The focus of the Nerlov laboratory is to use single cell genomics and functional analysis, combined with advanced mouse genetics, to study the function of hematopoietic stem– and progenitor cells 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 are specified, as well as those involved in malignant transformation in hematopoietic malignancies, such as acute myeloid leukemia (AML) and myeloproliferative disorders (MPD). We combine studies of genetically modified mice with analysis of human samples, including samples from patients with blood cancer, 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.
Biology of normal hematopoietic stem and progenitor cells:
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. Combining single cell RNAseq with genetic reporters and functional single cell assays (HSC transplantation, progenitor differentiation assays) we have characterized the spectrum of functional HSC subtypes (Sanjuan-Pla, Nature 2013; Carrelha, Nature 2018), and identified novel progenitor populations, generating a revised hierarchical model of hematopoiesis (Drissen, Nat Immunol. 2016; Drissen, Science Immunol. 2019). We are now combining single cell RNAseq and ATACseq with functional readouts to identify the transcriptional and chromatin states that determine HSC and progenitor fate restriction. Furthermore, we use advanced genetics (HSC subtype-specific reporters and intersectional lineage tracing) to determine the physiological importance of HSC subtypes and progenitor subsets during steady state and stress hematopoiesis (Grover, J. Exp. Med. 2014). Parallel studies of human HSCs (collaboration with Vyas laboratory) use barcoding, xenografting models and single cell profiling to identify human HSC heterogeneity.
The role of ageing in leukemia development and age-associated morbidity:
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. 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.
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 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 (RNAseq, ATACseq), 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 and students will have access to a wide-range of seminars and training opportunities through the many research institutes and centres based in Oxford.
All 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 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.
Funding for this project is available to scientists through the RDM Scholars Programme, which offers funding to outstanding candidates from any country. Successful candidates will have all tuition and college fees paid and will receive a stipend of £18,000 per annum.
For October 2020 entry, the application deadline is 10th January 2020 at 12 noon (midday).
Please visit our website for more information on how to apply.
Drissen, R., S. Thongjuea, K. Theilgaard-Mönch and C. Nerlov. 2019. Identification of two distinct pathways of human myelopoiesis. Sci. Immunol. 4:eaau7148.
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. *Equal contribution.
Buono, M., M.-L. Thézénas, A. Ceroni, R. Fischer and C. Nerlov. 2018. ¬¬Bi-directional signaling by membrane-bound KitL induces proliferation and co-ordinates thymic endothelial cell and thymocyte expansion. Nat. Comm. 9: 4685.
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. *Equal contribution.
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