Defining Roles for Phenotypically Transitioned Smooth Muscle Cells in Atherosclerosis 443 views

Human histopathology studies suggest that cell composition, not size, of atherosclerotic plaques is closely related to likelihood of plaque rupture leading to myocardial infarction. Recent lineage tracing studies have provided evidence that a substantial fraction of plaque cells are derived from smooth muscle cells (SMC) from the artery wall, which have lost traditional markers and undergone phenotypic switching. To understand what phenotypes these transitioned SMC take on and what functions they perform, we developed a dual lineage tracing mouse that tracks the transition of Myh11+ SMC to an Lgals3+ phenotype. Remarkably, we found that up to 60-80% of all SMC in plaques had undergone this Lgals3 transition, while most medial SMC had not. Using single-cell RNA sequencing, we provide evidence that Lgals3+ SMC are not transcriptionally similar to plaque macrophage, but rather take on three main phenotypes: inflammatory/stem-like, extracellular-matrix remodeling, and osteogenic. We also provide evidence that transition of SMC to an osteogenic state depends on pluripotency transcription factor Klf4. In the first rigorous test of phenotypically modified SMC function, we show that knockout of the cytokine MCP1 in Lgals3+ SMC increases plaque stability and reduces inflammatory phenotypes of SMC and macrophage. However, knockout of MCP1 in all Myh11+ SMC led to a surprising increase in blood monocyte levels and larger plaques, suggesting these subtypes of SMC have divergent roles regulating the immune response to atherosclerosis. Finally, we identify Lgals3-transitioned SMC “pioneer” cells with privileged ability to migrate into lesions, and rare microvascular Lgals3-transitioned SMC that move following silver nitrate burn, suggesting that this transition may have evolved for injury response.

PHD (Doctor of Philosophy)

smooth muscle cell; lineage tracing; atherosclerosis; single cell RNAseq; MCP1; CCL2; Lgals3; vascular; inflammation; microvascular

English

2020-04-29