Abstract Body: Atherosclerosis, a major cause of global mortality, is a chronic inflammatory disease characterized by the accumulation of lipid-laden foam cells within the arterial wall. Its development results from intricate interactions among macrophages, foam cells, vascular smooth muscle cells, and their surrounding environment. Cellular pathological phenotypic changes and secreted molecules within the microenvironment contribute to plaque vulnerability and size.
A comprehensive multi-omic cell atlas of human atherosclerotic coronary arteries offers significant insights for forming therapeutic hypotheses to reduce foam cell formation, promote foam cell regression, or manipulate the intricate crosstalk among various cell types. To validate the hypothesis, we develop in vitro cell disease models for mechanistic studies and the screening of new therapeutic targets.
In our study, we developed an in vitro THP-1 derived foamy macrophage cell model that replicates the characteristics of foam cells present in human atherosclerotic plaques. We observed the accumulation of oxidized low-density lipoprotein (oxLDL) in THP-1 derived macrophages and identified the enrichment of human foam cell marker genes, such as SPP1, GPNMB, and FABP5, within these cells. Utilizing single-cell RNA sequencing, we demonstrated that THP-1 foamy macrophages closely resemble pathological cells from human patients, with a high mapping score. Additionally, we analyzed the secreted molecules from these pathological cells using multi-plex ELISA assays and investigated cell interactions through media swap methods. Notably, we observed increased markers of modulated vascular smooth muscle cells (VSMCs) in the VSMCs following incubation with foamy macrophage media. The model provides an efficient and cost-effective approach for future target screening.
In conclusion, we successfully developed a THP-1 derived foamy macrophage model that mimics foam cells from patients with coronary artery disease, demonstrating that molecules secreted by foamy macrophages can alter the status of vascular smooth muscle cells.