The role of hematopoeitic stem cell heterogeneity in hematopoietic emergency responses
Supervisors: Professor Claus Nerlov and Professor Sten Eirik Jacobsen
Background and project overview
Maintaining a stable hematopoietic output is an essential part of physiological homeostasis, as blood cells are essential for oxygen transport, vascular integrity and immunity. When either of these functions is challenged the hematopoietic system responds by increasing the output of the cell type urgently required, a phenomenon known as emergency hematopoiesis.
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 cells or lymphoid cells.
To understand the physiological significance of HSC heterogeneity this project will investigate how HSC subtypes participate in different types of emergency hematopoiesis. Using genetic lineage tracing and single cell transplantation the different biased HSC subtypes will be exposed to anemia, thrombocytopenia or infection, allowing their contributions to different emergency responses to be determined. In parallel, biased HSCs populations will be molecularly profiled using single cell RNA sequencing and their contributions to the hematopoietic hierarchy analyzed, both in the presence and absence of hematopoietic stress. Together, these experiments will shed light on the on how HSC heterogeneity contributes to the ability of the organism to respond to physiological emergencies, and in particular how it manages to simultaneously deal with multiple such challenges.
- To determine the contributions of lineage-biased HSCs subtypes to hematopoietic emergency responses
- To identify the molecular and cellular mechanisms of stress-dependent HSC activation.
- 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 hematopoietic stem cells. Nat Commun 7: 11075.
- Grover, A., E. Mancini, S. Moore, A.J. Mead, D. Atkinson, K.D. Rasmussen, D. O'Carroll, S.E. Jacobsen, and C. Nerlov. 2014. Erythropoietin guides multipotent hematopoietic progenitor cells toward an erythroid fate. J Exp Med. 211:181-188.
- Sanjuan-Pla, A., I.C. Macaulay, C.T. Jensen, P.S. Woll, T.C. Luis, A. Mead, S. Moore, C. Carella, S. Matsuoka, T.B. Jones, O. Chowdhury, L. Stenson, M. Lutteropp, J.C. Green, R. Facchini, H. Boukarabila, A. Grover, A. Gambardella, S. Thongjuea, J. Carrelha, P. Tarrant, D. Atkinson, S.A. Clark, C. Nerlov, and S.E. Jacobsen. 2013. Platelet-biased stem cells reside at the apex of the hematopoietic stem-cell hierarchy. Nature. 502:232-236.
For further information, please contact: Prof Claus Nerlov