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Hematopoietic stem cells (HSCs) all share the ability to self-renew, and to reconstitute hematopoiesis in the long term. However, their production of the different hematopoietic cell types is highly variable: by transplanting single HSCs we have found that some HSCs produce all hematopoietic cell types, whereas others produce predominantly platelets, myeloid cell or lymphoid cells. To understand the physiological significance of HSC heterogeneity this project will investigate how the different HSC subtypes respond to emergency hematopoiesis.

By challenging biased HSCs with the key cytokines involved in the response to anemia (Epo) and infection (GM-CSF, G-CSF), and by using physiological anemia and infection models, we will determine which HSC subsets participate in the different emergency responses, and how this allows the organism to simultaneously deal with multiple challenges. The functional studies will be complemented with single-cell level gene expression profiling to identify the molecular determinants of cytokine responsiveness within the HSC compartment.

Training Opportunities

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.

As well as the specific training detailed above, students will have access to a wide-range of seminars and training opportunities through the many research institutes and centres based in Oxford. Students are also able to attend the Methods and Techniques course run by the MRC Weatherall Institute of Molecular Medicine. This course runs through the year, ensuring that students have the opportunity to build a broad-based understanding of differing research techniques. 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 MRC WIMM.

Generic skills training is offered through the Medical Sciences Division's Skills Training Programme. This programme offers a comprehensive range of courses covering many important areas of researcher development: knowledge and intellectual abilities, personal effectiveness, research governance and organisation, and engagement, influence and impact. Students are actively encouraged to take advantage of the training opportunities available to them.

The Department has a successful mentoring scheme, open to graduate students, which provides an additional possible channel for personal and professional development outside the regular supervisory framework. We hold an Athena SWAN Silver Award in recognition of our efforts to support the careers of female students and staff.

Publications

1 Sanjuan-Pla A, Macaulay IC, Jensen CT, Woll PS, Luis TC, Mead A, Moore S, Carella C, Matsuoka S, Bouriez Jones T, Chowdhury O, Stenson L, Lutteropp M, Green JC, Facchini R, Boukarabila H, Grover A, Gambardella A, Thongjuea S, Carrelha J, Tarrant P, Atkinson D, Clark SA, Nerlov C, Jacobsen SE. 2013. Platelet-biased stem cells reside at the apex of the haematopoietic stem-cell hierarchy.Nature,  502 (7470), pp. 232-6. - http://www.ncbi.nlm.nih.gov/pubmed/23934107
2 Grover A, Mancini E, Moore S, Mead AJ, Atkinson D, Rasmussen KD, O'Carroll D, Jacobsen SE, Nerlov C. 2014. Erythropoietin guides multipotent hematopoietic progenitor cells toward an erythroid fate.J. Exp. Med.,  211 (2), pp. 181-8. - http://www.ncbi.nlm.nih.gov/pubmed/24493804
3 Grover A, Sanjuan-Pla A, Thongjuea S, Carrelha J, Giustacchini A, Gambardella A, Macaulay I, Mancini E, Luis TC, Mead A, Jacobsen SE, Nerlov C. 2016. Single-cell RNA sequencing reveals molecular and functional platelet bias of aged haematopoietic stem cells.Nat Commun,  7pp. 11075. - http://www.ncbi.nlm.nih.gov/pubmed/27009448
4 Pietras EM, Mirantes-Barbeito C, Fong S, Loeffler D, Kovtonyuk LV, Zhang S, Lakshminarasimhan R, Chin CP, Techner JM, Will B, Nerlov C, Steidl U, Manz MG, Schroeder T, Passegué E. 2016. Chronic interleukin-1 exposure drives haematopoietic stem cells towards precocious myeloid differentiation at the expense of self-renewal.Nat. Cell Biol.,  18 (6), pp. 607-18. - http://www.ncbi.nlm.nih.gov/pubmed/27111842

Research Themes, Tools and Technologies

Supervisors

Additional Supervisors

Prof Sten Eirik Jacobsen, Radcliffe Department of Medicine

Key Dates for October 2018 Entry

Application deadline:  12 noon GMT on Monday 8 January 2018

Interviews for shortlisted candidates: Week commencing Monday 22 January 

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How to apply

To apply for a place on the DPhil in Medical Sciences you will need to submit an application using the online application form.

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