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Biography
Diploma in Biology, Universität Tübingen 1991, Dr. rer. nat., Universität Tübingen 1995; Postdoctoral Research Associate, Universität Tübingen 1995-96; Research Associate, University of Cambridge 1996-99; Research Fellow, University of Nottingham 2000-2004; Investigator Scientist, University of Oxford 2004-2005; Lecturer in Genetics, University of Nottingham 2005-current.
Research Summary
In my lab, we are interested in how blood cells form during vertebrate embryogenesis. Our main focus is on haematopoietic stem cells (HSCs), the cells that maintain our blood system throughout life.… read more
Current Research
In my lab, we are interested in how blood cells form during vertebrate embryogenesis. Our main focus is on haematopoietic stem cells (HSCs), the cells that maintain our blood system throughout life. In mammals, they reside in the bone marrow (BM). HSCs are immature cells that are multipotent (i.e. can give rise to cells of all blood lineages) and that have retained the ability to self-renew (i.e. divide and give rise to daughter cells that are themselves HSCs again). These cells are of enormous clinical importance as they constitute the active component of BM transplants that are used to re-establish blood formation in patients who have lost their blood system due to bone marrow failure or therapeutic treatment for leukaemia or solid cancers. Because of their longevity, HSCs are the ideal target for gene therapy approaches to curing inherited blood disorders. Autologous (using the patient's own BM) and allogeneic (using BM donated by an antigen-matched donor, often a close relative) BM transplants are used dependent on whether functional, disease-free HSCs can be obtained from the patient. Autologous BM transplants are preferred as allogeneic transplants bear the increased risks of graft rejection or graft-versus-host disease. In the future, we will hopefully be able to offer to patients currently receiving allogeneic transplants patient-specific HSCs that are derived from disease-free adult tissue. These adult cells would need to be reprogrammed into a naïve embryonic state and subsequently turned into HSCs that can be maintained in vitro. Although we know how to grow mature blood cells from embryonic stem cells, generation of transplantable HSCs from ES cells has proven difficult (without expressing transgenes from retroviral vectors in them), as has maintenance and expansion of isolated BM HSCs in vitro (Bordignon, 2006; Keller, 2005).
The vertebrate embryo forms HSCs and maintains them into adulthood. Using the zebrafish as a model system, we are examining the cellular origin and the molecular programming of forming HSCs in the embryo. As in all vertebrate embryos, haematopoieisis in zebrafish occurs in two waves, a transient primitive wave that gives rise to primitive red blood cells and some myeloid cells, and a second, definitive wave that forms all blood cell lineages, including the lymphoid lineages (T and B cells). HSCs form in this second wave of haematopoiesis. While in mammalian, amphibian and avian embryos, primitive and definitive haematopoiesis are spatially separated in the extraembryonic yolk sac (ventral blood island in frogs) and in the intraembryonic aorta-gonads-mesonephros (AGM) region, respectively (Durand and Dzierzak, 2005; Godin and Cumano, 2002), both waves occur in close proximity in the intermediate cell mass (ICM) of the zebrafish embryo (Fig. 1A). The ICM is a chord of cells located in the trunk midline between the notochord, the endoderm and the somites. that forms primitive red blood cells and the two major trunk vessels, the dorsal aorta (DA) and the posterior cardinal vein. The putative HSCs first appear just before the primitive red blood cells enter circulation at 24 hours post fertilisation (hpf). They are identified by the expression of the transcription factors Runx1 and c-Myb, and by their close association with the ventral wall of the DA (Fig. 1B, C and D (Gering and Patient, 2005)). We could demonstrate that runx1 is essential for definitive haematopoiesis as loss of Runx1 in runx1 morphants (embryos injected with a runx1 antisense morpholino that interferes with the normal splicing of the runx1 primary transcript (Fig. 1E)) causes loss of c-myb-expressing definitive progenitors (Gering and Patient, 2005; Kalev-Zylinska et al., 2002) and loss of T cells in the thymus (Fig. 1F;(Gering and Patient, 2005)). Since T cells are the first easily identifiable progeny of the HSC in vertebrate embryos, the