Single Cell Sequencing to Map Disease Processes Inside Atherosclerotic Plaques
Atherosclerotic plaques emerge from the dysfunction of macrophage cells tasked with clearing excess LDL particles and cholesterol from blood vessel walls. Once a plaque is established, however, it becomes a complex mess of maladaptive processes that interact with one another to contribute to further plaque growth, instability, and rupture. This includes an inflammatory feedback loop that draws in more macrophages to become overwhelmed and add their mass to the growing plaque, but also the involvement and transformation of other cell types in the blood vessel wall.
Cardiovascular diseases (CVDs), such as coronary artery disease (CAD), are the leading global causes of mortality and morbidity. The pathological hallmark of CAD is atherosclerosis, a chronic build-up of plaque inside arterial walls, which can lead to thrombus formation and myocardial infarction (MI) or stroke. This process involves a complex interplay of both immune and vascular cell types and cell state transitions along a continuum. In response to injury of the inner vessel wall layer, contractile smooth muscle cells (SMCs) transition to a more proliferative and migratory state and endothelial cells to a mesenchymal state in early and advanced atherosclerosis. Thus, a thorough assessment of cell heterogeneity and plasticity within the vessel wall is paramount to uncover new knowledge regarding atherosclerosis development and progression.
This study generates a comprehensive single-cell transcriptomic atlas of human atherosclerosis including 118,578 high-quality cells from atherosclerotic coronary and carotid arteries. By performing systematic benchmarking of integration methods, we mitigated data overcorrection while separating major cell lineages. Notably, we define cell subtypes that have not been previously identified from individual human atherosclerosis scRNA-seq studies.
Besides characterizing granular cell-type diversity and communication, we leverage this atlas to provide insights into smooth muscle cell (SMC) modulation. We integrate genome-wide association study data and uncover a critical role for modulated SMC phenotypes in CAD, myocardial infarction, and coronary calcification. Finally, we identify fibromyocyte/fibrochondrogenic SMC markers (LTBP1 and CRTAC1) as proxies of atherosclerosis progression and validate these through omics and spatial imaging analyses. Altogether, we create a unified atlas of human atherosclerosis informing cell state-specific mechanistic and translational studies of cardiovascular diseases.