The role of the microenvironment in hematopoietic ageing
Supervisor: Professor Claus Nerlov
Background and project overview
The hematopoietic system and it ability to generate the different hematopoietic cell types changes during ageing. In particular, the production of erythrocytes and lymphocytes decreases, leading to anemia and decline in adaptive immunity, both detrimental to organismal health. It is known that age-dependent changes to the hematopoietic stem cells (HSCs) in the bone marrow, and specifically to HSC lineage bias, underlies some of these changes, including the decline in lymphocyte production. However, it is currently unclear how these functional changes to HSCs are installed, and whether they can be mitigated or reversed.
This project will investigate how the bone marrow microenvironment changes with age, and how this influences the phenotype of HSCs and their ability to generate the different hematopoietic lineages. In particular, high-throughput single cell transcriptome analysis we have profiled both stromal cells and hematopoietic stem- and progenitor cells from young and aged mice and identified numerous age-dependent changes to their abundance and gene expression. These data will be used to identify stromal signals that are altered during the ageing process, which will be tested in genetic and pharmacological perturbation experiments for their role in the hematopoietic ageing process.
- To develop a molecular map of hematopoietic ageing that includes both hematopoietic and stromal cell populations.
- To identify and validate candidate signals that regulate altered HSC function and lineage output during ageing.
- Drissen, R., N. Buza-Vidas, P. Woll, S. Thongjuea, A. Gambardella, A. Giustacchini, E. Mancini, A. Zriwil, M. Lutteropp, A. Grover, A. Mead, E. Sitnicka, S. E. W. Jacobsen and C. Nerlov (2016). Distinct myeloid progenitor-differentiation pathways identified through single-cell RNA sequencing. Nat Immunol 17(6): 666-676.
- Grover, A., A. Sanjuan-Pla, S. Thongjuea, J. Carrelha, A. Giustacchini, A. Gambardella, I. Macaulay, E. Mancini, T. C. Luis, A. Mead, S. E. Jacobsen and C. Nerlov (2016). Single-cell RNA sequencing reveals molecular and functional platelet bias of aged haematopoietic stem cells. Nat Commun 7: 11075.
- Buono, M., R. Facchini, S. Matsuoka, S. Thongjuea, D. Waithe, T. C. Luis, A. Giustacchini, P. Besmer, A. J. Mead, S. E. Jacobsen and C. Nerlov (2016). A dynamic niche provides Kit ligand in a stage-specific manner to the earliest thymocyte progenitors. Nat Cell Biol 18(2): 157-167.
The WIMM has a very important role in training young scientists in Molecular Medicine and Stem Cell Biology and takes on several D.Phil (PhD) students each year. There are currently approximately 120 DPhil students in the WIMM. 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.
Nerlov laboratory have clearly defined protocols to support training in specific experimental techniques. Standard operating procedures are regularly updated to ensure that methods are optimal. The above project utilises a wide range of state of the art molecular and cell biological techniques, advanced genetic technologies, in vivo and in vitro stem cell- and progenitor assays and bioinformatics analysis, and will consequently provide an excellent foundation for a research career.
For further information please contact: Professor Claus Nerlov