Figure 2. Outstanding questions on VSMC phenotypic diversification in atherosclerotic lesions.

Schematic plot illustrating that single-cell RNA-seq (scRNA-seq) technologies have revealed the wide range of transcriptional profiles adopted by VSMC-derived cells in atherosclerotic lesions (A). Trajectory inference analysis suggests a transition from contractile VSMCs to a fibrochondrocytic state via an intermediate SEM (stem cell, endothelial, monocyte) state. However, the exact lineage relationships between VSMC-derived cells of different phenotypes remain to be fully determined, particularly the origin of VSMC-derived macrophage cells. Generation of scRNA-seq datasets requires dissociation of the tissue and thus loss of spatial information. Therefore, the impact of spatial localisation within the plaque on VSMC-derived cell fate transitions remains unknown (B). For example, would it be possible to inhibit the generation of plaque-destabilising phenotypes by inhibiting VSMC-derived cell entry into the lesion core? Moreover, the reversibility of cell transitions and the ability of VSMC-derived cells in the lesion to convert into other states remains unknown (A,C). This is of particular interest in the regressing plaque where alterations in the behaviour and/or fates of VSMC-derived cells are likely to have a significant role in plaque stabilising changes (C).