Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

Using single cell biology and genetics to understand how hematopoietic stem cells normally sustain blood formation, and how this process is altered during ageing and when leukemia develops.

Nerlov

About the Research

with advanced mouse genetics, to study the function of hematopoietic stem– and progenitor cell in normal development and during ageing.  We use the knowledge generated to identify the cellular and molecular mechanisms through which hematopoietic stem- and progenitor cells undergo transformation in hematopoietic malignancies, such as acute myeloid leukemia (AML) and myelo-proliferative disease (MPD). We combine studies of genetically modified mice with analysis of human samples, with the aim of identifying molecular and pharmacological strategies to treat disease and counteract the adverse effects of ageing on the hematopoietic system and overall human physiology.

Hematopoietic stem cells sustain life-long production of the many diverse hematopoietic cell types (lymphocytes, granulocytes, monocytes, erythrocytes, platelets). This occurs through a complex series of progenitor cells that become increasingly lineage-restricted as their differentiation progresses. We have used a combination of single cell RNA sequencing and functional single cell assays (HSC transplantation, progenitor differentiation) to show that hematopoietic stem cells (HSCs) are functionally heterogeneous, and that the composition of the HSC compartment changes during normal ageing (Sanjuan-Pla 2013; Grover 2016; Carrelha 2018). These studies have defined for the first time the spectrum of functional HSC subtypes, and an important research focus is now to use single cell RNA- and ATAC-sequencing to identify the transcriptional and chromatin states that determine HSC lineage fate restriction, and to use advanced genetics (transcriptional reporters and lineage tracing) to identify the physiological importance of HSC heterogeneity. Parallel studies of human HSCs (collaboration with Vyas laboratory) use advanced xenografting models and single cell profiling to identify human HSC heterogeneity.

To study the effects of ageing on the hematopoietic system, and how this contributes to age-related morbidities such as anaemia and immune-senescence, we are investigating how the hematopoietic microenvironment changes during physiological ageing. We have previously identified signalling mechanisms and associated cellular processes that promote emergency erythropoiesis and lymphopoiesis (Grover, 2014; Buono, 2016). By comprehensive molecular profiling of both hematopoietic and stromal cell types at different stages of the ageing process we are now identifying the molecular mechanisms that contribute to HSC ageing, and to age-associated alterations in the production of blood cells, as well as increased susceptibility to malignant disease. In parallel, we are (also in collaboration with the Vyas laboratory) using whole-tumour single cell profiling of acute myeloid leukemia (AML) to determine how remodelling of the tumour microenvironment contributes to therapy resistance, and how this relates to ageing.

Finally, we are using single cell RNA sequencing and single cell functional analysis to delineate the differentiation pathways used by progenitor cells under steady state and stress conditions (Drissen, 2016; Grover 2014). This work has led to a revised model of the murine hematopoietic hierarchy, and is now being extended to the human system, and used to identify genes de-regulated upon progenitor transformation in AML, followed by CRISPR/Cas9-based functional validation, to identify therapeutic targets.

Projects are available in all these areas, including the regulatory mechanisms underlying hematopoietic ageing; the molecular mechanisms underlying heterogeneity of HSC and progenitor cell populations; and the extrinsic and intrinsic factors contributing to progenitor transformation in AML, including the role of ageing in susceptibility to myeloid malignancy.

 

Training Opportunities

Training is available in the areas of HSC and progenitor biology, biology of ageing, transcription factor biology, cytokine biology, single cell analysis of HSC/progenitor function, single cell functional genomics, advanced flow cytometry, advanced mouse genetics, CRISPR/Cas9-based genome editing and library screening technologies. Advanced training in bioinformatics is available through the MRC WIMM Centre for Computational Biology.

 

Students will be enrolled on the MRC WIMM DPhil Course, which takes place in the autumn of their first year. Running over several days, this course helps students to develop basic research and presentation skills, as well as introducing them to a wide-range of scientific techniques and principles, ensuring that students have the opportunity to build a broad-based understanding of differing research methodologies.

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.

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.

All MRC WIMM graduate students are encouraged to participate in the successful mentoring scheme of the Radcliffe Department of Medicine, which is the host department of the MRC WIMM. This mentoring scheme provides an additional possible channel for personal and professional development outside the regular supervisory framework. The RDM also holds an Athena SWAN Silver Award in recognition of our efforts to build a happy and rewarding environment where all staff and students are supported to achieve their full potential.

 

Publications

Carrelha, J., Y. Meng, L. Kettyle, T.C. Luis, R. Norfo, V. Alcolea Devesa, F. Grasso, A. Gambardella, A. Grover, K. Högstrand, A. Matheson Lord, A. Sanjuan-Pla, P. Woll, C. Nerlov*, S.E.W. Jacobsen*. 2018. Hierarchically related lineage-restricted fates of multipotent haematopoietic stem cells. Nature 554: 106-110

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. 17:666–676.

Grover A., A. Sanjuan-Pla, S. Thongjuea, J. Carrelha, A. Giustacchini, A. Gambardella, I. Macaulay, E. Mancini, T.C. Luis, A. Mead, S.E.W. Jacobsen* and C. Nerlov*. 2016. Single cell global gene profiling reveals molecular and functional platelet bias of aged hematopoietic stem cells. Nat. Comm. 7:11075

Buono, M., R. Facchini, S. Matsuoka, S. Thongjuea, D. Waithe, T. C. Luis, A. Giustacchini, P. Besmer, A. J. Mead, S.E.W. Jacobsen* and C. Nerlov*. 2016. A dynamic niche provides Kit ligand in a stage-specific manner to the earliest thymocyte progenitors. Nat. Cell. Biol. 18:157-167

Grover, A., E. Mancini, S. Moore, A. Mead, D. Atkinson, K.D. Rasmussen, D. O’Carroll, S.E.W. Jacobsen and C. Nerlov. 2014. Erythopoietin guides multipotent hematopoietic progenitor cells towards an erythroid fate. J. Exp. Med. 211:181-8.

Sanjuan-Pla A., I. Macaulay, C.T. Jensen, P.S. Woll, T.C. Luis, A. Mead, S. Moore, C. Carella, T. Bouriez-Jones, O. Chowdhury, L. Stenson, M. Lutteropp, J.A.C. Green, R. Facchini, H. Boukarabila, A. Grover, A. Gambardella, J. Carrelha,P. Tarrant, D. Atkinson, S.-A. Clark, C. Nerlov* and S.E.W. Jacobsen*. 2013. Platelet-biased stem cells reside at the apex of the hematopoietic stem cell hierarchy. Nature, 502: 232-236.

Supervisors