Barcoding atherosclerotic plaque cells: single cell sequencing to reveal heterogeneity and functional impact of atherosclerotic plaque cells

09-02-2020

PhD Position

A position for a PhD-student is available in dr. Sluimer’s team in the experimental vascular Pathology Dept. (http://www.pathologie.mumc.nl/medewerkers/sluimer). The team is embedded in the Cardiovascular Research Institute Maastricht (CARIM) of Maastricht University Medical Center and studies the role of hypoxia, inflammation and matrix turnover in atherosclerosis.

Atherosclerosis develops in the large arteries under the influence of high plasma cholesterol, hypertension and diabetes. Our group investigates the rupture of an atherosclerotic plaque, which is the actual cause of a myocardial infarct and / or stroke. We already know that this is partly due to a disturbed connective tissue production and degradation. In this project, supported by a prestigious Dutch VIDI grant, we will now investigate the underlying cause of this. The project will focus on mesenchymal cells, only recently detected in human and murine atherosclerosis. This intriguing cell exists in different subtypes, has great impact on matrix turnover, interacts with inflammatory cells and can stimulate the formation of new microscopic blood vessels (angiogenesis) in other pathologies, but its function and heterogeneity in atherosclerosis is unknown.

Here, we will use a very new technology to study the expression profiles of individual cells: single cell sequencing. Until recently, expression in whole pieces of tissue was studied, containing all kinds of different cells and subtypes, and it was impossible to determine the contribution of one cell type. This new technology offers the possibility to recognize new subtypes and study their function. The aim of the project is to detect new subtypes of mesenchymal cells in the vessel wall and to investigate whether they can repair the disturbed inflammation, and matrix turnover in plaques in order to prevent  myocardial infarct and / or stroke in the future.

The experimental techniques involve basic research in cell culture models of cell death,  genetic and pharmaceutical interventions in animal models of atherosclerosis with fluorescent reporters for markers expressed by new and established matrix-producing cells, and analysis of human plaque biopsies. Specific techniques include single cell sequencing, isolation of cell populations by flow assisted cell sorting, flow cytometry, single cell sequencing processing and bio-informatics (optional), gene silencing, gene/protein expression analysis, immunohistochemistry and high content, automated (confocal) microscopy with fluorescent probes to analyse collagen production, cell death, proliferation, migration, inflammation, angiogenesis, lipid uptake, etc.

CARIM offers an outstanding scientific environment including shared core-facilities equipped with state-of-art instrumentation and knowledge, and an international reputation of excellence in research. The pathology lab consists of 20 international researchers involved in inflammation and atherosclerotic plaque stability. An extensive network of local, national and international collaborations is maintained with leading research groups, and international work visits are possible to stimulate the project quality.