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Understanding The Endothelial to Hematopoietic Transition In Mouse Development

Vargel, Özge

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The endothelial to hematopoietic transition (EHT) is a key developmental event leading to the formation of blood stem and progenitor cells during embryogenesis. A small subset of cells called hemogenic endothelial cells (HE) undergoes the EHT by becoming pre-hematopoietic stem and progenitor cells (Pre-HSPC). Eventually after losing all their endothelial characteristics they become HSPC. Despite extensive studies on this process, there are several questions remaining: What are the differences between hemogenic and non hemogenic endothelial cells? How different is the EHT process in the aorta-gonad-mesonephros (AGM) generating mostly blood stem cells (self-renewing and generating all cell types) and the yolk sac (YS) producing mostly blood progenitors (non self-renewing and generating only a few cell types)? To address these questions, I used single cell transcriptomics because of the scarcity of the HE and the Pre-HSPC within the endothelial population in the AGM and YS. I examined the cells isolated at E9.0, E10.5 and E11.0 mouse embryos. I showed that the major endothelial population of AGM and YS is different from each other, which might be linked with their distinct hematopoietic program. I showed that the pre-HSPC in AGM and YS are transcriptionally alike suggesting that the different hematopoietic program between AGM and YS could be due to the microenvironment. Additionally, I identified a new population detected only in YS at E10.5 co-expressing endothelial and erythroid genes. The molecular mechanism of the EHT is still not understood. Since the TGFβ signaling triggers a similar event during heart development called endothelial to mesenchymal transition (EndMT), we hypothesized that TGFβ activity may play a similar role in EHT. When I activated the TGFβ signaling by adding TGFβ2 during in vitro EHT differentiation, I observed surprisingly a complete block of the hematopoiesis. When I inhibited it by adding the Tgfbr1 inhibitor, it enhanced blood development. Additionally, the mRNA profile of the treated cells confirmed that inhibition of Alk5 is promoting the EHT, while the TGFβ activation results in cells with a phenotype closer to cardiac and mesenchymal cells. Consequently, despite the fact that both EndMT and EHT lead to a loss of endothelial cell identity and the generation of mobile cells, our study suggests that the signaling events initiating both processes are different.

Item Type: Dissertation
Supervisor: Wölfl, Prof. Dr. Stefan
Date of thesis defense: 10 March 2015
Date Deposited: 27 Apr 2015 12:52
Date: 2016
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
The Faculty of Bio Sciences > Institute of Pharmacy and Molecular Biotechnology
Subjects: 500 Natural sciences and mathematics
570 Life sciences
Controlled Keywords: Hematopoiesis, Endothelial to hematopoietic transition, Mouse development
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