RUNX1 IN HSCS · Hematopoietc Stem Cells emergence in the mouse embryo: function(s) of RUNX1 and its binding partner CBFbeta
FP6 — Marie Curie Actions (Human Resources and Mobility)
- Duration
- 2006-03-01 → 2008-02-29
- EU contribution
- €148,142
- Participants
- 1
- Scheme
- EIF
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Results in brief
Final Activity Report Summary - RUNX1 IN HSCS (Hematopoietc Stem Cells emergence in the mouse embryo: function(s) of RUNX1 and its binding partner CBFbeta)
During adult life, hematopoietic stem cells (HSCs) are responsible for the constant production of blood cells. The overall goal of this project is to further our understanding of molecular and cellular events controlling HSC generation and maintenance during embryogenesis. During the achievement of part 1, we showed the precise expression pattern of RUNX1 and its patner CBFb, two key regulators of HSC development. Our results allow us to design a new strategy for functional studies of mouse HSC development. HSC development is also tightly regulated by microenvironmental signals. During the achievement of part 2, we found that the BMP signalling pathway is involved in this regulation. Using a mouse model reporting BMP signalling activity, we correlated the localisation and the identity of BMP signalling and responsive cells during HSC developement. Our results provide new insights concerning the control of HSCs by BMPs and the functioning of the first microenvironment for HSCs. During embryogenesis, HSCs are sequencially found in distinct sites. In human, cord blood is known to be an important source of HSCs used in blood-related therapies. During the achievement of part 3, we identify and characterised HSCs in the human placenta. Our studies provide important data to improve clinical use of HSCs.
Data: CORDIS, © European Union
Project objective
Newly formed mature hematopoietic cells are generated through a complex maturation process based on the differentiation of Hematopoietic Stem Cells (HSC). In the mouse embryo, HSCs are first detected in the Aorta-Gonade-Mesonephros (AGM) region at midgestation.They arise from the major arteries and are thought to differentiate from a population of hemogenic endothelial cells (EC). Cellular events that occur during AGM-associated hematopoiesis are well-documented, but the underlying molecular mechanisms are still under investigation. The overall objective of the present project is to further our understanding of molecular regulations governing early production of HSCs from hemogenic ECs.It is focused on the RUNX1 transcription factor, a key regulator of HSC production and a frequent target in human haematological malignancies. In mouse embryo, disruption of either Runx1 or its co-factor Cbfb leads to complete failure in HSC development. RUNX1 is known to govern this process at the level of hemogenic ECs and to mark all HSCs at midgestation.However, since the requirement of CBFb in this process is poorly understood and the accurate function of RUNX1 is not known, the specific aims of this project are:1) To describe the expression of the RUNX1 binding partner, CBFb, in midgestation aortic HSCs and ECs2) To conditionally knockout Runx1 during different stages of the EC to HSC transition in the midgestation aorta.For this purpose, transgenic mouse models will be generated and AGM-associated hematopoiesis will be analysed using a large panel of descriptive and functional approaches. Innovative methodologies will be undertaken to analyse the complex biological activity of RUNX1.We will use fluorescent markers to follow genes expression and cell fate and also design a Cre-loxP recombination systems to conditionally disrupt Runx1 function. This study will allow us to explore in detail biological activity and function of both RUNX1 and CBFb in HSCs production.
Original text from CORDIS.
Participants
- ERASMUS MC · ROTTERDAMCoordinatorCity levelNetherlands
Links
Data: CORDIS, © European Union