Research
Title: Investigating the role of vascular smooth muscle cells marked by Sca1 in disease
Abstract: Vascular disorders such as in-stent restenosis and atherosclerosis underpin heart attack and stroke, the two leading causes of death globally. A key hallmark of these vascular disorders is the accumulation of vascular smooth muscle cells (VSMCs), a cell type that normally exists in a quiescent, contractile state and regulates vascular tone and blood pressure. However, in atherosclerosis and in response to injury (e.g. stenting), the development of pathological lesions coincides with VSMC ‘activation’, which is characterised by exit from the contractile state and acquisition of a proliferative, migratory, inflammatory and extracellular matrix (ECM)-producing phenotype.
We have previously employed multicolour genetic lineage-tracing of VSMCs and shown that lesional accumulation of these cells in atherosclerosis and following injury is generated from clonal expansion of just one or a few cells. Further, we have shown that a small subpopulation of VSMCs expressing stem cell antigen 1 (Sca1) are present in healthy mouse vessels and show downregulation of contractile genes along with increased expression of genes associated with an activated state (termed the ‘response signature’), suggesting that these cells may be primed for activation. Sca1 expression is also a hallmark of VSMC activation in culture and following injury, and we also identified Sca1+ VSMCs within atherosclerotic lesions. Importantly, we and others have also identified Sca1-coexpressed genes in VSMCs and a corresponding expression profile in healthy and diseased human arteries. Together, these data suggest VSMCs marked by Sca1 expression play a key role in the development of vascular lesions.
We hypothesise that Sca1 marks VSMCs in an intermediate state that gives rise to the phenotypically diverse VSMC-derived cells (e.g. macrophage-like cells) found in atherosclerotic plaques. To test this idea, I combine single-cell transcriptomic analysis of Sca1+ VSMCs with functional testing of candidate regulators of Sca1+ VSMC state transitions, as well as human genomics approaches. My goal is to robustly characterise the role of Sca1+ VSMCs in atherosclerosis and identify the molecular determinants of their fate trajectories, which could represent promising therapeutic targets.
Supervisor: Dr Helle Jørgensen
