Molecular mechanisms of hematopoietic stem cell aging

The hematopoietic system generates cells with highly diverse functions, including oxygen transport (erythrocytes), maintenance of vascular integrity (platelets), and viral and bacterial immunity (lymphoid and myeloid cells). Overall, there are more than 10 different hematopoietic cell types, all of which are continuously generated throughout life from a small pool of hematopoietic stem cells (HSCs). However, both the hematopoietic system and HSCs undergo significant changes as the mammalian organism ages. The stem cell compartment expands, but individual HSCs display lower cellular output. In addition, the cellular output from young HSCs is biased towards adaptive immune cells (B- and T-lymphocytes), but towards innate immune cells (myeloid cells: macrophages, granulocytes) in the aged organism. An important consequence of this is decreased adaptive immunity in older individuals.

We have recently, using Vwf-EGFP reporter mice that fluorescently label platelets, found that also the formation this cell type is increased with age. To understand how these changes in lineage output are implemented, we have identified a number of transcription factors that are up-regulated in aged HSCs. The goal of the project is, from this shortlist, to identify those factors that induce the increased myeloid and platelet production observed during aging. This will be achieved through both gain-of-function and loss-of-function genetics combined with competitive repopulation experiments. Multicolor flow cytometry will be used to monitor the output of multiple hematopoietic lineages (including platelets) from experimental HSCs. Next-generation sequencing will identify changes in the transcriptome of HSCs with altered lineage bias, in order to determine which part of the global ageing-specific gene expression pattern each factor regulates. This will be combined with chromatin immunoprecipitation (ChIP)-sequencing to identify the genomic binding sites for the relevant transcription factors in normal and aged HSCs.

The overall aim is to derive a transcriptional code that explains the altered lineage output of aged HSCs, and eventually devise treatment modalities that can revert the age-associated decrease in adaptive immunity.

This project will be based in the MRC Molecular Hematology Unit at the Weatherall Institute of Molecular Medicine, with access to state-of-the-art facilities. The project provides an opportunity for training in a broad range of different techniques.

In addition to training opportunities through the University, in the WIMM we run a course on basic techniques for new students of approximately 20 lectures. There are also courses on Immunology and Bioinformatics and others may be added. Institute Seminars are held on a weekly basis and regularly attract world-class scientists in haematopoiesis research. Informal exchange of ideas in the coffee area is encouraged and is an attractive feature of the WIMM.