Show simple item record

dc.contributor.advisorMedvinsky, Alexanderen
dc.contributor.advisorTravers, Paulen
dc.contributor.authorBatsivari, Antonianaen
dc.date.accessioned2017-12-20T16:40:22Z
dc.date.available2017-12-20T16:40:22Z
dc.date.issued2016-07-02
dc.identifier.urihttp://hdl.handle.net/1842/25802
dc.description.abstractIn adults blood stem cells, called haematopoietic stem cells (HSC), give rise to all blood cells throughout life. The origin and biology of HSCs during embryo development has been an intensely studied topic. Definitive HSCs are generated intra-embryonically in the aorta-gonad-mesonephros (AGM) region of the mid-gestation embryo. Recent research revealed that HSCs emerge through multistep maturation of precursors: proHSC → preHSC I → preHSC II → definitive HSC (dHSC). A hallmark of the HSC emergence is the appearance of intra-aortic haematopoietic clusters that are considered to be sites of haematopoiesis. It was shown in vitro that the E11.5 HSCs are slowly cycling compared to progenitor cells. However, cell cycle status and its role during early HSC development remain unclear. Here I used Fucci transgenic mice that enable in vivo visualisation of the cell cycle. Functional and phenotypic analysis showed that in the early embryo the proHSC precursors cycle slowly, whereas committed progenitors are actively cycling. Meanwhile the preHSC I precursors arising in the E10.5 AGM region become more rapidly cycling. They are located closer to the luminal cavity of the dorsal aorta, while their ancestors, the proHSCs, are slowly cycling and are located at base of the clusters. Furthermore, in the mid-gestation embryo the preHSC I become slowly cycling and are closer to the endothelial lining of the aorta, while they give rise to the actively cycling preHSC II that are located to the luminal area of the artery. Finally, definitive HSCs are mainly slowly cycling at this stage like their foetal liver counterparts. As expected, HSCs in adult bone marrow are mainly dormant. The data suggest that transition from one precursor type to another is accompanied by distinct changes in cell cycle profile and that HSCs become progressively quiescent during development. To test the role of cell cycle in HSC maturation, we used inhibitors against signalling pathways known to play important roles in HSC development. Notch inhibitor affected the cell cycle status of haematopoietic precursors, by possibly promoting them to rapidly proliferate and potentially blocking the maturation from preHSC I to preHSC II precursors. Shh antagonist had the opposite effect and enhanced the HSC activity from the preHSC I precursors. Altogether these results suggest that the cell cycle status plays an important role in the HSC development. A better understanding of the molecules that control this process will allow us to optimize the culture condition for generation of functional HSCs in the laboratory.en
dc.contributor.sponsorMedical Research Council (MRC)en
dc.language.isoen
dc.publisherThe University of Edinburghen
dc.relation.hasversionTracing the Origin of the HSC Hierarchy Reveals an SCF-Dependent, IL-3-Independent CD43− Embryonic Precursor, S. Rybtsov, A. Batsivari, K. Bilotkach, D. Paruzina, J. Senserrich, O. Neruslev, A. Medvinsky, Stem Cell Reports (2014)en
dc.relation.hasversionRunx1 is required for progression of CD41+ embryonic precursors into HSCs but not prior to this, A. Liakhovitskaia, S. Rybtsov, T. Smith, A. Batsivari, N. Rybtsova, C. Rode, M. de Bruijn, F. Buchholz, S. Gordon-Keylock, S. Zhao, A. Medvinsky, Development (2014)en
dc.relation.hasversionInductive interactions mediated by interplay of asymmetric signalling underlie development of adult hematopoietic stem cells, C. Souilhol, C. Gonneau, J. Lendinez, A. Batsivari, S. Rybtsov, H. Wilson, L. Morgado-Pallacin, D. Hills, S. Taoudi, J. Antonchuk, S. Zhao, A. Medvisnky, Nature Communications (2016)en
dc.subjecthaematopoietic stem cellsen
dc.subjectdevelopmenten
dc.subjectproliferationen
dc.subjectcell cycleen
dc.titleStudying the cell cycle status during haematopoietic stem cell developmenten
dc.typeThesis or Dissertationen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD Doctor of Philosophyen
dc.rights.embargodate2100-12-31
dcterms.accessRightsRestricted Accessen


Files in this item

This item appears in the following Collection(s)

Show simple item record