The impact of ageing on the human haematopoietic stem cell and memory T cell compartments through the lens of single cell transcriptome analysis

Thesis

Human biological ageing comprises the molecular and physiological changes that negatively affect homeostasis with age and are strongly associated with susceptibility to disease and ultimately death.

This thesis utilises single cell transcriptomics to study the haematopoietic stem and memory T cell compartments in humans and how ageing impacts on their potential functionality in the context of health and disease.

Firstly, we have studied the human haematopoietic stem cell (HSC) compartment utilising single cell transcriptomic datasets from young and old males to address the existence in humans HSCs expressing a gene signature indicative of an output biased towards platelet generation and the inflation of this population with age. Secondly, we have studied how ageing shapes the transcriptome of the memory T cell compartment utilising publicly available single cell transcriptomic datasets with a view to investigate if recovering from a severe case of COVID-19 shares biological processes with ageing in the context of the memory T cell compartment of a healthy donor cohort.

Our study of the HSC compartment has shown that a computationally defined HSC populations exhibiting the gene expression patterns associated with platelet bias in murine HSCs can be identified in healthy human males. The previously identified HSC population is enriched in old individuals. Moreover, this population exhibited the transcriptomic features associated with previously documented HSC populations with high self-renewal capacity and quiescence. With ageing there were no major shifts in which pathways were upregulated or downregulated, but more of an accentuation of the transcriptomic programmes already present at younger ages.

An ageing-associated inflammatory gene expression signature was identified at the level of the memory T cell compartment of the studied healthy human cohort. Known signalling pathways and gene families associated with ageing in the T cell compartment such as IL-10 signalling were associated with this signature as well as novel ones such as the aminoacyl-tRNA synthetases. By leveraging a machine learning-based methodology, it was shown that at the level of the memory T cell compartment, the most important biological processes that are shared between ageing and recovering from COVID-19 are IL-10 signalling and BAX-mediated apoptosis.

The potential functional implications of the ageing associated observations made in the human HSC and memory T cell compartments remain open questions that could potentially allow us to understand what are the signals that determine fate specifications in HSCs and the long-term deleterious effects of experiencing a respiratory viral infection on the functionality of the adaptive immune system.

Authors: Gafencu, GA

• DOI: 10.5287/ora-bxnkg2jyo
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Subjects: Single cell transcriptomics; T cell; Hematopoietic stem cells; Aging