Cellular and molecular dynamics of healthy ageing in the human Haematopoietic Stem Cell compartment

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Blood comprises more than a dozen distinct cell types which have vital functions and are constantly replaced, at a rate of 30 millions cells per minute in humans. This extreme regenerative capacity can be maintained thanks to haematopoietic stem cells (HSC), rare cells that have the unique ability to produce more of themselves as well as all blood cell types. Interestingly there isn't a single type of HSC but rather HSC come in different flavours (subtypes), which vary in their capacity to divide and have preferences for production of particular differentiated blood cell types. Importantly it is thanks to this heterogeneity in the HSC compartment that blood production can be maintained under normal conditions or after injury or infection. The unique potential of HSC is exploited in bone marrow transplantation, a procedure routinely used in the clinic to treat leukaemia and other conditions. HSC are harvested from different haematopoietic organs depending on the clinical case. There is evidence that the source of HSC can affect the outcome of the transplantation, but why is not currently understood. In addition, work with animal models has demonstrated that HSC function is compromised with age. Correspondingly, in elderly people there are many changes in the composition of the blood and an increased incidence of infections, anaemia and blood cancers. However despite their importance for human health and for treatment, almost nothing is known to date on the composition of the human HSC compartment in different organs, how it changes with ageing, and what are the consequences for blood production. This project will use a number of innovative single cell analysis techniques and computational methods to compare the composition of the healthy human HSC compartment in different haematopoietic organs: neonatal cord blood as well as adult bone marrow, peripheral blood and spleen. For each organ we will define how many HSC subsets there are, and identify their gene expression profiles, epigenetic features and functional properties. We will also determine how these change with healthy ageing by analysing samples ranging from infants to 70 years old individuals. Single cell resolution is absolutely necessary to understand how HSC age. The information derived from this comprehensive study will characterise how human HSC, and consequently blood production, change over a lifetime. Our molecular characterisation will also provide a resource to develop new strategies to improve current transplantation protocols and to identify targets that may help to pharmacologically rejuvenate old HSC and correct some of the age-related blood deficiencies.