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Hematopoietic Stem Cell Genetics: 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.

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  • Full or part time
    Prof Claus Nerlov
    Dr P Vyas
  • Application Deadline
    No more applications being accepted
  • Self-Funded PhD Students Only
    Self-Funded PhD Students Only

Project Description

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.

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 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.
As well as the specific training detailed above, students will have access to high-quality training in scientific and generic skills, as well as access to a wide-range of seminars and training opportunities through the many research institutes and centres based in Oxford.

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 build a happy and rewarding environment where all staff and students are supported to achieve their full potential.


Funding Notes

Our main deadline for applications for funded places has now passed. Supervisors may still be able to consider applications from students who have alternative means of funding (for example, charitable funding, clinical fellows or applicants with funding from a foreign government or equivalent). Prospective applicants are strongly advised to contact their prospective supervisor in advance of making an application.

Please note that any applications received after the main funding deadline will not be assessed until all applications that were received by the deadline have been processed. This may affect supervisor availability.

References

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.

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FTE Category A staff submitted: 238.51

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