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Joel Chappell

BHF Cambridge Centre of Excellence PhD Student

Research themes

Stem Cells:

Research Interests

Supervisor: Dr Helle Jørgensen

Title: VSMC clonality and proliferation in health and disease

Abstract: Vascular smooth muscle cells (VSMCs) play important roles in the development of coronary artery disease (CAD) including atherothrombosis. VSMCs are generally quiescent and display a “contractile” phenotype that regulates vascular tone. However, upon inflammation and injury, contractile genes are downregulated and VSMC proliferation, migration and secretion of extracellular matrix (ECM) proteins increase. This is a reversible process that ensures tissue homeostasis and allows vascular remodelling. In CAD, misregulation of VSMC proliferation and migration result in intimal growth, whereas VSMCs in the atherosclerotic cap region deposit ECM, which reduces plaque vulnerability and prevents thrombosis. Understanding VSMC plasticity is therefore clinically relevant.

VSMC phenotypic switching has been observed both in vivo and in vitro -  however whether all VSMCs have the capacity to undergo phenotypic switching and whether all hallmarks of phenotypic switching are displayed in every VSMC in disease remain open questions. This is important since atherosclerosis has been proposed to arise from selective proliferation of single cells or clones within the artery. In fact, extensive diversity of VSMC phenotype has reported both in healthy and diseased tissue. This includes regional variation in embryonic origin of VSMCs and profound variation in the expression of contractile VSMC marker genes between VSMCs within the same vascular bed. These differences are clonally heritable in vivo and in vitro, although the local micro-environment can alter phenotypes. However, it remains to be seen whether this cellular heterogeneity reflects the existence of discrete VSMC subpopulations of distinct plasticity that may contribute differently to the phenotypic transformation seen in disease.

We propose that the reported heterogeneity in VSMCs reflects variation in
cellular plasticity that affects the outcome of population-wide manipulation of VSMC phenotype. To test this hypothesis we will assess the clonality of VSMCs in an atherosclerosis disease model and test how this is affected by compounds know to change VSMC proliferation. Phenotypic heterogeneity of VSMC clones will then be examined by using transcriptome profiling. This work is important for the interpretation of population-based VSMC studies and is
central to our understanding of CAD development and progression.

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