Characterising the phenotypic and functional role of monocyte-derived foam cells in atherosclerosis

Begum, Jenefa (2025). Characterising the phenotypic and functional role of monocyte-derived foam cells in atherosclerosis. University of Birmingham. Ph.D.

Begum2025PhD.pdf
Text - Accepted Version
Available under License All rights reserved.
Download (49MB)

Abstract

Atherosclerosis is a chronic inflammatory disease characterised by the accumulation lipid deposits within the arterial wall, leading to restricted blood flow and increased risk of cardiovascular events. Central to the development of atherosclerosis is the formation of foam cells which are derived from macrophages as a result of excessive accumulation of modified low-density lipoproteins (LDL). Upon oxLDL internalisation, macrophages transform into foam cells through the storage of lipid droplets that are primarily composed of cholesteryl esters which can be hydrolysed to generate free cholesterol. The balance between lipid uptake, storage, and degradation within foam cells is critical to maintain cholesterol homeostasis.
Dysregulation in these processes contribute to foam cell persistence and plaque progression. Foam cells contribute significantly to the inflammatory microenvironment within plaque, causing perpetual local inflammation, recruitment of immune cells and plaque instability. The interplay between lipid metabolism and inflammatory signalling within foam cells exacerbates their retention and survival.

Understanding the inflammatory role of foam cells in atherosclerosis is crucial for identifying novel therapeutic targets aimed specifically at reducing foam cell-driven inflammation. However, till today identifying and characterising foam cells within atherosclerotic plaques remains a challenge due to significant overlap in markers with other immune cells. One of the aims of this study is to characterise foam cells both at a protein and genomic level via flow cytometry analysis, bulk RNA-sequencing and whole genome spatial transcriptomics to identify potential markers specific to foam cells themselves. Contradictory to the nature of a foam cell phenotype, our results show that foam cells exhibit an anti-inflammatory and lipid metabolising profile genomic profile which coincides with existing data from recent transcriptomic studies.

Given that plaque is a heterogenous cellular environment, investigating the role of foam cells in isolation may not accurately represent their realistic function. Therefore, in this study I also examined the functional characteristics of foam cells in co-culture with endothelium in vitro. This approach allowed us to identify changes in lipid mediator secretion due to cell-cell crosstalk where I identified an enrichment in pro-inflammatory prostaglandin secretion in foam cell-endothelial cell co-cultures compared to foam cells alone.

In conclusion this study explores the characterisation of foam cells using multiple different avenues. I found that minimal differences were observed between macrophage and foam cell profiles and that monocyte-origin appear to have little to no effect on the genotype of foam cells. Additionally, I show that the foam cells potentially exhibit their pro-inflammatory functional phenotype through cellular crosstalk with endothelium via the secretion of pro-inflammatory lipid mediators.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):