Tracking the embryonic origin of the adult haematopoietic system

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When a patient who has undergone chemotherapy or radiotherapy receives a bone marrow transplant, it includes blood stem cells also known as haematopoietic stem cells (HSCs) which are the long-term source of normal blood. However, there is a shortage of bone marrow and umbilical cord transplants and there is a major interest to generate HSCs in the laboratory conditions. Although HSCs develop during embryo development, it is not yet clear how to reproduce this process in cultured cells. To understand mechanisms that the embryo uses to generate HSCs, researchers need to first trace their origin in the embryo and track their development, which is a surprisingly poorly understood process. The first blood cells in the early embryo develop outside its body in a membrane called the yolk sac. However, true HSCs which can persist in the adult animal appear later in a specific part of the developing embryo. The main objective of this research proposal is to identify the precise site of origin of adult HSCs. The chick embryo is very useful for this research as we can see its development in a dish or in the egg, without disrupting normal development. To this end we have developed new tools - transgenic chickens that express fluorescent proteins, so that their cells can be easily followed in live embryos under the microscope. By transplantation of precise transgenic chick embryonic tissue fragments from regions suspected to harbour the ancestors of HSCs into normal chicken embryos we will monitor whether they develop into blood. This will allow us to define the exact location of embryonic cells from which HSCs develop. Novel transgenic chick strains where particular cell types are labelled by different fluorescent reporter proteins will further define more precise localisation of embryonic ancestors of HSCs. The development of these new tools will give us a unique opportunity to identify and characterise HSCs. In the longer terms, this knowledge will inform the development of methods for generation of HSCs from embryonic stem cells for treatment of patients whose blood formation was impaired due to chemo- or radiotherapy.