Contribution of smooth muscle-derived vascular progenitor cells to atherosclerosis

Purpose: Atherosclerosis is a major cause of morbidity and mortality worldwide, but current therapies fail to adequately meet clinical needs. Emerging evidence implicates the outer layer of the blood vessel, the adventitia, in the pathogenesis of atherosclerosis. Specifically, it has been suggested that expansion of adventitial microvessels, the vasa vasorum (VV), drives atherosclerosis progression by facilitating inflammatory cell infiltration. Our group previously identified a unique population of multipotent resident vascular stem cells (AdvSca1-SM cells) that derive from mature vascular smooth muscle cells (SMCs) and reside in the vessel adventitia, where they are poised to respond to vascular injury. We hypothesized that in the setting of atherosclerosis, AdvSca1-SM cells contribute to VV expansion to drive disease progression.

Methods: We generated a highly specific lineage tracing mouse model to track AdvSca1-SM cells in vivo even if they differentiate into other cell types. Lineage tracing mice were placed on either normal chow or modified Western diet for between 8 and 30 weeks, then vascular tissue was analyzed using IF microscopy, scRNA-Seq, and flow cytometry.

Results: scRNA-Seq and flow cytometry revealed that there is a large reservoir of AdvSca1-SM cells in a stem-like state in the setting of atherosclerosis. However, this population shows significant phenotypic shifts in atherogenic compared to control conditions and seems to influence the transcriptional profiles of non-AdvSca1-SM-derived cells in the vessel wall. When AdvSca1-SM cells differentiate into other cell types, they primarily become mature SMCs, modulated SMCs, and myofibroblasts. Contrary to our preliminary data, AdvSca1-SM cells very rarely differentiate into endothelial cells.

Conclusions: As in our findings in acute vascular injury, AdvSca1-SM cells in atherosclerosis predominantly differentiate into SMCs and myofibroblasts, or else remain in a stem-like state. Future studies on advanced lesions will define the functional role of AdvSca1-SM cells in atherosclerotic plaque progression.