Mouse, pig, and human atherosclerotic lesions have common and distinct mesenchymal cell populations

The proliferation and phenotypic modulation of smooth muscle cells (SMCs) to alternative mesenchymal states is a key process by which atherosclerotic lesions grow. The underlying mechanisms can be studied in mouse and pig atherosclerosis, but it remains unclear to what extent the mesenchymal plaque cell types in these species recapitulate human disease. Here, we integrate published and new single-cell RNA sequencing data of plaque mesenchymal cells from human carotid and coronary arteries, pig aorta and coronary arteries, and mouse brachiocephalic arteries. By applying consensus across multiple integration and gene homology-matching strategies, we identify a conserved core continuum of mesenchymal plaque cells, ranging from SMCs to extracellular matrix-producing fibroblast-like cells, which is stable across species and vascular beds. Notably, several other populations differed between human and experimental lesions. Subpopulations of SMCs marked by DLX5 and RERGL expression were specific to human carotid and coronary plaques, respectively. Mesenchymal cell states with strong pro-angiogenic and inflammation-associated gene signatures were identified in pig, but not human, coronary plaque datasets, with the pro-angiogenic phenotype associated with early stages of necrotic core development. Pericytes were solely present in pig and human plaques, while chondrocyte-like cells were unique to mouse lesions. The presented interspecies maps of mesenchymal cell diversity, and their markers may inform translational research into the role of SMCs and their derived progeny in atherosclerosis.