Mouse, Pig, and Human Atherosclerotic Lesions Have Common and Distinct Mesenchymal Cell Populations

Smooth muscle cell (SMC) proliferation and phenotypic transitioning drive the accumulation of a heterogeneous population of mesenchymal cells in advanced atherosclerosis, with additional contributions reported from endothelial-mesenchymal transitioning and invading adventitial cells. Animal models enable investigations of their recruitment and function, but it remains unclear to what extent mesenchymal cell populations in these models recapitulate human disease. Here, we compared mesenchymal cell diversity in typical mouse and pig experimental lesions with clinically relevant human plaques.

Single-cell RNA sequencing data sets from human carotid and coronary arteries, pig aorta and coronary arteries, and mouse brachiocephalic arteries were integrated using multiple parallel integration algorithms and gene homology-matching strategies. Cross-species comparisons were based on consensus among multiple methods, and cell populations of interest were localized in plaques using immunofluorescence and in situ hybridization.

The cross-species analysis revealed a conserved mesenchymal cell continuum, spanning contractile smooth muscle cells to extracellular matrix-producing fibroblast-like cells, that was stable across species and vascular beds. Yet several other populations differed between human and experimental lesions. Subpopulations of smooth muscle cells marked by DLX5 and RERGL expression were unique to human carotid and coronary plaques, respectively. Mesenchymal cell states with strong pro-angiogenic and inflammation-associated gene signatures were enriched in pig compared with human coronary lesions, with the proangiogenic phenotype associated with early stages of necrotic core development. Pericytes were solely present in pig and human plaques, while chondrocyte-like cells were abundant in mouse lesions, uncommon in pigs, and absent in the analyzed human lesions.

Human and experimental atherosclerosis share core mesenchymal cell phenotypes, but several distinct subtypes differ in presence or abundance. Recognizing these differences-whether reflecting species-specific regulation or variations in lesion site, stage, or disease activity-can inform the use of animal models to investigate smooth muscle cell-derived and other types of mesenchymal cells in atherosclerosis.