The transcriptional diversity of the human endothelium
File(s)
Author(s)
Barnett, Sam
Type
Thesis
Abstract
Endothelial cells represent the major cell type of the vascular system, transporting blood and lymph within a vast network of vessels across the human body. Their functional roles include delivery of oxygen and nutrients, organ development and tissue homeostasis, regulation of stem cell niches and regeneration, while also contributing to disease progression in vascular and non-vascular diseases. These functions reflect an intrinsic heterogeneity whose molecular determinants remain largely unknown across multiple tissues.
Single cell transcriptomics can be used to explore cellular heterogeneities, providing key information on gene expression, cell prevalence and cell heterogeneity across tissues. Here, single cell transcriptomics was used to profile endothelial cell populations across 18 human donor tissues. This highlighted angiotypic signatures, including subsets of arterial endothelial cells within different calibre vessels, and populations restricted to specific organs, including splenic sinusoidal endothelial cells involved in blood filtration. Furthermore, a novel in silico drug screening tool was used to predict drug targeting discrete of EC populations, indicating potential regulators of vascular tone, and implications in the spleen and kidney EC.
To explore the role of the endothelium in COVID-19 lung injury, single cell RNA-sequencing data were integrated with spatial transcriptomics and histopathological analysis. This uncovered the transcriptional changes occurring across varying stages of diffuse alveolar damage in COVID-19. Specifically, this highlighted a key role for endothelial cells in mediating coagulopathy and impaired fibrinolysis.
In summary, the assembly of the first human endothelial cell atlas provides a unique resource for the scientific community to improve our understanding of vascular biology in health and disease, and for translational applications such as in silico drug screening. Additionally, EC profiling in COVID-19 lung provides an increased understanding of their role in disease progression, and highlights potential targets for therapeutic intervention.
Single cell transcriptomics can be used to explore cellular heterogeneities, providing key information on gene expression, cell prevalence and cell heterogeneity across tissues. Here, single cell transcriptomics was used to profile endothelial cell populations across 18 human donor tissues. This highlighted angiotypic signatures, including subsets of arterial endothelial cells within different calibre vessels, and populations restricted to specific organs, including splenic sinusoidal endothelial cells involved in blood filtration. Furthermore, a novel in silico drug screening tool was used to predict drug targeting discrete of EC populations, indicating potential regulators of vascular tone, and implications in the spleen and kidney EC.
To explore the role of the endothelium in COVID-19 lung injury, single cell RNA-sequencing data were integrated with spatial transcriptomics and histopathological analysis. This uncovered the transcriptional changes occurring across varying stages of diffuse alveolar damage in COVID-19. Specifically, this highlighted a key role for endothelial cells in mediating coagulopathy and impaired fibrinolysis.
In summary, the assembly of the first human endothelial cell atlas provides a unique resource for the scientific community to improve our understanding of vascular biology in health and disease, and for translational applications such as in silico drug screening. Additionally, EC profiling in COVID-19 lung provides an increased understanding of their role in disease progression, and highlights potential targets for therapeutic intervention.
Version
Open Access
Date Issued
2024-02-02
Date Awarded
01/12/2024
Copyright Statement
Creative Commons Attribution NonCommercial Licence
License URL
Advisor
Noseda, Michela
Randi, Anna
Publisher Department
National Heart & Lung Institute
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)