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Single-cell Transcriptome Analysis Reveals Dynamic Cell Populations and Differential Gene Expression Patterns in Control and Aneurysmal Human Aortic Tissue

ABSTRACT: BACKGROUND: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE155468 | GEO | 2020/10/01

REPOSITORIES: GEO

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Project description:The ascending aorta is a common site for age-related aortic diseases. Therefore, age-related changes in the cellular composition and development in the normal human ascending aorta tissue is associated with the pathogenesis of aortic diseases. In this study, we performed single-cell transcriptome sequencing of the normal ascending aorta tissues from 6 organ donors of different ages, namely, the young group (3 months, 1 year, 3 years, and 12 years) and the old group (57 years and 58 years), and evaluated the changes in the composition of the cell types, cellular phenotypes, and the cell-cell communication. The single-cell sequencing data analysis of 65,470 cells from the 6 donor aortic wall specimens identified ten cell types (27 high-resolution subtypes of cells), including endothelial cells, smooth muscle cells, fibroblasts, mesenchymal cells, mesenchymal-fibroblast cells, macrophages, Schwann cells, T cells, natural killer cells, and B cells. In comparison with the young group, the aortic wall tissue of the old group showed significant reduction in the proportion of endothelial cells (young vs. old, 22.47% vs. 10.37%), smooth muscle cells (20.40% vs. 18.50%), fibroblasts (30.21% vs. 13.29%), and mesenchymal cells (5.12% vs 1.55%) and significant increase in the proportion of macrophages (10.94% vs. 17.02%) and T cells (3.80% vs. 26.01%). Functional enrichment analysis of the ligand-receptor pairs between the macrophages and the T cells demonstrated enrichment of pathways related to inflammation and endocrine resistance in the elderly group. Immunohistochemical analysis of the aortic tissue from the 58-year-old donor showed higher expression of the M2 macrophage marker, CD163, in comparison with the aortic tissue of the 12-year-old donor. This confirmed the results of the single-cell sequencing analysis. In summary, single-cell sequencing analysis of the normal ascending aorta tissues from multiple donors of different ages demonstrated significant age-related changes in the proportions of multiple cell types, cellular phenotypes, and cell-cell communications. These age-related changes are likely involved in the pathogenesis of age-related aortic diseases.

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Single-cell Transcriptome Analysis Reveals Dynamic Cell Populations and Differential Gene Expression Patterns in Control and Aneurysmal Human Aortic Tissue

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