Human Single Cell Transcriptomics Reveals Dynamic Role of Smooth Muscle Cells and Enrichment of Immune Cell Subsets in Abdominal Aortic Aneurysms
Frank M. Davis, Lam Tsoi, Rachael Wasikowski, Johann Gudjonsson, Peter Henke, Katherine Gallagher
Surgery, University of Michigan, Ann Arbor, Michigan, United States
Objectives: Abdominal aortic aneurysms (AAA) represent the most common aortic aneurysm and are a highly prevalent life-threatening disease, characterized by aortic wall degradation leading to the fatal consequence of aortic rupture. Both immune and structural cells within the arterial wall contribute to aortic pathogenesis, however, gene specific alterations in these subsets are poorly understood.
Methods: We performed single-cell RNA (scRNA-seq) sequencing analysis of fresh human AAA tissue and control aorta harvested during surgery. Cells extracted from aortic tissue were analyzed and categorized with cluster identification. AAA-related changes were then examined by comparing characteristics of immune and structural cell types in AAA and control tissues, as well as detailed receptor-ligand interactions between cells in AAA tissue. We also examined which genes may be critical for AAAs by performing an integrative analysis of our scRNA-seq data with data from large GWAS on peripheral blood from AAA patients.
Results: Here, using scRNA-seq we provide the first comprehensive characterization of the cellular landscape in human AAA tissues. Unbiased clustering analysis of transcriptional profiles identified seventeen clusters representing eight-cell lineages. For immune cells, clustering analysis identified four T-cell subpopulations and five monocyte/macrophage subpopulations, with distinct transcriptional profiles in AAA tissue compared to controls (Figure A, B). Gene enrichment analysis on immune subsets identified multiple pathways that were only expressed in AAA tissue, including those involved in mitochondrial dysfunction, proliferation, and cytokine secretion. Moreover, detailed receptor-ligand analysis defined robust interactions between smooth muscle cells and myeloid populations in AAA tissues. Lastly, we integrated our aortic tissue scRNA-seq data with peripheral blood-based GWAS data to determine if previously identified biomarkers demonstrate tissue and cell-specific relevance for AAA development. Our analysis suggests that expression of SORT1 is significantly expressed in vascular smooth muscle cells from AAA tissue, is important for maintaining normal aortic wall function.
Conclusions: This study provides the first comprehensive evaluation of the cellular composition of the abdominal aortic wall and reveals how the gene expression landscape is altered in human AAAs. The identification of specific cellular subsets in human AAAs, as well as identification of important pathways and cell-cell interactions will allow for targeted therapies for AAAs.
Back to 2022 Abstracts