Endothelio-Mesenchymal Interaction Controls runx1 Expression and Modulates the notch Pathway to Initiate Aortic Hematopoiesis

SummaryHematopoietic stem cells (HSCs) are produced by a small cohort of hemogenic endothelial cells (ECs) during development through the formation of intra-aortic hematopoietic cell (HC) clusters. The Runx1 transcription factor plays a key role in the EC-to-HC and -HSC transition. We show that Runx1 expression in hemogenic ECs and the subsequent initiation of HC formation are tightly controlled by the subaortic mesenchyme, although the mesenchyme is not a source of HCs. Runx1 and Notch signaling are involved in this process, with Notch signaling decreasing with time in HCs. Inhibiting Notch signaling readily increases HC production in mouse and chicken embryos. In the mouse, however, this increase is transient. Collectively, we show complementary roles of hemogenic ECs and mesenchymal compartments in triggering aortic hematopoiesis. The subaortic mesenchyme induces Runx1 expression in hemogenic-primed ECs and collaborates with Notch dynamics to control aortic hematopoiesis

Etude de la voie TGFb/BMP au cours de l'hématopoïèse embryonnaire aortique chez les vertébrés amniotes

Le système hématopoïétique est composé de nombreux types cellulaires, tous générés à partir d un seul type de cellule, la cellule souche hématopoïétique (CSH). Les premières CSH sont produites dans le sac vitellin, puis dans la région aortique. Ce dernier site hématopoïétique est particulièrement important, car c est là que sont générées les CSH retrouvées chez l adulte. Les CSH aortiques sont produites à partir de l endothélium aortique ventral. Les cellules endothéliales (CE) subissent un changement phénotypique radical. Elles perdent leur morphologie et leurs marqueurs endothéliaux, pour acquérir une identité hématopoïétique, et émerger dans la lumière aortique sous forme de clusters hématopoïétiques. Au cours de ma thèse je me suis intéressée aux signaux régulant l hématopoïèse aortique et la transition endothélio-hématopoïétique. Cela m a conduit à étudier la voie TGFb/BMP. L étude systématique des différents acteurs de cette voie nous a permis de montrer que les Smads 1/5/8 sont activées dans les CE, mais pas dans les clusters hématopoïétiques. Notre hypothèse, basée sur le niveau d expression des différents récepteurs de cette signalisation, est que les récepteurs Alk1/TgfbR2/Endogline sont responsables de cette activation des Smads, et que leur perte est nécessaire à la production de cellules hématopoïétiques à partir de CE.Hematopoietic system is composed of many cell types, all generated from one cell type, the hematopoietic stem cell (HSC). The firs HSC are produced in the yolk sac, then in the aortic region. The adult HSC are generated in this last hematopoietic site. Aortic HSC are produce from ventral aortic endothelium. The endothelial cells (ECs) undergo a radical modification of their phenotype. They loose theirs endothelial markers, acquire a hematopoietic identity, and emerge in the aortic lumen in the shape of clusters. During my PhD, I study the signaling pathways regulating hematopoiesis and the endothelium to hematopoietic transition. I focus on the TGFb/BMP pathway. The systematic study of all this pathway actors shows that Smads 1/5/8 are activated in the ECs, but not in hematopoietic clusters. Our hypothesis, based on the level of expression of all TGFb/BMP receptors, is that Alk1/TgfbR2/Endogline are responsive for the Smads activation, and their loss in necessary to the hematopoietic production in the aorta from ECs.PARIS-BIUSJ-Biologie recherche (751052107) / SudocSudocFranceF

Tissue to tissue dialogue and modulation of the Notch pathway control aortic haematopoiesis

International audienceno abstrac

Dorso-ventral contributions in the formation of the embryonic aorta and the control of aortic hematopoiesis

International audienceThe embryonic dorsal aorta plays a pivotal role in the production of the first hematopoietic stem cells (HSCs), the founders of the adult hematopoietic system. HSC production is polarized by being restricted to the aortic floor where a specialized subset of endothelial cells (ECs) endowed with hemogenic properties undergo an endothelial-to-hematopoietic production resulting in the formation of the intra-aortic hematopoietic clusters. This production is tightly time- and space-controlled with the transcription factor Runx1 playing a key role in this process and the surrounding tissues controlling the aortic shape and fate. In this paper, we shall review (a) how hemogenic ECs differentiate from the mesoderm, (b) how the different aortic components assemble coordinately to establish the dorso-ventral polarity, and (c) how this results in the initiation of Runx1 expression in hemogenic ECs and the initiation of the hematopoietic program. These observations should elucidate the first steps in HSC commitment and help in developing techniques to manipulate adult HSCs