smooth muscle cells, mast cells, B cells, myeloid cells, and T cells and identified multiple cellular activation states and suggested cellular interconversions. Within the endothelial cell population, we defined subsets with angiogenic capacity plus clear signs of endothelial to mesenchymal transition. CD4+ and CD8+ T cells showed activation-based subclasses, each with a gradual decline from a cytotoxic to a more quiescent phenotype. Myeloid cells included 2 populations of proinflammatory macrophages showing IL (interleukin) 1B or TNF (tumor necrosis factor) expression as well as a foam cell-like population expressing TREM2 (triggering receptor expressed on myeloid cells 2) and displaying a fibrosis-promoting phenotype. ATACseq data identified specific transcription factors associated with the myeloid subpopulation and T cell cytokine profiles underlying mutual activation between both cell types. Finally, cardiovascular disease susceptibility genes identified using public genome-wide association studies data were particularly enriched in lesional macrophages, endothelial, and smooth muscle cells. This study provides a transcriptome-based cellular landscape of human atherosclerotic plaques and highlights cellular plasticity and intercellular communication at the site of disease. This detailed definition of cell communities at play in atherosclerosis will facilitate cell-based mapping of novel interventional targets with direct functional relevance for the treatment of human disease.