Single-Cell Transcriptome Analysis Reveals Dynamic Cell Populations and Differential Gene Expression Patterns in Control and Aneurysmal Human Aortic Tissue.
Single-Cell Transcriptome Analysis Reveals Dynamic Cell Populations and Differential Gene Expression Patterns in Control and Aneurysmal Human Aortic Tissue.
复制标题
DOI：
10.1161/circulationaha.120.046528
复制
发表时间：
2020-10-06
期刊：
影响因子：
37.8
通讯作者：
LeMaire SA
中科院分区：
文献类型：
--
作者：
Li Y;Ren P;Dawson A;Vasquez HG;Ageedi W;Zhang C;Luo W;Chen R;Li Y;Kim S;Lu HS;Cassis LA;Coselli JS;Daugherty A;Shen YH;LeMaire SA
胸升主动脉瘤（ATAA）是由主动脉壁逐渐减弱和扩张引起的，可导致主动脉夹层、破裂和其他危及生命的并发症。为了提高我们对ATAA发病机制的理解，我们试图全面表征升主动脉壁的细胞组成，并确定人类ATAA组织中每个细胞群的分子变化。我们对11名研究参与者的升主动脉组织进行了单细胞RNA测序（sc-RNAseq）分析，包括8名ATAA患者（4名女性和4名男性）和3名对照组（2名女性和1名男性）。利用sc-RNAseq数据对主动脉组织中提取的细胞进行分析和分类，进行聚类鉴定。然后通过比较ATAA和对照组织之间每种细胞类型的比例和基因表达谱来检查ATAA相关的变化。我们还通过将sc-RNAseq数据与全基因组关联研究（GWAS）的公开数据进行整合分析，研究了哪些基因可能对ATAA至关重要。我们鉴定了人类升主动脉组织中的11种主要细胞类型;这些细胞的高分辨率重新聚类进一步将它们分为40个亚型。平滑肌细胞、巨噬细胞和T淋巴细胞有多种亚型，表明这些细胞在主动脉壁有多种功能群。一般来说，与对照组织相比，ATAA组织的非免疫细胞较少，免疫细胞（尤其是T淋巴细胞）较多。差异基因表达数据表明，ATAA组织中存在广泛的线粒体功能障碍。此外，我们的sc-RNAseq数据与公开的GWAS数据和启动子捕获Hi-C数据的综合分析表明，ERG （ETS[红母细胞转化特异性]相关基因）在维持正常的主动脉壁功能中发挥重要作用。我们的研究提供了升主动脉壁细胞组成的全面评估，并揭示了人类ATAA组织中基因表达景观是如何改变的。这一研究成果对认识ATAA的形成和演化具有重要意义。
Ascending thoracic aortic aneurysm (ATAA) is caused by the progressive weakening and dilatation of the aortic wall and can lead to aortic dissection, rupture, and other life-threatening complications. To improve our understanding of ATAA pathogenesis, we sought to comprehensively characterize the cellular composition of the ascending aortic wall and to identify molecular alterations in each cell population of human ATAA tissues. We performed single-cell RNA sequencing (sc-RNAseq) analysis of ascending aortic tissues from 11 study participants, including 8 patients with ATAA (4 women and 4 men) and 3 controls (2 women and 1 man). Cells extracted from aortic tissue were analyzed and categorized by using sc-RNAseq data to perform cluster identification. ATAA-related changes were then examined by comparing the proportions of each cell type and the gene expression profiles between ATAA and control tissues. We also examined which genes may be critical for ATAA by performing the integrative analysis of our sc-RNAseq data with publicly available data from genome-wide association studies (GWAS). We identified 11 major cell types in human ascending aortic tissue; the high-resolution reclustering of these cells further divided them into 40 subtypes. Multiple subtypes were observed for smooth muscle cells, macrophages, and T lymphocytes, suggesting that these cells have multiple functional populations in the aortic wall. Generally, ATAA tissues had fewer nonimmune cells and more immune cells, especially T lymphocytes, than did control tissues. Differential gene expression data suggested the presence of extensive mitochondrial dysfunction in ATAA tissues. In addition, integrative analysis of our sc-RNAseq data with public GWAS data and promoter capture Hi-C data suggested that ERG (ETS [erythroblast transformation-specific] related gene) exerts an important role in maintaining normal aortic wall function. Our study provides a comprehensive evaluation of the cellular composition of the ascending aortic wall and reveals how the gene expression landscape is altered in human ATAA tissue. The information from this study makes important contributions to our understanding of ATAA formation and progression.