Transcriptional and epigenetic mechanisms of HSC subtype diversification

The blood cells in the human body perform various tasks, including blood clotting, oxygen supply and diverse immune responses. A rare population of hematopoietic stem cells (HSCs) can produce all blood cells. During ageing, the ability of HSCs to generate blood cells significantly declines. They produce less red blood cells that transport oxygen and less immune cells that fight against infections, which are the potential causes of ageing-associate anaemia, immune deficiency and blood cancers. Yet, it is not clear how these changes of HSCs occur during ageing. In this project we aim to identify critical molecules that are controlling the blood cell production of HSCs. We have developed a technique that allows us to measure the blood cell production of a single HSC, and found that there are different types of HSCs with vastly different ability to make different types of blood cells. We now wish to examine if changes to the abundance of the different HSC subtypes can account for the declined production of red cells and immune cells in aged people. The aim of these studies is to identify key molecules that have influences on HSCs, and by targeting these molecules to prevent or ultimately revert the decline in blood cell production in aged people.

This project will examine the molecular mechanism of HSC diversification both in normal condition and during ageing. The guiding hypothesis is that there are distinct HSC subtypes with different lineage differentiation patterns at steady state and the altered abundance of HSC subtypes is the potential cause of the skewed lineage production in haematopoietic ageing. We have developed a Vwf-tdTomato/Gata1-eGFP transgenic report line that allows us to track the production of platelets, erythrocytes and leukocytes from a single HSC simultaneously with high accuracy. Using this technique, we have described lineage-restricted HSC subtypes that are intrinsically programmed. We have also adapted stat-of-art sequencing methods to dissect the molecular profiles of single HSCs. In this project, we will perform transcriptomic and epigenomic analysis of HSC subtypes from both young and old mice at single cell level. Molecular profiling of single HSCs will be used to develop signatures specific for different HSC subtypes, and to discover potential intrinsic regulators of lineage-restriction. By functionally validating candidate regulators in HSC subtypes, we will identify key molecular pathways in regulating the lineage fate of HSCs. Furthermore, we will validate candidate mediators in old mice to determine if they can revert the biased lineage output of aged HSCs.

Given the considerable and increasing health burden associated with immune-senescence, we anticipate that there will be considerable interest for translational research and drug development in this area. The proposed research therefore has the potential to benefit the UK biotech area, and we will interact with the appropriate structure within Oxford and surroundings to achieve this (Oxford Innovation, Lab282 (www.lab282.org)).

This project also has the potential to improve population health, a significant benefit to the general public, and to reduce hospitalisation costs for respiratory infections, another public benefit. This will be explored in collaboration with local haematologists through the Oxford Biomedical Research Centre and Oxford Centre for Hematology.