Transcriptional and Cellular Diversity of the Human Heart.
Transcriptional and Cellular Diversity of the Human Heart.
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DOI：
10.1161/circulationaha.119.045401
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发表时间：
2020-08-04
期刊：
影响因子：
37.8
通讯作者：
Ellinor PT
中科院分区：
文献类型：
--
作者：
Tucker NR;Chaffin M;Fleming SJ;Hall AW;Parsons VA;Bedi KC Jr;Akkad AD;Herndon CN;Arduini A;Papangeli I;Roselli C;Aguet F;Choi SH;Ardlie KG;Babadi M;Margulies KB;Stegmann CM;Ellinor PT
人类心脏需要一组复杂的特殊细胞类型来完成它的基本功能。对心脏复杂的细胞环境有更深入的了解，对于增进我们对心脏稳态和病理的理解至关重要。由于低输入rna测序的最新进展已经允许在单细胞分辨率下大规模定义细胞转录组，在这里，我们应用这些方法来评估非衰竭人类心脏的细胞和转录多样性。采用微流控封装和条形码技术对来自7名无明显心脏疾病的人类供体样本进行单核RNA测序。然后根据高度可变基因的转录谱对单个核转录组进行聚类。这些聚类被用作室间和性别间差异基因表达分析的基础，并与遗传和药理学数据交叉。我们对287269个单个心脏细胞核的转录组进行了测序，揭示了人类心脏中9种主要细胞类型和20种细胞类型亚群。细胞亚类包括两组不同的常驻巨噬细胞，四种内皮细胞亚型和两种成纤维细胞亚群。通过心脏室或性别对细胞转录组进行比较，不仅揭示了心肌细胞转录程序的多样性，而且还揭示了参与细胞外基质重塑和血管形成的亚型的多样性。利用遗传关联数据，我们确定了细胞亚型在心脏特征和疾病中的作用。最后，我们的数据集与心脏临床测试面板上的基因和可药物基因组的交叉揭示了细胞特异性的惊人模式。使用大规模单核RNA测序，我们已经定义了正常人类心脏的转录和细胞多样性。我们对心脏内离散细胞亚型和差异表达基因的鉴定将最终促进心血管疾病新疗法的发展。
The human heart requires a complex ensemble of specialized cell types to perform its essential function. A greater knowledge of the intricate cellular milieu of the heart is critical to increase our understanding of cardiac homeostasis and pathology. As recent advances in low input RNA-sequencing have allowed definitions of cellular transcriptomes at single cell resolution at scale, here we have applied these approaches to assess the cellular and transcriptional diversity of the non-failing human heart. Microfluidic encapsulation and barcoding was used to perform single nuclear RNA sequencing with samples from seven human donors, selected for their absence of overt cardiac disease. Individual nuclear transcriptomes were then clustered based upon transcriptional profiles of highly variable genes. These clusters were used as the basis for between-chamber and between-sex differential gene expression analyses and intersection with genetic and pharmacologic data. We sequenced the transcriptomes of 287,269 single cardiac nuclei, revealing a total of 9 major cell types and 20 subclusters of cell types within the human heart. Cellular subclasses include two distinct groups of resident macrophages, four endothelial subtypes, and two fibroblasts subsets. Comparisons of cellular transcriptomes by cardiac chamber or sex reveal diversity not only in cardiomyocyte transcriptional programs, but also in subtypes involved in extracellular matrix remodeling and vascularization. Using genetic association data, we identified strong enrichment for the role of cell subtypes in cardiac traits and diseases. Finally, intersection of our dataset with genes on cardiac clinical testing panels and the druggable genome reveals striking patterns of cellular specificity. Using large-scale single nuclei RNA sequencing, we have defined the transcriptional and cellular diversity in the normal human heart. Our identification of discrete cell subtypes and differentially expressed genes within the heart will ultimately facilitate the development of new therapeutics for cardiovascular diseases.