Professor Elaine Dzierzak
Elaine Dzierzak's lab aims to identify the molecules involved in the generation of haematopoietic stem cells (HSC) and to generate patient-specific HSCs for clinical cell replacement therapies to treat blood-related genetic diseases and leukaemia.
- Chris S Vink - Lab Manager (email)
- Samanta A Mariani - Senior Postdoctoral Fellow (email)
- Carmen Rodriguez Seoane - Postdoctoral Research Fellow (email)
Eoghan Forde - MRC DTP Precision Medicine PhD student (email)
Anna Popravko - Wellcome Trust Tissue Repair PhD Student (email)
Lorna Mackintosh - Wellcome Trust ECAT PhD Student (email)
Stem cells are the foundation of somatic tissues and are required for the constant renewal and/or replacement of cells either undergoing normal senescence or damage from exogenous agents. The haematopoietic system requires the constant production of billions of blood cells daily (erythrocytes, lymphocytes, platelets, macrophages, eosinphils, etc). These cells are provided through the functional activity of rare haematopoietic stem cells (HSCs) harbored in the bone marrow of the adult individual. For over 60 years, HSCs have been used in hundreds of thousands of transplantation therapies for blood-related genetic diseases and leukaemias. However, current clinical therapies are limited by the number of HSCs available for such transplantations and attempts to expand such cells ex vivo have been unsuccessful. Well aware of the important clinical uses, HSCs have been the most intensively studied somatic stem cells.
Our lab aims to identify the molecules involved in the generation of HSCs and to generate patient-specific HSCs for clinical cell replacement therapies to treat blood-related genetic diseases and leukaemia.
3D projection of mouse embryonic aorta containing HSC clusters (green). Endothelial cells lining the vasculature are in magenta (Yokomizo T & Dzierzak E, Development. 2010).
Our laboratory was the first to show that HSCs are born in the aorta-gonad-mesonephros region of the developing mammalian embryo. We have also shown through a live imaging approach that HSCs arise from endothelial cells lining the wall of the embryonic aorta in a natural reprogramming event. This transdifferentiation is known as Endothelial cell-to Hematopoietic cell transition (EHT). We are one of the few groups worldwide that can isolate these special endothelial cells and show that they yield robust transplantable HSCs (the gold-standard for clinically relevant HSCs). Using our unique expertise and novel resources (models and reagents), our laboratory fosters new translational strategies to de novo generate human HSCs from patient somatic cells. Our specific goals are to:
- mark and manipulate the molecular program for HSC generation during the EHT
- define extrinsic molecules/factors affecting EHT and engineer novel niches to promote EHT
- molecularly reprogram human somatic cells or endothelial derived iPS cells directly to HSC
These goals will be realized through novel multi-colour in vivo reporter models and ES/iPS lines indicating EHT in real-time, allowing for the isolation and functional validation of de novo HSC generation. The results will significantly advance haematological research and technology, and should have a major impact on how HSCs are manipulated and used clinically.
Real-time birth of a HSC from an endothelial cell lining the wall of a mouse embryonic aorta (Boisset J-C. et al., Nature. 2010).
Recent work from the Dzierzak group
More recently our group has shown and published:
1. Unexpected redundancy of Gpr56 and Gpr97 during haematopoietic cell development and differentation
In Maglitto, Mariani et al. 2021, Blood Advances we show that:
- Lineage output of mouse foetal liver HSCs is dependent on Gpr56; upon Gpr56 deletion, Gpr97 is upregulated and HSC myeloid bias increases.
- Mouse Gpr97 rescues HS/PC generation in gpr56 morphant zebrafish; deletion of both Gpr56 and Gpr97 in mouse ESC abolishes HPC production.
2. Iterative single-cell analyses define the transcriptome of the first functional haematopoietic stem cells
In Vink et al. 2020, Cell Reports, we capture the transcriptome of the first functional HSCs in mouse by single-cell RNA-seq, index sorting, and in vivo and in vitro haematopoietic analyses. The HSC transcriptome is unique compared to HPCs, and heterogeneous expression of pivotal genes suggests that establishment of functional haematopoietic fate during cell emergence from embryonic aortic endothelium is stochastic.
Check the expression of your gene of interest in our highly enriched HSC population [here].
3. Pro-inflammatory aorta-associated macrophages are involved in embryonic development of haematopoietic stem cells
HSC-independent macrophages derive from the early yolk-sac stages of embryonic haematopoiesis. In Mariani et al. 2019, Immunity we demonstrate that specific pro-inflammatory embryonic HSC-independent macrophages recruited to the AGM (AGM-aMs) are crucial components of the AGM microenvironment, dynamically interact with emerging haematopoietic cells, and enhance HSC generation.
4. A role for macrophages in haematopoiesis in the embryonic head
In Li et al. 2019, Blood, we show that:
- Macrophages in the HBA region of the mouse embryo play a role in HS/PC expansion and/or maturation.
- Embryonic head macrophages produce the pro-inflammatory tumour necrosis factor-α and act as niche cells in vitro to enhance haematopoiesis.
The following PDF provides a brief visual summary of this group’s current research.
You can view a full catalogue of graphical research summaries for each group in the Centre for Inflammation Research by visiting our Research page.
Elaine Dzierzak obtained her PhD in Immunology from Yale University and did postdoctoral training in retroviral mediated gene transfer at the Whitehead Institute, MIT. She started her research laboratory at the National Institute for Medical Research, London (UK). In 1996 she moved to the Erasmus University Medical Center in Rotterdam (NL) where she was Professor of Developmental Biology, founder and co-director of the Master of Science Program in Molecular Medicine, and the Founding Director of the Erasmus Stem Cell Institute. She moved to The University of Edinburgh in 2013.
Honours and Awards
- Fellow of the Royal Society of Edinburgh (RSE)
- Elected member of EMBO
- Past President of the International Society for Experimental Hematology (ISEH)
- Founding Director of the Erasmus MC Stem Cell Institute
- Co-Director of the Netherlands Institute for Regenerative Medicine (NIRM)
- Fellow of The Academy of Medical Sciences (FMedSci)
- Elected member of the Journal of Experimental Medicine's Advisory Editorial Board
Principal Investigator Alumni
- Mihaela Crisan - Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK
- Emma de Pater - Department of Hematology, Erasmus MC, Rotterdam, The Netherlands
- Catherine Robin - Hubrecht Institute, Utrecht, The Netherlands
- Tomomasa Yokomizo - Department of Hematology, Juntendo U School of Medicine, Tokyo, Japan
- Katrin Ottersbach - Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK
- Marella de Bruijn - MRC Molecular Haematology Unit, Oxford University, Oxford, UK
- Charles Durand - UPMC, Laboratoire de Biologie du Developpement, Paris, France
- Robert Oostendorp - Technical University of Munich, Munich, Germany
- Alexander Medvinsky - Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK
- Maria-Jose Sanchez - Centro Andaluz de Biologia del Desarrollo, Pablo de Olavide University, Seville, Spain
- David Abraham - UCL Medical School - Royal Free Hospital, London, UK
- Colin Miles- Faculty of Medical Sciences, Newcastle University, Newcastle, UK
Current Sources of Funding