Phenotypically characterize and visualize primary definitive HSCs in the early embryo
Identify embryonic ancestor cells which develop into HSCs
Identify routes and mechanisms of hematopoietic stem cell migration
Identify and characterize transcription and growth factors as well as extracellular signaling and matrix molecules responsible for the process of initiation, expansion and migration of HSCs.
Based on the knowledge of mechanisms underlying development of HSCs in vivo, develop new protocols for generation of definitive long-term repopulating HSCs from ES cells (so far attempts to achieve this by different laboratories without employing genetic intervention have been unsuccessful).
Cells of PECAM-1highCD45+ population enriched for HSCs are associated with the luminal surface of the E11.5 dorsal aorta (PECAM1- red; CD45- green).
Background Haematopoietic stem cells (HSCs) developing in the embryo ultimately give rise to the adult haematopoietic system. The main direction of our research is to investigate cellular and molecular mechanisms involved in the generation and expansion of primitive hematopoietic stem cells (HSC) in the mammalian embryo.
Approaches and progress We broadly use methods to perform embryo manipulations and experimental haematology techniques such as advanced cell culture and flow cytometry for the analysis of the early biology of HSCs, including investigating the lineage relationship between endothelial and HSC cells. We have recently identified a specific niche for HSC development in the AGM region. We have developed new culture methods which allow us to dramatically expand HSCs in vitro and analyse intercellular interactions involved in HSC development. Several transgenic/ knockout/reporter mice have been generated in this laboratory, which we use for genetic analysis of HSC development (e.g. Runx1, Flk1, HoxB4 etc.). Microarray analysis is used for gene expression profiling in sites of embryonic development of HSCs. We are applying our functional analysis of HSC development in the embryo to develop new protocols enabling the in vitro generation of HSCs from ES cells.
Dynamics of foetal liver colonisation with haematopoietic stem cells from the AGM region and the yolk sac.
Ivanovs A, Rybtsov S, Welch L, Anderson RA, Turner ML, Medvinsky A. 2011. Highly potent human hematopoietic stem cells first emerge in the intraembryonic aorta-gonad-mesonephros region. J Exp Med. 2011 Oct 31. [Epub ahead of print]
Medvinsky A, Rybtsov S, Taoudi S. 2011. Embryonic origin of the adult hematopoietic system: advances and questions. Development 138(6):1017-31.
Rybtsov S, Sobiesiak M, Taoudi S, Souilhol C, Senserrich J, Liakhovitskaia A, Ivanovs A, Frampton J, Zhao S, Medvinsky A. 2011. Hierarchical organization and early hematopoietic specification of the developing HSC lineage in the AGM region. J Exp Med. 208(6):1305-15.
Taoudi S, Gonneau C, Moore K, Sheridan JM, Blackburn CC, Taylor E, Medvinsky A. 2008. Extensive Hematopoietic Stem Cell Generation in the AGM Region via Maturation of VE-Cadherin+CD45+ Pre-Definitive HSCs. Cell Stem Cell 3:99-108. Press Release.
Taoudi S and Medvinsky A. 2007. Functional Identification of the Hematopoietic Stem Cell Niche in the Ventral Domain of the Embryonic Dorsal Aorta. Proc Natl Acad Sci USA 104:9399-9403.
Samokhvalov I, Thomson AM, Liakhovitskaia A, Ure J, Medvinsky A. 2006. A multifunctional reversible knockout/ reporter system enabling fully functional reconstitution of the AML1/Runx1 locus and rescue of haematopoiesis. Genesis 44:115-121.
Taoudi S, Morrison A, Inoue H, Gribi R, Ure J, Medvinsky A. 2005. Progressive divergence of definitive haematopoietic stem cells from the endothelial compartment does not depend on contact with the foetal liver. Development 132:4179-4191.
Kumaravelu P, Hook L, Morrison AM, Ure J, Zhao S, Zuyev S, Ansell J, Medvinsky A. 2002. Quantitative developmental anatomy of definitive haematopoietic stem cells/long-term repopulating units (HSC/RUs): role of the aorta-gonad-mesonephros (AGM) region and the yolk sac in colonisation of the mouse embryonic liver. Development 129:4891-4899.
Medvinsky A and Dzierzak E. 1996. Definitive hematopoiesis is autonomously initiated by the AGM region. Cell 86:897-906.
Medvinsky AL, Samoylina NL, Müller AM, Dzierzak EA. 1993. An early pre-liver intra-embryonic source of CFU-S in the developing mouse. Nature 364:64-67.