Figure 2: SMC phenotypic diversity within the media and atherosclerotic lesion.

This schematic summarizes the main finding with respect to SMC diversity. scRNAseq studies revealed that the media is composed of multiple clusters of SMC. While it is unclear whether a particular cluster of SMC has the ability to clonally expand, there is clear evidence that SMC within the atherosclerotic lesion originate from a very limited number of clones. The same SMC clone can give rise to SMC-derived fibrous cap cells, macrophage-like cells, mesenchymal-stem cell like-cell and osteochondrogenic cells. A current hypothesis is that a transition to a mesenchymal-stem cell-like cell state would precede and be required for the transition to other lesion phenotypes (green dashed arrows). In addition, it has been postulated that SMC-derived lesion cells could originate from the medial Sca1⁺ SMC population. This hypothesis is indicated in the schematic by the annotation of the SMC clone expanding within the lesion with “Sca1⁺?”. Importantly, phenotypic modulation also occurs within the media, independently of clonal expansion during atherosclerosis (red arrows). Although the mechanisms controlling the investment of atherosclerotic lesions by a very limited number of SMC clones have not been fully characterized, there is evidence that myeloid-derived plaque macrophages inhibits SMC polyclonality within atherosclerotic plaque (gray dashed arrows). It is also postulated that medial or lesion environmental cues could inhibit the proliferation and investment of multiple medial SMC within the lesion (black dashed arrows). Finally, it is unclear whether a process of clonal selection consisting in the survival of dominant clones could as well take place (yellow dashed arrows). Figure created with Biorender.