Cellular mechanisms of haematopoietic lineage commitment

This project will analyse individual blood forming cells and the changes they undergo in cancer, during aging and under stress conditions (blood loss, infection) to understand how the body deals with and responds to these challenges.This will be done by using advanced DNA sequencing technology to measure which genes are expressed in each individual cell, and how this pattern changes in the presence of stress hormones, in stem cells that contain mutations that cause leukaemia, and in aged stem cells. The aim is toidentify different types of of blood forming stem cells, andto find outhow these populations change during aging. We will also analyse alsohow stress signals alterthe composition of the hematopoietic stem cell populations and influences their differentiation pattern. This will enable us to design and develop rational therapies to promote or counteract these changes, as required.

Haematopoiesis has served as a valuable paradigm for how multipotent stem cells are maintained and their differentiation regulated. Thus far elucidation of haematopoietic stem cells and their differentiation, as well as analysis of the alterations they undergo during aging, has generally been hypothesis-driven, enabled by the prospective isolation of discrete cell populations and their functional characterisation. However, recent progress has demonstrated a high degree of complexity of both the haematopoietic stem cell compartment and the pathways by which they form their differentiated progeny, indicating that the current models for how haematopoietic lineage separation are incomplete. With the advent of single cell transcriptome analysis we now have the opportunity to interrogate stem- and progenitor cell populations in a non-biased manner in order to define progenitor populations and their relationships. By combining this technology with novel reporter lines allowing identification of novel stem- and progenitor cell subsets, as well as sensitive readout of erythroid cells and platelets, and the use of lineage tracing, we are now in a position to comprehensively analyse, at the single cell level, the transcriptomes, lineage potentials and cellular relationships within the haematopoietic stem- and progenitor cell compartments. Such studies will allow us to address with a much higher degree of accuracy the impact of aging and oncogenic mutations on the haematopoietic system, and increase our understanding of how immune cell output is modulated by cytokines during microbial insult.